bims-mimcad Biomed News
on Mitochondrial metabolism and cardiometabolic diseases
Issue of 2024–10–27
fifty-nine papers selected by
Henver Brunetta, Karolinska Institutet
  1. Advances in myocardial energy metabolism: metabolic remodeling in heart failure and beyond.
  2. HFpEF's Fuel Flaw: Impaired Fatty Acid Oxidation Stalls Mitophagy.
  3. Measurement of Mitochondrial Respiration in Human and Mouse Skeletal Muscle Fibers by High-Resolution Respirometry.
  4. Age-dependent changes in visceral adiposity are associated with decreased plasma levels of DHEA-S in sigma-1 receptor knockout male mice.
  5. Recent Advances Associated with Cardiometabolic Remodeling in Diabetes-induced Heart Failure.
  6. Sex differences in the association between skeletal muscle energetics and perceived physical fatigability: the Study of Muscle, Mobility and Aging (SOMMA).
  7. Time-restricted feeding mediated modulation of microbiota leads to changes in muscle physiology in Drosophila obesity models.
  8. Impact of early postnatal overnutrition on cardiac mitochondrial dysfunction in adult mice with ischemia/reperfusion.
  9. Unbiased complexome profiling and global proteomics analysis reveals mitochondrial impairment and potential changes at the intercalated disk in presymptomatic R14Δ/+ mice hearts.
  10. Diabetes Mellitus Disrupts LncRNA Malat1 Regulation of Cardiac Mitochondrial Genome-Encoded Protein Expression.
  11. Calorie restriction modulates mitochondrial dynamics and autophagy in leukocytes of patients with obesity.
  12. The Acute and Chronic influence of Exercise on Mitochondrial Dynamics in Skeletal Muscle.
  13. Postnatal surge of adipose-secreted leptin is a robust predictor of fat mass trajectory in mice.
  14. The prognostic value of Epicardial and Pericoronary Adipose Tissue in Heart Failure with Preserved Ejection Fraction Using Coronary Computed Tomography Angiography.
  15. Repetitive transcranial magnetic stimulation elicits weight loss and improved insulin sensitivity in type 2 diabetic rats.
  16. GLP-1 receptor agonists as promising anti-inflammatory agents in heart failure with preserved ejection fraction.
  17. Severity of sleep apnea impairs adipose tissue insulin sensitivity in individuals with obesity and newly diagnosed obstructive sleep apnea.
  18. Annonaceous acetogenins mimic AA005 targets mitochondrial trifunctional enzyme alpha subunit to treat obesity in male mice.
  19. Obesity cardiomyopathy could contribute to sudden cardiac death: a Japanese epidemiological morphological study.
  20. Decreased mitochondrial-related gene expression in adipose tissue after acute sprint exercise in humans: A pilot study.
  21. Gpr55 deficiency crucially alters cardiomyocyte homeostasis and counteracts angiotensin II induced maladaption in female mice.
  22. Mitochondrial fatty acid oxidation drives senescence.
  23. Relationships among Dioxin-like Mitochondria Inhibitor Substances (MIS)-Mediated Mitochondria Dysfunction, Obesity, and Lung Function in a Korean Cohort.
  24. Comparison of exercise training modalities and change in peak oxygen consumption in heart failure with preserved ejection fraction: a secondary analysis of the OptimEx-Clin trial.
  25. Mitochondrial Bioenergetics of Functional Wound Closure is Dependent on Macrophage-Keratinocyte Exosomal Crosstalk.
  26. Impact of reduced hepatic ceramide levels in high-fat diet mice on glucose metabolism.
  27. Cardiomyocyte-derived USP28 negatively regulates antioxidant response and promotes cardiac hypertrophy via deubiquitinating TRIM21.
  28. A novel model of cardiovascular-kidney-metabolic syndrome combining unilateral nephrectomy and high-salt-sugar-fat diet in mice.
  29. Allele-specific dysregulation of lipid and energy metabolism in early-stage hypertrophic cardiomyopathy.
  30. Effect of spermidine intake on skeletal muscle regeneration after chemical injury in male mice.
  31. Calorie restriction increases insulin sensitivity to promote beta cell homeostasis and longevity in mice.
  32. Mitochondrial Stress as a Central Player in the Pathogenesis of Hypoxia-Related Myocardial Dysfunction: New Insights.
  33. Mitochondrial Abundance and Function Differ Across Muscle Within Species.
  34. Preferential binding of ADP-bound mitochondrial HSP70 to the nucleotide exchange factor GRPEL1 over GRPEL2.
  35. Carnitine is a friend in HFpEF and foe in HFrEF.
  36. Study on the mechanism of Xinmailong injection against chronic heart failure based on transcriptomics and proteomics.
  37. Decreased Mrpl42 expression exacerbates myocardial ischemia and reperfusion injury by inhibiting mitochondrial translation.
  38. Catheter Ablation Versus Antiarrhythmic Therapy for Atrial Fibrillation in Heart Failure with Preserved Ejection Fraction.
  39. Deficiency of GPR10 and NPFFR2 receptors leads to sex-specific prediabetic syndrome and late-onset obesity in mice.
  40. RNA-seq analysis of mitochondria-related genes regulated by AMPK in the human trophoblast cell line BeWo.
  41. Association of Cardiovascular Risk Factors and Coronary Calcium Burden with Epicardial Adipose Tissue Volume Obtained from PET-CT Imaging in Oncological Patients.
  42. Photobleaching and phototoxicity of mitochondria in live cell fluorescent super-resolution microscopy.
  43. Spatheliachromen mitigates methylglyoxal-induced myotube atrophy by activating Nrf2, inhibiting ubiquitin-mediated protein degradation, and restoring mitochondrial function.
  44. "Circulating Inflammation" and the Plasma Proteome in Heart Failure With Preserved Ejection Fraction.
  45. The sympathetic nervous system in heart failure with preserved ejection fraction.
  46. Endothelial Beta 1 Integrins are Necessary for Microvascular Function and Glucose Uptake.
  47. Atrial cardiomyopathy resulting from loss of plakophilin-2 expression: Response to adrenergic stimulation and implications for the exercise response.
  48. The value of blood flow velocity and pressure gradient in differentiating patients with different types of heart failure.
  49. Targeted deletion of Fibroblast Growth Factor-23 rescues metabolic dysregulation of diet-induced obesity in female mice.
  50. Binding of α-synuclein to ACO2 promotes progressive mitochondrial dysfunction in Parkinson's disease models.
  51. Identification of genetic polymorphisms associated with interindividual variability of vitamin A concentration in adipose tissue of healthy male adults.
  52. Screening and analysis of GULP1 downstream target genes based on transcriptomic sequencing.
  53. Mitochondrial non-energetic function and embryonic cardiac development.
  54. Effects of overnight-fasted versus fed-state exercise on the components of energy balance and interstitial glucose across four days in healthy adults.
  55. Sirt1-mediated deacetylation of PGC-1α alleviated hepatic steatosis in type 2 diabetes mellitus via improving mitochondrial fatty acid oxidation.
  56. Role of ferroptosis in mitochondrial damage in diabetic retinopathy.
  57. Insight into the oxidation mechanism of coconut globulin by atmospheric cold plasma focusing on side chain amino acids.
  58. Differential expression of nuclear-derived mitochondrial succinate dehydrogenase genes in metabolically active buffalo tissues.
  59. Sex Differences in Fat Distribution and Muscle Fat Infiltration in the Lower Extremity: A Retrospective Diverse-Ethnicity 7T MRI Study in a Research Institute Setting in the USA.
  1. Cardiovasc Res. 2024 Oct 25. pii: cvae231. [Epub ahead of print]
    Advances in myocardial energy metabolism: metabolic remodeling in heart failure and beyond.
    Qiuyu Sun, Qutuba G Karwi, Nathan Wong, Gary D Lopaschuk.
      The very high energy demand of the heart is primarily met by ATP production from mitochondrial oxidative phosphorylation, with glycolysis providing a smaller amount of ATP production. This ATP production is markedly altered in heart failure, primarily due to a decrease in mitochondrial oxidative metabolism. Although an increase in glycolytic ATP production partly compensates for the decrease in mitochondrial ATP production, the failing heart faces an energy deficit, that contributes to the severity of contractile dysfunction. The relative contribution of the different fuels for mitochondrial ATP production dramatically changes in the failing heart, which depends to a large extent on the type of heart failure. A common metabolic defect in all forms of heart failure (including HFrEF, HFpEF, and diabetic cardiomyopathies) is a decrease in mitochondrial oxidation of pyruvate originating from glucose (i.e. glucose oxidation). This decrease in glucose oxidation occurs regardless of whether glycolysis is increased, resulting in an uncoupling of glycolysis from glucose oxidation that can decrease cardiac efficiency. The mitochondrial oxidation of fatty acids by the heart increases or decreases, depending on the type of heart failure. For instance, in HFpEF and diabetic cardiomyopathies myocardial fatty acid oxidation increases, while in HFrEF myocardial fatty acid oxidation either decreases or remains unchanged. The oxidation of ketones (which provides the failing heart with an important energy source) also differs depending on the type of heart failure, being increased in HFrEF, and decreased in HFpEF and diabetic cardiomyopathies. The alterations in mitochondrial oxidative metabolism and glycolysis in the failing heart are due to transcriptional changes in key enzymes involved in the metabolic pathways, as well as alterations in redox state, metabolic signaling, and posttranslational epigenetic changes in energy metabolic enzymes. Of importance, targeting the mitochondrial energy metabolic pathways has emerged as a novel therapeutic approach to improving cardiac function and cardiac efficiency in the failing heart.
    Keywords:  HFpEF; HFrEF; fatty acid oxidation; glucose oxidation; ketone oxidation
    DOI:  https://doi.org/10.1093/cvr/cvae231
  2. Circ Res. 2024 Oct 25. 135(10): 1018-1020
    HFpEF's Fuel Flaw: Impaired Fatty Acid Oxidation Stalls Mitophagy.
    Xi Fang, Åsa B Gustafsson.
      
    Keywords:  Editorials; diet, high-fat; heart failure; metabolism; mitochondria, heart; myocytes, cardiac
    DOI:  https://doi.org/10.1161/CIRCRESAHA.124.325501
  3. J Vis Exp. 2024 Oct 04.
    Measurement of Mitochondrial Respiration in Human and Mouse Skeletal Muscle Fibers by High-Resolution Respirometry.
    Terri A Pietka, Rita T Brookheart.
      Mitochondrial function, a cornerstone of cellular energy production, is critical for maintaining metabolic homeostasis. Its dysfunction in skeletal muscle is linked to prevalent metabolic disorders (e.g., diabetes and obesity), muscular dystrophies, and sarcopenia. While there are many techniques to evaluate mitochondrial content and morphology, the hallmark method to assess mitochondrial function is the measurement of mitochondrial oxidative phosphorylation (OXPHOS) by respirometry. Quantification of mitochondrial OXPHOS provides insight into the efficiency of mitochondrial oxidative energy production and cellular bioenergetics. A high-resolution respirometer provides highly sensitive, robust measurements of mitochondrial OXPHOS in permeabilized muscle fibers by measuring real-time changes in mitochondrial oxygen consumption rate. The use of permeabilized muscle fibers, as opposed to isolated mitochondria, preserves mitochondrial networks, maintains mitochondrial membrane integrity, and ultimately allows for more physiologically relevant measurements. This system also allows for the measurement of fuel preference and metabolic flexibility - dynamic aspects of muscle energy metabolism. Here, we provide a comprehensive guide for mitochondrial OXPHOS measurements in human and mouse skeletal muscle fibers using a high-resolution respirometer. Skeletal muscle groups are composed of different fiber types that vary in their mitochondrial fuel preference and bioenergetics. Using a high-resolution respirometer, we describe methods for evaluating both aerobic glycolytic and fatty acid substrates to assess fuel preference and metabolic flexibility in a fiber-type-dependent manner. The protocol is versatile and applicable to both human and rodent muscle fibers. The goal is to enhance the reproducibility and accuracy of mitochondrial function assessments, which will improve our understanding of an organelle important to muscle health.
    DOI:  https://doi.org/10.3791/66834
  4. Biochim Biophys Acta Mol Cell Biol Lipids. 2024 Oct 18. pii: S1388-1981(24)00121-5. [Epub ahead of print] 159571
    Age-dependent changes in visceral adiposity are associated with decreased plasma levels of DHEA-S in sigma-1 receptor knockout male mice.
    Stelfa Gundega, Miteniece Anna, Svalbe Baiba, Vavers Edijs, Makrecka-Kuka Marina, Kupats Einars, Kunrade Liga, Parfejevs Vadims, Riekstina Una, Dambrova Maija, Zvejniece Liga.
      The sigma-1 receptor (S1R) is involved in intracellular lipid synthesis and transport. Recent studies have shown that its genetic inactivation impairs adipogenic differentiation in vitro. This study investigated the role of S1R in adipose tissue physiology and metabolic health using adult and old WT and S1R KO mice. Visceral fat mass was increased in adult, but not old S1R-KO male mice compared to that of WT mice, despite having similar body weights, food intake, and energy expenditure. The average adipocyte size was 64 % larger in adult KO mice than in adult WT mice. Adult S1R-KO mice showed reduced plasma dehydroepiandrosterone sulfate (DHEA-S) and elevated fasting plasma leptin concentrations. Lipidomic analysis revealed alterations in plasma metabolite concentrations, particularly reduced levels of sphingomyelins, ceramides, phosphatidylcholines, lysophosphatidylcholines, and cholesteryl esters in adult mice. Decreased expression of Pparγ, Adipoq, and Atgl was detected in visceral white adipose tissue (vWAT) isolated from adult KO mice. Additionally, Fabp4 and Adipoq expression levels were significantly lower in KO adipose-derived stromal cells than in WT adipose-derived stromal cells. A fivefold increase in the mitochondrial fatty acid oxidation rate and a 43 % increase in electron transfer coupling capacity were detected in adult S1R-KO vWAT. In summary, our investigation revealed an age-dependent association between increased visceral adiposity and decreased plasma levels of DHEA-S in S1R-deficient male mice. These findings underscore the potential role of S1R in regulating metabolic processes in adipose tissue and suggest that DHEA-S is a potential mediator of adiposity changes in the absence of S1R.
    Keywords:  Adipose tissue-derived stromal cells; Dehydroepiandrosterone sulfate; Lipid metabolism; Mitochondrial function; Sigma-1 receptor; White adipose tissue
    DOI:  https://doi.org/10.1016/j.bbalip.2024.159571
  5. Am J Physiol Heart Circ Physiol. 2024 Oct 25.
    Recent Advances Associated with Cardiometabolic Remodeling in Diabetes-induced Heart Failure.
    Gaurav Sharma, Shyam S Chaurasia, Mark A Carlson, Paras K Mishra.
      Diabetes mellitus (DM) is characterized by chronic hyperglycemia, and despite intensive glycemic control, the risk of heart failure in diabetic patients remains high. Diabetes-induced heart failure (DHF) presents a unique metabolic challenge, driven by significant alterations in cardiac substrate metabolism, including increased reliance on fatty acid oxidation, reduced glucose utilization, and impaired mitochondrial function. These metabolic alterations lead to oxidative stress, lipotoxicity, and energy deficits, contributing to the progression of heart failure. Emerging research has identified novel mechanisms involved in the metabolic remodeling of diabetic hearts, such as autophagy dysregulation, epigenetic modifications, polyamine regulation, and branched-chain amino acid (BCAA) metabolism. These processes exacerbate mitochondrial dysfunction and metabolic inflexibility, further impairing cardiac function. Therapeutic interventions targeting these pathways-such as enhancing glucose oxidation, modulating fatty acid metabolism, and optimizing ketone body utilization-show promise in restoring metabolic homeostasis and improving cardiac outcomes. This review explores the key molecular mechanisms driving metabolic remodeling in diabetic hearts and advanced methodology, highlighting the latest therapeutic strategies to mitigate the progression of DHF. Understanding these emerging pathways offers new opportunities to develop targeted therapies that address the root metabolic causes of heart failure in diabetes.
    Keywords:  Cardiac metabolism; Diabetes mellitus; Metabolic therapies; Mitochondrial dysfunction; Oxidative stress
    DOI:  https://doi.org/10.1152/ajpheart.00539.2024
  6. Geroscience. 2024 Oct 22.
    Sex differences in the association between skeletal muscle energetics and perceived physical fatigability: the Study of Muscle, Mobility and Aging (SOMMA).
    Emma L Gay, Paul M Coen, Stephanie Harrison, Reagan E Garcia, Yujia Susanna Qiao, Bret H Goodpaster, Daniel E Forman, Frederico G S Toledo, Giovanna Distefano, Philip A Kramer, Sofhia V Ramos, Anthony J A Molina, Barbara J Nicklas, Steven R Cummings, Peggy M Cawthon, Russell T Hepple, Anne B Newman, Nancy W Glynn.
      Greater perceived physical fatigability and lower skeletal muscle energetics are both predictors of mobility decline. Characterizing associations between muscle energetics and perceived fatigability may provide insight into potential targets to prevent mobility decline. We examined associations of in vivo (maximal ATP production, ATPmax) and ex vivo (maximal carbohydrate supported oxidative phosphorylation [max OXPHOS] and maximal fatty acid supported OXPHOS [max FAO OXPHOS]) measures of mitochondrial energetics with two measures of perceived physical fatigability, Pittsburgh Fatigability Scale (PFS, 0-50, higher = greater) and Rating of Perceived Exertion (RPE Fatigability, 6-20, higher = greater) after a slow treadmill walk. Participants from the Study of Muscle, Mobility and Aging (N = 873) were 76.3 ± 5.0 years old, 59.2% women, and 85.3% White. Higher muscle energetics (both in vivo and ex vivo) were associated with lower perceived physical fatigability, all p < 0.03. When stratified by sex, higher ATPmax was associated with lower PFS Physical for men only; higher max OXPHOS and max FAO OXPHOS were associated with lower RPE Fatigability for both sexes. Higher skeletal muscle energetics were associated with 40-55% lower odds of being in the most (PFS ≥ 25, RPE Fatigability ≥ 12) vs least (PFS 0-4, RPE Fatigability 6-7) severe fatigability strata, all p < 0.03. Being a woman was associated with 2-3 times higher odds of being in the most severe fatigability strata when controlling for ATPmax but not the ex vivo measures (p < 0.05). Better mitochondrial energetics were linked to lower fatigability and less severe fatigability in older adults. Findings imply that improving skeletal muscle energetics may mitigate perceived physical fatigability and prolong healthy aging.
    Keywords:  Aging; Epidemiology; Fatigue; Mitochondria; Oxidative phosphorylation
    DOI:  https://doi.org/10.1007/s11357-024-01373-z
  7. Aging Cell. 2024 Oct 24. e14382
    Time-restricted feeding mediated modulation of microbiota leads to changes in muscle physiology in Drosophila obesity models.
    Christopher Livelo, Yiming Guo, Jagathnarayan Madhanagopal, Casey Morrow, Girish C Melkani.
      Recent research has highlighted the essential role of the microbiome in maintaining skeletal muscle physiology. The microbiota influences muscle health by regulating lipid metabolism, protein synthesis, and insulin sensitivity. However, metabolic disturbances such as obesity can lead to dysbiosis, impairing muscle function. Time-restricted feeding (TRF) has been shown to mitigate obesity-related muscle dysfunction, but its effects on restoring healthy microbiomes remain poorly understood. This study utilizes 16S microbiome analysis and bacterial supplementation to investigate the bacterial communities influenced by TRF that may benefit skeletal muscle physiology. In wild-type and obese Drosophila models (axenic models devoid of natural microbial communities), the absence of microbiota influence muscle performance and metabolism differently. Specifically, axenic wild-type Drosophila exhibited reduced muscle performance, higher glucose levels, insulin resistance, ectopic lipid accumulation, and decreased ATP levels. Interestingly, in obese Drosophila (induced by a high-fat diet or predisposed obesity mutant Sk2), the absence of microbiota improved muscle performance, lowered glucose levels, reduced insulin resistance, and increased ATP levels. TRF was found to modulate microbiota composition, notably increasing Acetobacter pasteurianus (AP) and decreasing Staphylococcus aureus (SA) in both obesity models. Supplementation with AP improved muscle performance and reduced glucose and insulin resistance, while SA supplementation had the opposite effect. This study provides novel insights into the complex interactions between TRF, microbiota, and skeletal muscle physiology in different Drosophila models.
    Keywords:  16S microbiome analysis; ATP; Drosophila obesity models; insulin sensitivity and resistance; metabolic homeostasis; muscle metabolism; skeletal muscle physiology; time‐restricted feeding
    DOI:  https://doi.org/10.1111/acel.14382
  8. Nutr Metab Cardiovasc Dis. 2024 Sep 10. pii: S0939-4753(24)00356-9. [Epub ahead of print]
    Impact of early postnatal overnutrition on cardiac mitochondrial dysfunction in adult mice with ischemia/reperfusion.
    Anatalia K G Vieira, Amélia F Bernardo, Fabiana A Neves, Vivian M Soares, Roberta M Guedes, Patrícia N Soares, Patrícia C Lisboa, Erika Cortez, Egberto G Moura, Bruna G da Silva, Erica P Garcia-Souza, Anibal S Moura.
       BACKGROUND AND AIMS: Nutritional imbalance at the beginning of life, a critical window period, leads to the development of obesity, overweight, dyslipidemia, diabetes, and cardiovascular disease in adulthood. In this study, the effects and associations of overnutrition during lactation on energy metabolism and oxidative stress in cardiomyocytes of adult male Swiss mice were examined.
    METHODS AND RESULTS: Animals were divided into two groups (control and overfed) subjected to baseline and ischemia/reperfusion conditions, forming four groups: control baseline (CBL), control ischemia/reperfusion (CIR), overfed baseline (OBL), and overfed ischemia/reperfusion (OIR). The hearts were analyzed for hemodynamics using the Langendorff technique, mitochondrial energy metabolism using the Oroboros apparatus, ATP production, oxidative stress, and SIRT1, pSTAT3 and STAT3 protein content by Western blotting. Hemodynamic abnormalities in the cardiovascular system were associated with mitochondrial dysfunction, as demonstrated by impaired carbohydrate and fatty acid oxidation capacity, decreased mitochondrial coupling in the OG, and reduced ATP production in the OIR group. Alteration in pSTAT3 and SIRT1 proteins expression in overfed mice reinforce energy metabolism impairment. Lipid and/or protein degradation is altered in the heart of OG, suggesting increased oxidative stress.
    CONCLUSION: Overnutrition during lactation associated with heart ischemia leads to molecular cardiac alterations in STAT3 and SIRT1 proteins, compromising energy metabolism via reduced mitochondrial oxidation capacity, ATP production and increased lipid peroxidation.
    Keywords:  Cardiovascular disease; Ischemia/reperfusion; Mitochondrial energy; Overnutrition; Oxidative stress
    DOI:  https://doi.org/10.1016/j.numecd.2024.09.007
  9. PLoS One. 2024 ;19(10): e0311203
    Unbiased complexome profiling and global proteomics analysis reveals mitochondrial impairment and potential changes at the intercalated disk in presymptomatic R14Δ/+ mice hearts.
    Brian Foo, Hugo Amedei, Surmeet Kaur, Samir Jaawan, Angela Boshnakovska, Tanja Gall, Rudolf A de Boer, Herman H W Silljé, Henning Urlaub, Peter Rehling, Christof Lenz, Stephan E Lehnart.
      Phospholamban (PLN) is a sarco-endoplasmic reticulum (SER) membrane protein that regulates cardiac contraction/relaxation by reversibly inhibiting the SERCA2a Ca2+-reuptake pump. The R14Δ-PLN mutation causes severe cardiomyopathy that is resistant to conventional treatment. Protein complexes and higher-order supercomplexes such as intercalated disk components and Ca+2-cycling domains underlie many critical cardiac functions, a subset of which may be disrupted by R14Δ-PLN. Complexome profiling (CP) is a proteomics workflow for systematic analysis of high molecular weight (MW) protein complexes and supercomplexes. We hypothesize that R14Δ-PLN may alter a subset of these assemblies, and apply CP workflows to explore these changes in presymptomatic R14Δ/+ mice hearts. Ventricular tissues from presymptomatic 28wk-old WT and R14Δ/+ mice were homogenized under non-denaturing conditions, fractionated by size-exclusion chromatography (SEC) with a linear MW-range exceeding 5 MDa, and subjected to quantitative data-independent acquisition mass spectrometry (DIA-MS) analysis. Unfortunately, current workflows for the systematic analysis of CP data proved ill-suited for use in cardiac samples. Most rely upon curated protein complex databases to provide ground-truth for analysis; however, these are derived primarily from cancerous or immortalized cell lines and, consequently, cell-type specific complexes (including cardiac-specific machinery potentially affected in R14Δ-PLN hearts) are poorly covered. We thus developed PERCOM: a novel CP data-analysis strategy that does not rely upon these databases and can, furthermore, be implemented on widely available spreadsheet software. Applying PERCOM to our CP dataset resulted in the identification of 296 proteins with disrupted elution profiles. Hits were significantly enriched for mitochondrial and intercalated disk (ICD) supercomplex components. Changes to mitochondrial supercomplexes were associated with reduced expression of mitochondrial proteins and maximal oxygen consumption rate. The observed alterations to mitochondrial and ICD supercomplexes were replicated in a second cohort of "juvenile" 9wk-old mice. These early-stage changes to key cardiac machinery may contribute to R14Δ-PLN pathogenesis.
    DOI:  https://doi.org/10.1371/journal.pone.0311203
  10. Am J Physiol Heart Circ Physiol. 2024 Oct 25.
    Diabetes Mellitus Disrupts LncRNA Malat1 Regulation of Cardiac Mitochondrial Genome-Encoded Protein Expression.
    Andrew D Taylor, Quincy A Hathaway, Ethan M Meadows, Andrya J Durr, Amina Kunovac, Mark V Pinti, Chris C Cook, Brianna R Miller, Remi Nohoesu, Roxy Nicoletti, Hafsat O Alabere, Aaron R Robart, John M Hollander.
      Understanding the cellular mechanisms behind diabetes-related cardiomyopathy is crucial as it is a common and deadly complication of diabetes mellitus. Dysregulation of the mitochondrial genome has been linked to diabetic cardiomyopathy, and can be ameliorated by altering microRNA (miRNA) availability in the mitochondrion. Long non-coding RNAs (lncRNAs) have been identified to downregulate miRNAs. This study aimed to determine if diabetes mellitus impacts the mitochondrial localization of lncRNAs, their interaction with miRNAs, and how this influences mitochondrial and cardiac function. In mouse and human non-diabetic and type 2 diabetic cardiac tissue, RNA was isolated from purified mitochondria and sequenced (Ilumina HiSeq). Malat1 was significantly downregulated in both human and mouse cardiac mitochondria. Use of a mouse model with an insertional deletion of Malat1 transcript expression resulted in exacerbated systolic and diastolic dysfunction when evaluated in conjunction with a high-fat diet. The cardiac effects of a high-fat diet were countered in a mouse model with transgenic overexpression of Malat1. MiR-320a, a miRNA that binds to both mitochondrial genome-encoded gene NADH-ubiquinone oxidoreductase chain 1 (MT-ND1) as well as Malat1, was upregulated in human and mouse diabetic mitochondria. Conversely, MT-ND1 was downregulated in human and mouse diabetic mitochondria. Mice with an insertional inactivation of Malat1 displayed increased recruitment of both miR-320a and MT-ND1 to the RNA-induced silencing complex (RISC). In vitro pulldown assays of Malat1 fragments with conserved secondary structure confirmed binding capacity for miR-320a. In vitro Seahorse assays indicated that Malat1 knockdown and miR-320a overexpression impaired overall mitochondrial bioenergetics and Complex I functionality. In summary, the disruption of Malat1 presence in mitochondria as observed in diabetic cardiomyopathy is linked to cardiac dysfunction and mitochondrial genome regulation.
    Keywords:  Heart; LncRNA; Malat1; MiRNA; Mitochondria
    DOI:  https://doi.org/10.1152/ajpheart.00607.2024
  11. Free Radic Biol Med. 2024 Oct 22. pii: S0891-5849(24)00997-3. [Epub ahead of print]
    Calorie restriction modulates mitochondrial dynamics and autophagy in leukocytes of patients with obesity.
    Zaida Abad-Jiménez, Sandra López-Domènech, María Pelechá, Laura Perea-Galera, Susana Rovira-Llopis, Celia Bañuls, Ana Blas-García, Nadezda Apostolova, Carlos Morillas, Víctor Manuel Víctor, Milagros Rocha.
       BACKGROUND: Although it is established that caloric restriction offers metabolic and clinical benefits, the molecular mechanisms underlying these effects remain unclear. Thus, this study aimed to investigate whether caloric restriction can modulate mitochondrial function and remodelling and stimulate autophagic flux in the PBMCs of patients with obesity.
    METHODS: This was an interventional study of 38 obese subjects (BMI > 35 kg/m2) who underwent 6 months of dietary therapy, including a 6-week very-low-calorie diet (VLCD) followed by an 18-week low-calorie diet (LCD). We determined clinical variables, mitochondrial function parameters (by fluorescence imaging of mitochondrial ROS and membrane potential), and protein expression of markers of mitochondrial dynamics (MNF1, MFN2, OPA, DRP1 and FIS1) and autophagy (LC3, Beclin, BCL2 and NBR1) by western blot.
    RESULTS: Caloric restriction induced an improvement in metabolic outcomes that was accompanied by an increase in AMPK expression, a decrease of mitochondrial ROS and mitochondrial membrane potential, which was associated with increased markers of mitochondrial dynamics (MFN2, DRP1 and FIS1) and activation of autophagy as evidenced by augmented LC3 II/I, Beclin1 and NBR1, and a decrease in BCL2.
    CONCLUSION: These findings shed light on the specific molecular mechanisms by which caloric restriction facilitates metabolic improvements, highlighting the relevance of pathways involving energy homeostasis and cell recovery, including mitochondrial function and dynamics and autophagy.
    Keywords:  Obesity; PBMCs; VLCD; autophagy; mitochondrial quality control; oxidative stress
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.10.295
  12. Am J Physiol Endocrinol Metab. 2024 Oct 23.
    The Acute and Chronic influence of Exercise on Mitochondrial Dynamics in Skeletal Muscle.
    Elya Janis Ritenis, Camila S Padilha, Matthew B Cooke, Christos George Stathis, Andrew Philp, Donny M Camera.
      Exercise and nutritional modulation are potent stimuli for eliciting increases in mitochondrial mass and function. Collectively, these beneficial adaptations are increasingly recognized to coincide with improvements to skeletal muscle health. Mitochondrial dynamics of fission and fusion are increasingly implicated as having a central role in mediating aspects of key organelle adaptions that are seen with exercise. Exercise-induced mitochondrial adaptations that dynamics have been implicated in are: 1) Increases to mitochondrial turnover, resulting from elevated rates of mitochondrial synthesis (biogenesis) and degradative (mitophagy) processes. 2) Morphological changes to the 3D tubular network, known as the mitochondrial reticulum, that mitochondria form in skeletal muscle. Notably, mitochondrial fission has also been implicated in coordinating increases in mitophagy, following acute exercise. Further, increased fusion following exercise training promotes increased connectivity of the mitochondrial reticulum and is associated with improved metabolism and mitochondrial function. However, the molecular basis and fashion in which exercise infers beneficial mitochondrial adaptations through mitochondrial dynamics remains poorly understood. This review attempts to highlight recent developments investigating the effects of exercise on mitochondrial dynamics, while attempting to offer a perspective of the methodological refinements and potential variables, such as substrate/glycogen availability, which should be considered going forward.
    Keywords:  Exercise; Mitochondrial Dynamics; Skeletal Muscle
    DOI:  https://doi.org/10.1152/ajpendo.00311.2024
  13. Am J Physiol Endocrinol Metab. 2024 Oct 23.
    Postnatal surge of adipose-secreted leptin is a robust predictor of fat mass trajectory in mice.
    Olga Horakova, Petra Janovska, Ilaria Irodenko, Jana Buresova, Inge van der Stelt, Sara Stanic, Eliska Haasova, Nivasini Shekhar, Tatyana Kobets, Jaap Keijer, Petr Zouhar, Martin Rossmeisl, Jan Kopecky, Kristina Bardova.
      The transient postnatal increase in circulating leptin levels, known as leptin surge, may increase later susceptibility to diet-induced obesity in rodents. However, the source of leptin during the surge needs to be better characterized, and the long-term effects of leptin are contradictory. Characterization of the interaction of leptin with the genetic background, sex, and other factors is required. Here, we focused on the impact of circulating leptin levels and several related variables, measured in 2- and 4-week-old (i) obesity-prone C57BL/6 (B6) and (ii) obesity-resistant A/J mice. In total, 264 mice of both sexes were used. Posttranscriptionally controlled leptin secretion from subcutaneous white adipose tissue, the largest adipose tissue depot in mice pups, was the primary determinant of plasma leptin levels. When the animals were randomly assigned standard chow or high-fat diet (HFD) between 12 - 24 weeks of age, the obesogenic effect of HFD-feeding was observed in B6 but not A/J mice. Only leptin levels at 2 weeks, i.e., close to the maximum in the postnatal leptin surge, correlated with both body weight (BW) trajectory throughout the life and adiposity of the 24-week-old mice. Leptin surge explained 13 and 7 % of the variance in BW and adiposity of B6 mice and 9 and 35 % of the variance in these parameters in A/J mice, with a minor role of sex. Our results prove the positive correlation between the leptin surge and adiposity in adulthood, reflecting the fundamental biological role of leptin. This role could be compromised in obese subjects.
    Keywords:  Adiposity; Leptin surge; Mice; Obesity
    DOI:  https://doi.org/10.1152/ajpendo.00237.2024
  14. Br J Radiol. 2024 Oct 25. pii: tqae216. [Epub ahead of print]
    The prognostic value of Epicardial and Pericoronary Adipose Tissue in Heart Failure with Preserved Ejection Fraction Using Coronary Computed Tomography Angiography.
    Shuangxiang Lin, Chenjia Liu, Shuyue Wang, Xingfa Ding, Jiaxing Wu, Xinhong Wang, Sun Jianzhong.
       OBJECTIVES: To assess the prognostic significance of epicardial adipose tissue volume (EATv) and pericoronary adipose tissue attenuation (PCATa) in patients with heart failure with preserved ejection fraction (HFpEF).
    METHODS: This retrospective study was based on HFpEF and controls who underwent coronary computed tomography angiography (CCTA) screening to rule out coronary disease. Comparisons of EATv and PCATa were made between HFpEF patients and a control group, employing statistical analyses including Kaplan-Meier and Cox regression to assess prognostic significance.
    RESULTS: A total of 224 patients were retrospectively analyzed. The EATv was 56.1 cm3 ± 11.9 and PCATa in the right coronary artery (PCATa-RCA) was -74.7 HU ± 3.82 in HFpEF patients, which increased significantly compared with controls. Among them, 112 HFpEF patients (mean age: 71.9 ± 8.5 years; 40% male) were followed up for a median of 27 ± 0.6 months (range 2-47 months). EATv and PCATa-RCA were predictive of outcome with an optimal threshold of 56.29 cm3 and -71.17 HU, respectively. In Kaplan-Meier analysis, the high EATv and PCATa-RCA attenuation had significantly higher rates of composite outcomes (log-rank test, all P < 0.01). EATv and PCATa-RCA were independently predictive of outcome following adjustment for confounding variables (EATv: hazard ratio [HR] 1.03; 95% confidence interval [CI] (1.01-1.06); p < 0.01, PCTAa-RCA: HR 1.44; 95% CI 1.27-1.62; p < 0.001)).
    CONCLUSIONS: Increased EATv and PCATa-RCA are associated with worse clinical outcomes in HFpEF patients.
    ADVANCES IN KNOWLEDGE: This study highlights the potential of CCTA-derived adipose tissue metrics as novel, non-invasive biomarkers for risk stratification in HFpEF.
    DOI:  https://doi.org/10.1093/bjr/tqae216
  15. Animal Model Exp Med. 2024 Oct 22.
    Repetitive transcranial magnetic stimulation elicits weight loss and improved insulin sensitivity in type 2 diabetic rats.
    Xuanjin Chen, Ruru Wang, Xin Wang, Ming Liu, Zhipeng Liu, Tao Yin, Chen Li.
       BACKGROUND: Type 2 diabetes (T2D) accounts for the majority of diabetes incidences and remains a widespread global chronic disorder. Apart from early lifestyle changes, intervention options for T2D are mainly pharmaceutical.
    METHODS: Repetitive transcranial magnetic stimulation (rTMS) has been approved by the FDA as a therapeutic intervention option for major depressive disorders, with further studies also indicating its role in energy metabolism and appetite. Considering its safe and non-invasive properties, we evaluated the effects of rTMS on systemic metabolism using T2D rats.
    RESULTS: We observed that rTMS improved glucose tolerance and insulin sensitivity in T2D rats after a 10-day exposure. Improved systemic insulin sensitivity was maintained after a 21-day treatment period, accompanied by modest yet significant weight loss. Circulating serum lipid levels, including those of cholesteryl ester, tryglyceride and ceramides, were also reduced following rTMS application. RNA-seq analyses further revealed a changed expression profile of hepatic genes that are related to sterol production and fatty acid metabolism. Altered expression of hypothalamic genes that are related to appetite regulation, neural activity and ether lipid metabolism were also implicated.
    CONCLUSION: In summary, our data report a positive impact of rTMS on systemic insulin sensitivity and weight management of T2D rats. The underlying mechanisms via which rTMS regulates systemic metabolic parameters partially involve lipid utilization in the periphery as well as central regulation of energy intake and lipid metabolism.
    Keywords:  fatty acid synthesis and metabolism; insulin sensitivity; rTMS; type 2 diabetes; weight loss
    DOI:  https://doi.org/10.1002/ame2.12483
  16. Heart Fail Rev. 2024 Oct 19.
    GLP-1 receptor agonists as promising anti-inflammatory agents in heart failure with preserved ejection fraction.
    Giovanni Battista Bonfioli, Luca Rodella, Marco Metra, Enrico Vizzardi.
      Heart Failure with Preserved Ejection Fraction (HFpEF) represents a significant challenge in modern cardiovascular medicine, characterized by diastolic dysfunction and a chronic pro-inflammatory milieu. The high prevalence of comorbidities such as diabetes, visceral obesity, and aging, which contribute to systemic inflammation, plays a pivotal role in the pathogenesis and progression of HFpEF. Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RAs), a class of glucose-lowering drugs, have demonstrated a wide range of pleiotropic effects that extend beyond glycaemic control. These effects include the reduction of inflammation and oxidative stress, vasodilation, decreased arterial stiffness, and a reduction in myocardial fibrosis-key factors in the pathophysiology of HFpEF. Recent evidence from the STEP-HFpEF and STEP-HFpEF-DM trials provides the first robust data supporting the efficacy of GLP-1 RAs, specifically semaglutide, in improving the quality of life in obese patients with HFpEF. These trials also demonstrated a significant reduction in C-Reactive Protein (CRP) levels, reinforcing the hypothesis that suppressing the pro-inflammatory state may yield substantial clinical benefits in this patient population. These findings suggest that GLP-1 RAs could play a crucial role in the management of HFpEF, particularly in patients with obesity, by targeting the underlying inflammatory processes and contributing to better overall cardiovascular outcomes.
    Keywords:  GLP-1; Heart Failure with Preserved Ejection Fraction; Inflammation
    DOI:  https://doi.org/10.1007/s10741-024-10450-6
  17. Front Sleep. 2023 ;pii: 1295301. [Epub ahead of print]2
    Severity of sleep apnea impairs adipose tissue insulin sensitivity in individuals with obesity and newly diagnosed obstructive sleep apnea.
    Sara Rodrigues, Luiz Aparecido Bortolotto, Robbie A Beyl, Prachi Singh.
       Introduction: Obstructive sleep apnea (OSA) is a common sleep disorder associated with increased risk for the development of type 2 diabetes. While studies have examined the effects of sleep on whole-body insulin sensitivity, little is known about the effects of sleep on adipose tissue insulin sensitivity in patients with OSA. We analyzed if the severity of OSA, measured by apnea-hypopnea index (AHI), is associated with adipose tissue insulin sensitivity.
    Methods: We examined the relationship between sleep parameters and adipose tissue insulin sensitivity in non-diabetic participants with obesity and newly diagnosed OSA who underwent overnight polysomnography and a 2 h oral glucose tolerance test during which circulating free fatty acids were measured. In total, 16 non-diabetic participants with obesity and newly diagnosed OSA (sex, 81.3% males; mean age, 50.9 ± 6.7 y; BMI, 36.5 ± 2.9 kg/m2; AHI, 43 ± 20 events/h) were included in the analysis.
    Results: In our study participants, AHI is inversely associated with free-fatty acid suppression during oral glucose challenge (R = -0.764, p = 0.001). This relationship persisted even after statistical adjustment for age (R = -0.769, p = 0.001), body mass index (R = -0.733, p = 0.002), waist-to-hip ratio (R = -0.741, p = 0.004), or percent body fat mass (R = -0.0529, p = 0.041). Furthermore, whole-body insulin sensitivity as determined by the Matsuda index was associated with percent REM sleep (R = 0.552, p = 0.027) but not AHI (R = -0.119, p = 0.660).
    Conclusion: In non-diabetic patients with OSA, the severity of sleep apnea is associated with adipose tissue insulin sensitivity but not whole-body insulin sensitivity. The impairments in adipose tissue insulin sensitivity may contribute to the development of type 2 diabetes.
    Keywords:  REM sleep; adipose tissue; free fatty acids; insulin resistance; obstructive sleep apnea
    DOI:  https://doi.org/10.3389/frsle.2023.1295301
  18. Nat Commun. 2024 Oct 22. 15(1): 9100
    Annonaceous acetogenins mimic AA005 targets mitochondrial trifunctional enzyme alpha subunit to treat obesity in male mice.
    Bing Han, Zhan-Ming Li, Xu-Yun Zhao, Kai Liang, Yu-Qin Mao, Shi-Long Zhang, Li-Ying Huang, Chao-Yue Kong, Xin Peng, Hui-Ling Chen, Jia-Ting Huang, Zhao-Xia Wu, Jin-Qing Yao, Pei-Ran Cai, Zheng-Yan Zhang, Xu-Min Zhang, Zhu-Jun Yao, Guo-Qiang Chen, Li-Shun Wang.
      Obesity and related diseases pose a major health risk, yet current anti-obesity drugs inadequately addressing clinical needs. Here we show AA005, an annonaceous acetogenin mimic, resists obesity induced by high-fat diets and leptin mutations at non-toxic doses, with the alpha subunit of the mitochondrial trifunctional protein (HADHA) as a target identified through proteomics and in vitro validation. Pharmacokinetic analysis shows AA005 enriches in adipose tissue, prompting the creation of adipose-specific Hadha-deficient mice. These mice significantly mitigate diet-induced obesity, echoing AA005's anti-obesity effects. AA005 treatment and Hadha deletion in adipose tissues increase body temperature and energy expenditure in high-fat diet-fed mice. The beneficial impact of AA005 on obesity mitigation is ineffective without uncoupling protein 1 (UCP1), essential for thermogenesis regulation. Our investigation shows the interaction between AA005 and HADHA in mitochondria, activating the UCP1-mediated thermogenic pathway. This substantiates AA005 as a promising compound for obesity treatment, targeting HADHA specifically.
    DOI:  https://doi.org/10.1038/s41467-024-53118-3
  19. Cardiovasc Diabetol. 2024 Oct 24. 23(1): 378
    Obesity cardiomyopathy could contribute to sudden cardiac death: a Japanese epidemiological morphological study.
    Ryo Kaimori, Haruto Nishida, Mari Tamura, Kohji Kuroki, Kumi Murata, Kazuhiro Kawamura, Shinjiro Mori, Tsutomu Daa.
       BACKGROUND: We aimed to clarify the existence and pathological features of obesity cardiomyopathy (OCM) in Japan using our series of autopsy cases.
    METHODS: In this retrospective autopsy study, OCM was defined as cardiac hypertrophy (≥ 400 g in men, ≥ 320 g in women) of unknown aetiology in individuals with obesity (body mass index [BMI] ≥ 25 kg/m2 according to the Japanese definition of obesity). We compared cases of OCM with those with obesity without cardiac hypertrophy (OB) and normal weight without cardiac hypertrophy (normal control). Macroscopically, heart weight and cardiac parameters, including epicardial adipose tissue, were measured. Fibrosis, cardiomyocyte diameter, and adipose tissue infiltration were analysed microscopically.
    RESULTS: Of the 294 cases, we identified 19 cases of OCM (6.5%) and compared them with the OB and normal control groups. Patients with OCM were slightly younger than non-OCM patients (p = 0.081). The median heart weight was significantly heavier in OCM cases than in OB cases (435 g, interquartile range [IQR] 408-515 g vs. 360 g, IQR 341-385 g). Macroscopically, OCM hearts had a "globoid" appearance with a thickened right ventricular outflow tract. Some OCM cases showed focal interstitial fibrosis in the left ventricle. Approximately half the OCM cases were diagnosed with sudden cardiac death (SCD), with significant differences.
    CONCLUSIONS: The prevalence of OCM may be higher than expected in Japan, and this may be a specific pathological finding. Given that approximately half the cases of OCM were due to SCD, OCM may cause SCD, emphasizing the need to recognise and diagnose OCM.
    Keywords:  Autopsy; Cardiomyopathy; Metabolic syndrome; Obesity; Obesity cardiomyopathy; Pathology; Sudden cardiac death
    DOI:  https://doi.org/10.1186/s12933-024-02456-z
  20. Physiol Rep. 2024 Oct;12(20): e70088
    Decreased mitochondrial-related gene expression in adipose tissue after acute sprint exercise in humans: A pilot study.
    Mona Esbjörnsson, Håkan C Rundqvist, Barbara Norman, Ted Österlund, Eric Rullman, Jens Bülow, Eva Jansson.
      The aim was to examine the acute effects of sprint exercise (SIT) on global gene expression in subcutaneous adipose tissue (AT) in healthy subjects, to enhance understanding of how SIT influences body weight regulation. The hypothesis was that SIT upregulates genes involved in mitochondrial function and fat metabolism. A total of 15 subjects performed three 30-s all-out sprints (SIT). Samples were collected from AT, skeletal muscle (SM) and blood (brachial artery and a subcutaneous AT vein) up to 15 min after the last sprint. Results showed that markers of oxidative stress, such as the purines hypoxanthine, xanthine and uric acid, increased markedly by SIT in both the artery and the AT vein. Purines also increased in AT and SM tissue. Differential gene expression analysis indicated a decrease in signaling for mitochondrial-related pathways, including oxidative phosphorylation, electron transport, ATP synthesis, and heat production by uncoupling proteins, as well as mitochondrial fatty acid beta oxidation. This downregulation of genes related to oxidative metabolism suggests an early-stage inhibition of the mitochondria, potentially as a protective mechanism against SIT-induced oxidative stress.
    Keywords:  biopsy; high intensity; microarray analysis; skeletal muscle; sprint interval exercise; subcutaneous white adipose tissue; transcriptome
    DOI:  https://doi.org/10.14814/phy2.70088
  21. Br J Pharmacol. 2024 Oct 20.
    Gpr55 deficiency crucially alters cardiomyocyte homeostasis and counteracts angiotensin II induced maladaption in female mice.
    Brigitte Schopohl, Michael Kohlhaas, Alexander G Nickel, Anna-Florentine Schiuma, Sanne L Maas, Emiel P C van der Vorst, Yi Xuan Shia, Christoph Maack, Sabine Steffens, Sarah-Lena Puhl.
       BACKGROUND AND PURPOSE: Cannabis stimulates several G-protein-coupled-receptors and causes bradycardia and hypotension upon sustained consumption. Moreover, in vitro studies suggest an interference of cannabinoid-signalling with cardiomyocyte contractility and hypertrophy. We aimed at revealing a functional contribution of the cannabinoid-sensitive receptor GPR55 to cardiomyocyte homeostasis and neurohumorally induced hypertrophy in vivo.
    EXPERIMENTAL APPROACH: Gpr55-/- and wild-type (WT) mice were characterized after 28-day angiotensin II (AngII; 1·μg·kg-1 min-1) or vehicle infusion. In isolated adult Gpr55-/- and WT cardiomyocytes, mitochondrial function was assessed under naïve conditions, while cytosolic Ca2+ handling was additionally determined following application of the selective GPR55 antagonist CID16020046.
    KEY RESULTS: Gpr55 deficiency did not affect angiotensin II (AngII) mediated hypertrophic growth, yet, especially in females, it alleviated maladaptive pro-hypertrophic and -inflammatory gene expression and improved inotropy and adrenergic responsiveness compared to WT. In-depth analyses implied increased cytosolic Ca2+ concentrations and transient amplitudes, and accelerated sarcomere contraction kinetics in Gpr55-/- myocytes, which could be mimicked by GPR55 blockade with CID16020046 in female WT cells. Moreover, Gpr55 deficiency up-regulated factors involved in glucose and fatty acid transport independent of the AngII challenge, accelerated basal mitochondrial respiration and reduced basal protein kinase (PK) A, G and C activity and phospholemman (PLM) phosphorylation.
    CONCLUSIONS AND IMPLICATIONS: Our study suggests GPR55 as crucial regulator of cardiomyocyte hypertrophy and homeostasis presumably by regulating PKC/PKA-PLM and PKG signalling, and identifies the receptor as potential target to counteract maladaptation, adrenergic desensitization and metabolic shifts as unfavourable features of the hypertrophied heart in females.
    Keywords:  CID16020046; G‐protein coupled receptor GPR55; angiotensin II; cannabinoid receptor; cardiomyocyte homeostasis; hypertrophy
    DOI:  https://doi.org/10.1111/bph.17350
  22. Sci Adv. 2024 Oct 25. 10(43): eado5887
    Mitochondrial fatty acid oxidation drives senescence.
    Shota Yamauchi, Yuki Sugiura, Junji Yamaguchi, Xiangyu Zhou, Satoshi Takenaka, Takeru Odawara, Shunsuke Fukaya, Takao Fujisawa, Isao Naguro, Yasuo Uchiyama, Akiko Takahashi, Hidenori Ichijo.
      Cellular senescence is a stress-induced irreversible cell cycle arrest involved in tumor suppression and aging. Many stresses, such as telomere shortening and oncogene activation, induce senescence by damaging nuclear DNA. However, the mechanisms linking DNA damage to senescence remain unclear. Here, we show that DNA damage response (DDR) signaling to mitochondria triggers senescence. A genome-wide small interfering RNA screen implicated the outer mitochondrial transmembrane protein BNIP3 in senescence induction. We found that BNIP3 is phosphorylated by the DDR kinase ataxia telangiectasia mutated (ATM) and contributes to an increase in the number of mitochondrial cristae. Stable isotope labeling metabolomics indicated that the increase in cristae enhances fatty acid oxidation (FAO) to acetyl-coenzyme A (acetyl-CoA). This promotes histone acetylation and expression of the cyclin-dependent kinase inhibitor p16INK4a. Notably, pharmacological activation of FAO alone induced senescence both in vitro and in vivo. Thus, mitochondrial energy metabolism plays a critical role in senescence induction and is a potential intervention target to control senescence.
    DOI:  https://doi.org/10.1126/sciadv.ado5887
  23. Toxics. 2024 Oct 11. pii: 735. [Epub ahead of print]12(10):
    Relationships among Dioxin-like Mitochondria Inhibitor Substances (MIS)-Mediated Mitochondria Dysfunction, Obesity, and Lung Function in a Korean Cohort.
    Hoonsung Choi, Kyungho Ha, Jin Taek Kim, Min Kyong Moon, Hyojee Joung, Hong Kyu Lee, Youngmi Kim Pak.
      Mitochondrial dysfunction is closely linked to obesity and diabetes, with declining lung function in aging increasing diabetes risk, potentially due to elevated serum levels of dioxin-like mitochondria inhibitor substances (MIS) from prolonged exposure to environmental pollutants. However, the mechanisms connecting MIS, mitochondria, lung function, and metabolic disorder remain unclear. In this study, we analyzed data from 1371 adults aged 40-69 years in the 2008 Korean Genome Epidemiologic Study (KoGES) Ansung cohort. We indirectly estimated dioxin-like MIS levels by measuring intracellular ATP (MISATP) and reactive oxygen species (MISROS) in cultured cells treated with the serum of participants. Using correlation analysis and structural equation modeling (SEM), we explored the relationships among MIS, mitochondrial function, body mass index (BMI), and lung function (FEV1 and FVC). Our findings revealed that MISATP was associated with BMI in females and with FVC in males, while MISROS correlated with both BMI and FVC in males, not in females. Significant associations between BMI and FVC were found in the highest MIS subgroup in both sexes. SEM analyses demonstrated that MIS negatively influenced mitochondrial function, which in turn affected BMI and lung function. Age-related declines in lung function were also linked to mitochondrial dysfunction. This study underscores the potential of MIS assays as alternatives for assessing mitochondrial function and highlights the importance of mitochondrial health in metabolic disorders and lung function.
    Keywords:  MIS; dioxin-like chemicals; lung function; mitochondrial dysfunction; obesity; sex differences; structural equation modeling
    DOI:  https://doi.org/10.3390/toxics12100735
  24. Eur J Prev Cardiol. 2024 Oct 25. pii: zwae332. [Epub ahead of print]
    Comparison of exercise training modalities and change in peak oxygen consumption in heart failure with preserved ejection fraction: a secondary analysis of the OptimEx-Clin trial.
    Stephan Mueller, Marina Kabelac, Isabel Fegers-Wustrow, Ephraim B Winzer, Andreas B Gevaert, Paul Beckers, Bernhard Haller, Frank Edelmann, Jeffrey W Christle, Mark J Haykowsky, Vandana Sachdev, Dalane W Kitzman, Axel Linke, Volker Adams, Ulrik Wisloff, Burkert Pieske, Emeline van Craenenbroeck, Martin Halle.
       AIMS: Exercise training (ET) is an effective therapy in heart failure with preserved ejection fraction (HFpEF), but the influence of different ET characteristics is unclear. We aimed to evaluate the associations between ET frequency, duration, intensity [% heart rate reserve (%HRR)] and estimated energy expenditure (EEE) with the change in peak oxygen consumption (V̇O2) over 3 months of moderate continuous training (MCT, 5×/week) or high-intensity interval training (HIIT, 3×/week) in HFpEF.
    METHODS AND RESULTS: ET duration and heart rate (HR) were recorded with a smartphone application. EEE was calculated using the HR data during ET and the individual HR-V̇O2 relationships during cardiopulmonary exercise testing. Differences between groups and associations between ET characteristics and peak V̇O2 change were assessed with linear regression analyses. Peak V̇O2 improved by 9.2 ± 13.2% after MCT and 8.7 ± 15.9% after HIIT (P = 0.67). The average EEE of 1 HIIT session was equivalent to ∼1.42 MCT sessions and when adjusted for EEE, the mean difference between MCT and HIIT was -0.1% (P = 0.98). For both MCT and HIIT, peak V̇O2 change was positively associated with ET frequency (MCT: R2 = 0.103; HIIT: R2 = 0.149) and duration/week (MCT: R2 = 0.120; HIIT: R2 = 0.125; all P < 0.05). Average %HRR was negatively associated with peak V̇O2 change in MCT (R2 = 0.101; P = 0.034), whereas no significant association was found in HIIT (P = 0.234). Multiple regression analyses explained ∼1/3 of the variance in peak V̇O2 change.
    CONCLUSION: In HFpEF, isocaloric HIIT and MCT seem to be equally effective over 3 months. Within each mode, increasing ET frequency or duration/week may be more effective to improve peak V̇O2 than increasing ET intensity.
    Keywords:  Diastolic heart failure; Duration; Energy expenditure; Exercise capacity; High-intensity interval training; Intensity
    DOI:  https://doi.org/10.1093/eurjpc/zwae332
  25. ACS Nano. 2024 Oct 25.
    Mitochondrial Bioenergetics of Functional Wound Closure is Dependent on Macrophage-Keratinocyte Exosomal Crosstalk.
    Anu Sharma, Rajneesh Srivastava, Surya C Gnyawali, Pramod Bhasme, Adam J Anthony, Yi Xuan, Jonathan C Trinidad, Chandan K Sen, David E Clemmer, Sashwati Roy, Subhadip Ghatak.
      Tissue nanotransfection (TNT)-based fluorescent labeling of cell-specific exosomes has shown that exosomes play a central role in physiological keratinocyte-macrophage (mϕ) crosstalk at the wound-site. Here, we report that during the early phase of wound reepithelialization, macrophage-derived exosomes (Exomϕ), enriched with the outer mitochondrial membrane protein TOMM70, are localized in leading-edge keratinocytes. TOMM70 is a 70 kDa adaptor protein anchored in the mitochondrial outer membrane and plays a critical role in maintaining mitochondrial function and quality. TOMM70 selectively recognizes cytosolic chaperones by its tetratricopeptide repeat (TPR) domain and facilitates the import of preproteins lacking a positively charged mitochondrial targeted sequence. Exosomal packaging of TOMM70 in mϕ was independent of mitochondrial fission. TOMM70-enriched Exomϕ compensated for the hypoxia-induced depletion of epidermal TOMM70, thereby rescuing mitochondrial metabolism in leading-edge keratinocytes. Thus, macrophage-derived TOMM70 is responsible for the glycolytic ATP supply to power keratinocyte migration. Blockade of exosomal uptake from keratinocytes impaired wound closure with the persistence of proinflammatory mϕ in the wound microenvironment, pointing toward a bidirectional crosstalk between these two cell types. The significance of such bidirectional crosstalk was established by the observation that in patients with nonhealing diabetic foot ulcers, TOMM70 is deficient in keratinocytes of wound-edge tissues.
    Keywords:  TOMM70; functional wound closure; keratinocyte migration; macrophage-derived exosomes; macrophage–keratinocyte crosstalk; tissue nanotransfection; “don’t eat me” plasmid
    DOI:  https://doi.org/10.1021/acsnano.4c07610
  26. J Nutr Biochem. 2024 Oct 18. pii: S0955-2863(24)00216-X. [Epub ahead of print] 109785
    Impact of reduced hepatic ceramide levels in high-fat diet mice on glucose metabolism.
    Monika Imierska, Piotr Zabielski, Kamila Roszczyc-Owsiejczuk, Karolina Pogodzińska, Agnieszka Błachnio-Zabielska.
      Dysregulation of insulin action in hepatocytes, common in obesity, significantly contributes to insulin resistance, type 2 diabetes, and metabolic syndrome. Previous research highlights ceramides' role in these conditions. This study explores the impact of ceramides by silencing the serine palmitoyltransferase (Sptlc2) gene, crucial for the initial ceramide biosynthesis, using hydrodynamic gene delivery. Male C57BL/6 mice were randomly divided into three groups: one on a low-fat diet (LFD) receiving scrambled shRNA plasmids, another on a high-fat diet (HFD) with scrambled shRNA plasmids, and a third on HFD with a plasmid targeting Sptlc2. Analyses included RT-PCR for gene expression, western blot for protein levels, and UHPLC/MS/MS for lipid profiling. Glucose metabolism was evaluated via oral glucose tolerance tests, homeostatic model assessment of insulin resistance, and glucose-6-phosphate analysis. Results showed that HFD induces insulin resistance by inhibiting insulin signaling and increasing active lipid levels in hepatocytes. Sptlc2 silencing reduced ceramide accumulation, improving insulin signaling and glucose metabolism. Notably, ceramide synthesis inhibition did not significantly affect other lipid levels, highlighting ceramide's critical role in hepatic insulin resistance.
    Keywords:  ceramides; gene silencing; high fat diet; insulin resistance; liver
    DOI:  https://doi.org/10.1016/j.jnutbio.2024.109785
  27. Theranostics. 2024 ;14(16): 6236-6248
    Cardiomyocyte-derived USP28 negatively regulates antioxidant response and promotes cardiac hypertrophy via deubiquitinating TRIM21.
    Jibo Han, Liming Lin, Zimin Fang, Bozhi Ye, Xue Han, Jiachen Xu, Binjiang Han, Julian Min, Jinfu Qian, Gaojun Wu, Yi Wang, Guang Liang.
      Rationale: Cardiac hypertrophy is an important pathological basis for heart failure. Most physiological activities of cardiomyocytes are regulated by proteins and their post-translational modification. Deubiquitinating enzymes (DUBs) are involved in protein stability maintenance and closely related to myocardial hypertrophy. In this study, we aimed to clarify the regulatory role of a DUB, ubiquitin-specific peptidase 28 (USP28), in cardiac hypertrophy and explore the molecular mechanism behind. Methods: Transcriptome and single-cell mRNA sequencing was used to demonstrate the association of USP28 and cardiac hypertrophy. Cardiomyocyte-specific USP28 knockout mice (USP28CKO) were subjected to angiotensin II (Ang II) infusion or transverse aortic constriction (TAC) models. Coimmunoprecipitation combined mass spectrum analysis (Co-IP/MS) was applied to screen out the substrate of USP28. Results: We first showed the up-regulation of USP28 in cardiac hypertrophy, and its cellular localization of cardiomyocytes. USP28CKO protects mouse heart against Ang II- or TAC-induced cardiac dysfunction and hypertrophy. Mechanistically, we identified tripartite motif-containing protein 21 (TRIM21) as the potential substrate of USP28 by Co-IP/MS analysis. Cardiomyocyte USP28 deubiquitinates and stabilizes TRIM21 to negatively regulate nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant response, increasing oxidative stress in cardiomyocytes and promoting cardiac hypertrophy and injury. Finally, using a selective USP28 inhibitor Otilonium Bromide, we confirmed the therapeutic effect of pharmacological inhibition of USP28 against TAC-induced established hypertrophic heart failure. Conclusion: Our study illustrates a cardiomyocyte-specific USP28-TRIM21 axis in regulating hypertrophic cardiomyopathy and presents USP28 as a potential target for the treatment of cardiac hypertrophy.
    Keywords:  Cardiac hypertrophy; Cardiomyocyte; Deubiquitinating enzyme; TRIM21.; USP28
    DOI:  https://doi.org/10.7150/thno.99340
  28. Lab Anim (NY). 2024 Oct 22.
    A novel model of cardiovascular-kidney-metabolic syndrome combining unilateral nephrectomy and high-salt-sugar-fat diet in mice.
    Lucas Rannier R A Carvalho, Miho Shimari, Ariela Maína Boeder, Zhengbing Zhuge, Min Cai, Cecilia Leijding, Stefano Gastaldello, Andrei L Kleschyov, Tomas A Schiffer, Drielle Dantas Guimarães, Gaia Picozzi, Lars H Lund, Bengt Fellström, Eddie Weitzberg, Jon O Lundberg, Carolina E Hagberg, Gianluigi Pironti, Daniel C Andersson, Mattias Carlström.
      The aim of this study was to explore biological interaction and pathophysiology mechanisms in a new mouse model of cardiovascular-kidney-metabolic (CKM) syndrome, induced by chronic moderate renal failure in combination with consumption of a customized Western diet rich in carbohydrates, fat and salt. Male C57BL/6J mice were subjected to unilateral nephrectomy, fed a customized Western diet rich not only in sugar and fat but also in salt, and followed for 12 weeks or 20 weeks. Sham-operated mice on a standard chow served as healthy controls. Body composition, weight gain, glucose metabolism, fat distribution, blood pressure, cardiac function, vascular reactivity, renal function, inflammation and mitochondrial function were measured and combined with biochemical and histopathological analyses. The novel triple-hit model of CKM syndrome showed signs and symptoms of metabolic syndrome, disturbed glucose metabolism, impaired adipocyte physiology and fat redistribution, cardiovascular dysfunction, renal damage and dysfunction, systemic inflammation, elevated blood pressure and cardiac remodeling. The pathological changes were more pronounced in mice after prolonged exposure for 20 weeks, but no deaths occurred. In the present mouse model of CKM syndrome, profound and significant metabolic, cardiac, vascular and renal dysfunctions and injuries emerged by using a Western diet rich not only in fat and carbohydrates but also in salt. This multisystem disease model could be used for mechanistic studies and the evaluation of new therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41684-024-01457-5
  29. J Mol Cell Cardiol Plus. 2024 Jun;pii: 100073. [Epub ahead of print]8
    Allele-specific dysregulation of lipid and energy metabolism in early-stage hypertrophic cardiomyopathy.
    Arpana Vaniya, Anja Karlstaedt, Damla Gulkok, Tilo Thottakara, Yamin Liu, Sili Fan, Hannah Eades, Styliani Vakrou, Ryuya Fukunaga, Hilary J Vernon, Oliver Fiehn, M Roselle Abraham.
       Introduction: Hypertrophic cardiomyopathy (HCM) results from pathogenic variants in sarcomeric protein genes that increase myocyte energy demand and lead to cardiac hypertrophy. However, it is unknown whether a common metabolic trait underlies cardiac phenotype at the early disease stage. To address this question and define cardiac biochemical pathology in early-stage HCM, we studied two HCM mouse models that express pathogenic variants in cardiac troponin T (Tnt2) or myosin heavy chain (Myh6) genes, and have marked differences in cardiac imaging phenotype, mitochondrial function at early disease stage.
    Methods: We used a combination of echocardiography, transcriptomics, mass spectrometry-based untargeted metabolomics (GC-TOF, HILIC, CSH-QTOF), and computational modeling (CardioNet) to examine cardiac structural and metabolic remodeling at early disease stage (5 weeks of age) in R92W-TnT+/- and R403Q-MyHC+/- mutant mice. Data from mutants was compared with respective littermate controls (WT).
    Results: Allele-specific differences in cardiac phenotype, gene expression and metabolites were observed at early disease stage. LV diastolic dysfunction was prominent in TnT mutants. Differentially-expressed genes in TnT mutant hearts were predominantly enriched in the Krebs cycle, respiratory electron transport, and branched-chain amino acid metabolism, whereas MyHC mutants were enriched in mitochondrial biogenesis, calcium homeostasis, and liver-X-receptor signaling. Both mutant hearts demonstrated significant alterations in levels of purine nucleosides, trisaccharides, dicarboxylic acids, acylcarnitines, phosphatidylethanolamines, phosphatidylinositols, ceramides and triglycerides; 40.4 % of lipids and 24.7 % of metabolites were significantly different in TnT mutants, whereas 10.4 % of lipids and 5.8 % of metabolites were significantly different in MyHC mutants. Both mutant hearts had a lower abundance of unsaturated long-chain acyl-carnitines (18:1, 18:2, 20:1), but only TnT mutants showed enrichment of FA18:0 in ceramide and cardiolipin species. CardioNet predicted impaired energy substrate metabolism and greater phospholipid remodeling in TnT mutants than in MyHC mutants.
    Conclusions: Our systems biology approach revealed marked differences in metabolic remodeling in R92W-TnT and R403Q-MyHC mutant hearts, with TnT mutants showing greater derangements than MyHC mutants, at early disease stage. Changes in cardiolipin composition in TnT mutants could contribute to impairment of energy metabolism and diastolic dysfunction observed in this study, and predispose to energetic stress, ventricular arrhythmias under high workloads such as exercise.
    Keywords:  HCM mouse models; Hypertrophic cardiomyopathy; Lipidomics; RNAseq; Untargeted metabolomics
    DOI:  https://doi.org/10.1016/j.jmccpl.2024.100073
  30. Physiol Rep. 2024 Oct;12(20): e70092
    Effect of spermidine intake on skeletal muscle regeneration after chemical injury in male mice.
    Tomohiro Iwata, Takanaga Shirai, Kazuki Uemichi, Riku Tanimura, Tohru Takemasa.
      Skeletal muscle has a high regenerative ability and maintains homeostasis by rapidly regenerating from frequent damage caused by intense exercise or trauma. In sports, skeletal muscle damage occurs frequently due to intense exercise, so practical methods to promote skeletal muscle regeneration are required. Recent studies have shown that it may be possible to promote skeletal muscle regeneration through new pathways, such as promoting autophagy and improving mitochondrial function. Spermidine is a type of polyamine, and oral intake of spermidine promotes autophagy and improves mitochondrial function without inhibiting mTOR. Therefore, we evaluate the effects of spermidine intake on skeletal muscle regeneration after injury using a mouse model of cardiotoxin-induced muscle injury. Our results showed no significant change in skeletal muscle wet weight with spermidine intake at all time points. In addition, although spermidine intake significantly increased the mean fiber cross-sectional area 14 days after injury, these effects were not observed at other time points. In addition, we analyzed stem cells, autophagy, mTOR signaling, inflammation, and mitochondria, but no significant effects of spermidine intake were observed at almost all time points and protein expression levels. Therefore, spermidine intake does not affect skeletal muscle regeneration after chemical injury, and if there is any, it is very limited.
    Keywords:  autophagy; mTOR signaling; mitochondria; skeletal muscle regeneration; spermidine
    DOI:  https://doi.org/10.14814/phy2.70092
  31. Nat Commun. 2024 Oct 21. 15(1): 9063
    Calorie restriction increases insulin sensitivity to promote beta cell homeostasis and longevity in mice.
    Cristiane Dos Santos, Amanda Cambraia, Shristi Shrestha, Melanie Cutler, Matthew Cottam, Guy Perkins, Varda Lev-Ram, Birbickram Roy, Christopher Acree, Keun-Young Kim, Thomas Deerinck, Danielle Dean, Jean Philippe Cartailler, Patrick E MacDonald, Martin Hetzer, Mark Ellisman, Rafael Arrojo E Drigo.
      Caloric restriction (CR) can extend the organism life- and health-span by improving glucose homeostasis. How CR affects the structure-function of pancreatic beta cells remains unknown. We used single nucleus transcriptomics to show that CR increases the expression of genes for beta cell identity, protein processing, and organelle homeostasis. Gene regulatory network analysis reveal that CR activates transcription factors important for beta cell identity and homeostasis, while imaging metabolomics demonstrates that beta cells upon CR are more energetically competent. In fact, high-resolution microscopy show that CR reduces beta cell mitophagy to increase mitochondria mass and the potential for ATP generation. However, CR beta cells have impaired adaptive proliferation in response to high fat diet feeding. Finally, we show that long-term CR delays the onset of beta cell aging hallmarks and promotes cell longevity by reducing beta cell turnover. Therefore, CR could be a feasible approach to preserve compromised beta cell structure-function during aging and diabetes.
    DOI:  https://doi.org/10.1038/s41467-024-53127-2
  32. Int J Med Sci. 2024 ;21(13): 2502-2509
    Mitochondrial Stress as a Central Player in the Pathogenesis of Hypoxia-Related Myocardial Dysfunction: New Insights.
    Zhijiang Guo, Yingjie Tian, Nanyang Liu, Ye Chen, Xiaohan Chen, Guoxing Yuan, An Chang, Xing Chang, Jie Wu, Hao Zhou.
      Hypoxic injury is a critical pathological factor in the development of various cardiovascular diseases, such as congenital heart disease, myocardial infarction, and heart failure. Mitochondrial quality control is essential for protecting cardiomyocytes from hypoxic damage. Under hypoxic conditions, disruptions in mitochondrial homeostasis result in excessive reactive oxygen species (ROS) production, imbalances in mitochondrial dynamics, and initiate pathological processes including oxidative stress, inflammatory responses, and apoptosis. Targeted interventions to enhance mitochondrial quality control, such as coenzyme Q10 and statins, have shown promise in mitigating hypoxia-induced mitochondrial dysfunction. These treatments offer potential therapeutic strategies for hypoxia-related cardiovascular diseases by regulating mitochondrial fission and fusion, restoring mitochondrial biogenesis, reducing ROS production, and promoting mitophagy.
    Keywords:  Hypoxia; Mitochondrial Homeostasis; Myocardial Injury
    DOI:  https://doi.org/10.7150/ijms.99359
  33. Metabolites. 2024 Oct 16. pii: 553. [Epub ahead of print]14(10):
    Mitochondrial Abundance and Function Differ Across Muscle Within Species.
    Con-Ning Yen, Jocelyn S Bodmer, Jordan C Wicks, Morgan D Zumbaugh, Michael E Persia, Tim H Shi, David E Gerrard.
      Background: Mitochondria are considered the powerhouse of cells, and skeletal muscle cells are no exception. However, information regarding muscle mitochondria from different species is limited. Methods: Different muscles from cattle, pigs and chickens were analyzed for mitochondrial DNA (mtDNA), protein and oxygen consumption. Results: Bovine oxidative muscle mitochondria contain greater mtDNA (p < 0.05), protein (succinate dehydrogenase, SDHA, p < 0.01; citrate synthase, CS, p < 0.01; complex I, CI, p < 0.05), and oxygen consumption (p < 0.01) than their glycolytic counterpart. Likewise, porcine oxidative muscle contains greater mtDNA (p < 0.01), mitochondrial proteins (SDHA, p < 0.05; CS, p < 0.001; CI, p < 0.01) and oxidative phosphorylation capacity (OXPHOS, p < 0.05) in comparison to glycolytic muscle. However, avian oxidative skeletal muscle showed no differences in absolute mtDNA, SDHA, CI, complex II, lactate dehydrogenase, or glyceraldehyde 3 phosphate dehydrogenase compared to their glycolytic counterpart. Even so, avian mitochondria isolated from oxidative muscles had greater OXPHOS capacity (p < 0.05) than glycolytic muscle. Conclusions: These data show avian mitochondria function is independent of absolute mtDNA content and protein abundance, and argue that multiple levels of inquiry are warranted to determine the wholistic role of mitochondria in skeletal muscle.
    Keywords:  metabolism; mitochondria; skeletal muscle
    DOI:  https://doi.org/10.3390/metabo14100553
  34. Protein Sci. 2024 Nov;33(11): e5190
    Preferential binding of ADP-bound mitochondrial HSP70 to the nucleotide exchange factor GRPEL1 over GRPEL2.
    Pooja Manjunath, Gorazd Stojkovič, Liliya Euro, Svetlana Konovalova, Sjoerd Wanrooij, Kristian Koski, Henna Tyynismaa.
      Human nucleotide exchange factors GRPEL1 and GRPEL2 play pivotal roles in the ADP-ATP exchange within the protein folding cycle of mitochondrial HSP70 (mtHSP70), a crucial chaperone facilitating protein import into the mitochondrial matrix. Studies in human cells and mice have indicated that while GRPEL1 serves as an essential co-chaperone for mtHSP70, GRPEL2 has a role regulated by stress. However, the precise structural and biochemical mechanisms underlying the distinct functions of the GRPEL proteins have remained elusive. In our study, we present evidence revealing that ADP-bound mtHSP70 exhibits remarkably higher affinity for GRPEL1 compared to GRPEL2, with the latter experiencing a notable decrease in affinity upon ADP binding. Additionally, Pi assay showed that GRPEL1, but not GRPEL2, enhanced the ATPase activity of mtHSP70. Utilizing Alphafold modeling, we propose that the interaction between GRPEL1 and mtHSP70 can induce the opening of the nucleotide binding cleft of the chaperone, thereby facilitating the release of ADP, whereas GRPEL2 lacks this capability. Additionally, our findings suggest that the redox-regulated Cys87 residue in GRPEL2 does not play a role in dimerization but rather reduces its affinity for mtHSP70. Our findings on the structural and functional disparities between GRPEL1 and GRPEL2 may have implications for mitochondrial protein folding and import processes under varying cellular conditions.
    Keywords:  Alphafold; GRPEL1; GRPEL2; co‐chaperone; cysteines; interactions; mitochondria; mtHSP70; nucleotide exchange factor
    DOI:  https://doi.org/10.1002/pro.5190
  35. iScience. 2024 Oct 18. 27(10): 111018
    Carnitine is a friend in HFpEF and foe in HFrEF.
    Huiqing Wang, Haoran Wei, Mingming Zhao, Junfang Wu, Min Fei, Nan Lin, Rui Zhan, Qingyuan Liu, Qi Zhang, Xiaodong Yao, Yufei Wu, Wenxin Shan, Hongtu Cui, Liang Ji, Bing Pan, Lu Fang, Yujie Zhu, Xin Li, Yansong Guo, Dao Wen Wang, Lemin Zheng.
      Heart failure (HF) is a global concern, particularly HF with preserved ejection fraction (HFpEF), lacking effective treatments. Understanding the differences of metabolic profiles between HFpEF and HFrEF (heart failure with reduced ejection fraction) patients is crucial for therapeutic advancements. In this study, pseudotargeted metabolomics was employed to analyze for disparities of plasma metabolic profiles between HFpEF and HFrEF in two cohorts: discovery (n = 514) and validation (n = 3368). Plasma-free carnitine levels were significant changed in HF patients. A non-linear and U-shaped (for HFpEF) or J-shaped (for HFrEF) association between circulating free carnitine levels and the composite risk of cardiac events were observed. Interestingly, HFpEF patients with low free carnitine (≤40.18 μmol/L) displayed a poorer survival, contrasting with HFrEF where higher levels (≥35.67 μmol/L) were linked to poorer outcomes, indicating distinct metabolism pathways. In conclusion, these findings offer insights into HFpEF metabolic profiles, suggesting potential therapeutic targets.
    Keywords:  Cardiovascular medicine; Health sciences; Human physiology; Metabolomics
    DOI:  https://doi.org/10.1016/j.isci.2024.111018
  36. J Pharm Biomed Anal. 2024 Oct 18. pii: S0731-7085(24)00571-5. [Epub ahead of print]253 116529
    Study on the mechanism of Xinmailong injection against chronic heart failure based on transcriptomics and proteomics.
    Yanni Xue, Changling Lv, Lu Jin, Di Tan, Dingyu Wu, Fang Peng.
      Xinmailong (XML), a traditional Chinese medicine derived from Periplaneta americana, is commonly used in China to treat chronic heart failure (CHF). However, its pharmacological mechanism remains unclear. In our research, we employed Doxorubicin (Dox) to create a CHF animal model and administered XML treatment to investigate the pharmacological effects of XML on CHF rats by combining transcriptomic and proteomic analyses. XML improved dox-induced CHF and improved cardiac function, and a joint multi-omics analysis demonstrated that it reduced cardiomyocyte fibrosis during CHF. There is further evidence that XML may alleviate cardiomyocyte fibrosis through its effects on the cGMP-PKG signaling pathway or by reducing the expression levels of COL1A1, COL3A1, MMP9, and CXCR2. In this study, the effects of XML on rats with CHF are examined at the transcriptional and protein levels, as well as its mechanism and mode of action in treating CHF. There may be novel therapeutic targets or clinical indications for XML-based CHF therapy resulting from the study's identification of significant differential genes and signaling pathways.
    Keywords:  Chronic heart failure; Proteomics mechanism; Transcriptomics; Xinmailong injection
    DOI:  https://doi.org/10.1016/j.jpba.2024.116529
  37. Cell Signal. 2024 Oct 22. pii: S0898-6568(24)00457-1. [Epub ahead of print] 111482
    Decreased Mrpl42 expression exacerbates myocardial ischemia and reperfusion injury by inhibiting mitochondrial translation.
    Xiaomeng Zhang, Xiaoqian Chang, Jingyu Deng, Congye Li, Yuan Li, Yangzhi Zheng, Rongjin Yang, Xiaoming Xu, Wenjun Yan, Fuyang Zhang, Yunlong Xia, Huishou Zhao, Pingping Xing, Guigao Guo, Fengyue Ding, Ling Tao, Shan Wang.
      Mammalian mitochondrial DNA (mtDNA) encodes a total of 13 proteins, all of which are subunits of enzyme complexes of the oxidative phosphorylation. The mtDNA-encoded protein synthesis depends on the mitochondrial ribosomal proteins (MRPs), which assemble to form a specialized form of ribosome. Some mtDNA-encoded proteins have been reported to be reduced after myocardial ischemic injury. However, the molecular mechanisms responsible for this decrease and whether this decrease is involved in myocardial ischemia/reperfusion (I/R) injury remains unknown. Here, we found that the mtDNA-encoded protein levels were significantly decreased after I/R injury, while the mRNA levels of these genes were either increased or had no significant change. Subsequently, by querying and analyzing public database resources, we found that the expression of many mitochondrial translation-related proteins tended to decrease after myocardial infarction injury, and the reduction in the expression of these proteins was most obvious for Mrpl42. Furthermore, we found that cardiac Mrpl42 knockdown aggravated I/R-induced cardiac contractile dysfunction and cardiomyocyte death, while restoring Mrpl42 expression in the heart reduced I/R injury. Mrpl42 knockdown impaired the translation of mtDNA-encoded genes, ultimately led to aberrations in mitochondrial morphology and respiratory function. In addition, we found that the decrease in the expression of Mrpl42 after I/R injury was caused by the downregulation of Nrf2, which directly regulates Mrpl42 transcription. Our study revealed that ischemic downregulation of Mrpl42 expression and subsequent inhibition of mitochondrial translation contribute to cardiac I/R injury. Targeting Mrpl42 may be a novel therapeutic intervention for cardiac I/R injury and myocardial infarction.
    Keywords:  Mitochondria encoded gene; Mitochondria translation; Mrpl42; Myocardial ischemia/reperfusion injury
    DOI:  https://doi.org/10.1016/j.cellsig.2024.111482
  38. Heart Rhythm. 2024 Oct 22. pii: S1547-5271(24)03460-X. [Epub ahead of print]
    Catheter Ablation Versus Antiarrhythmic Therapy for Atrial Fibrillation in Heart Failure with Preserved Ejection Fraction.
    Marisa R DeLuca, Bilal Ali, Yasir Tarabichi, Beni R Verma, Saima Karim.
       BACKGROUND: Clinical outcomes among patients with atrial fibrillation (AF) and heart failure with preserved ejection fraction (HFpEF) treated with catheter ablation (CA) versus antiarrhythmic therapy (AAT) are not well-known.
    OBJECTIVES: This study compared morbidity and mortality among patients with AF and HFpEF treated with CA versus AAT.
    METHODS: AF and HFpEF patients from January 2017-June 2023 were identified in TriNetX, a large global population-based database. Patients with prior diagnosis of HFrEF or crossover between AAT and CA were excluded. Baseline characteristics including age, sex, BMI, type of AF, comorbidities, and cardiovascular medications were compared. The two groups were 1:1 propensity matched for outcomes analysis. All-cause mortality, cerebrovascular accident (CVA)/transient ischemic attack (TIA), and acute HF were compared with Kaplan-Meier curves.
    RESULTS: Patients treated with CA (n=1959) and AAT (n=7689) were 1:1 propensity matched yielding 3632 patients with no significant differences in baseline characteristics. Compared to AAT, CA was associated with decreased mortality (9.2% vs. 20.5%; hazard ratio [HR]: 0.431; 95% confidence interval [CI]: 0.359 to 0.518; p<0.001). Additionally, CA was associated with reduced HFpEF (HR: 0.638; 95% CI, 0.550 to 0.741; p<0.001) and acute HFrEF (HR: 0.645; 95% CI, 0.452 to 0.920; p=0.015). There was no difference in composite of CVA/TIA (HR: 0.935; 95% CI: 0.725 to 1.207; p=0.607).
    CONCLUSION: In this retrospective study of patients with AF and HFpEF, CA was associated with lower mortality and risk of acute heart failure when compared with AAT.
    Keywords:  Diastolic heart failure; HFpEF; HFrEF; anti-arrhythmic therapy; paroxysmal atrial fibrillation; persistent atrial fibrillation; systolic heart failure
    DOI:  https://doi.org/10.1016/j.hrthm.2024.10.034
  39. Biosci Rep. 2024 Oct 30. pii: BSR20241103. [Epub ahead of print]44(10):
    Deficiency of GPR10 and NPFFR2 receptors leads to sex-specific prediabetic syndrome and late-onset obesity in mice.
    Alena Morgan, Nivasini Shekhar, Veronika Strnadová, Zdenko Pirník, Eliška Haasová, Jan Kopecký, Andrea Pačesová, Blanka Železná, Jaroslav Kuneš, Kristina Bardová, Lenka Maletínská.
      GPR10 and neuropeptide FF receptor 2 (NPFFR2) play important role in the regulation of food intake and energy homeostasis. Understanding the interaction between these receptors and their specific ligands, such as prolactin-releasing peptide, is essential for developing stable peptide analogs with potential for treating obesity. By breeding and characterizing double knockout (dKO) mice fed standard or high-fat diet (HFD), we provide insights into the metabolic regulation associated with the GPR10 and NPFFR2 deficiency. Both WT and dKO mice were subjected to behavioral tests and an oral glucose tolerance test. Moreover, dual-energy X-ray absorptiometry (DEXA) followed by indirect calorimetry were performed to characterize dKO mice. dKO mice of both sexes, when exposed to an HFD, showed reduced glucose tolerance, hyperinsulinemia, and insulin resistance compared with controls. Moreover, they displayed increased liver weight with worsened hepatic steatosis. Mice displayed significantly increased body weight, which was more pronounced in dKO males and caused by higher caloric intake on a standard diet, while dKO females displayed obesity characterized by increased white adipose tissue and enhanced hepatic lipid accumulation on an HFD. Moreover, dKO females exhibited anxiety-like behavior in the open field test. dKO mice on a standard diet had a lower respiratory quotient, with no significant changes in energy expenditure. These results provide insights into alterations associated with disrupted GPR10 and NPFFR2 signaling, contributing to the development of potential anti-obesity treatment.
    Keywords:  GPR10/NPFFR2-deficient mice; double KO mice; impaired glucose utilization; insulin resistance; obesity
    DOI:  https://doi.org/10.1042/BSR20241103
  40. Animal Model Exp Med. 2024 Oct 24.
    RNA-seq analysis of mitochondria-related genes regulated by AMPK in the human trophoblast cell line BeWo.
    Bin Wu, Albert Gao, Bin He, Yun Chen, Xiangfeng Kong, Fayuan Wen, Haijun Gao.
       BACKGROUND: How AMP activated protein kinase (AMPK) signaling regulates mitochondrial functions and mitophagy in human trophoblast cells remains unclear. This study was designed to investigate potential players mediating the regulation of AMPK on mitochondrial functions and mitophagy by next generation RNA-seq.
    METHODS: We compared ATP production in protein kinase AMP-activated catalytic subunit alpha 1/2 (PRKAA1/2) knockdown (AKD) and control BeWo cells using the Seahorse real-time ATP rate test, then analyzed gene expression profiling by RNA-seq. Differentially expressed genes (DEG) were examined by Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. Then protein-protein interactions (PPI) among mitochondria related genes were further analyzed using Metascape and Ingenuity Pathway Analysis (IPA) software.
    RESULTS: Both mitochondrial and glycolytic ATP production in AKD cells were lower than in the control BeWo cells (CT), with a greater reduction of mitochondrial ATP production. A total of 1092 DEGs were identified, with 405 upregulated and 687 downregulated. GO analysis identified 60 genes associated with the term 'mitochondrion' in the cellular component domain. PPI analysis identified three clusters of mitochondria related genes, including aldo-keto reductase family 1 member B10 and B15 (AKR1B10, AKR1B15), alanyl-tRNA synthetase 1 (AARS1), mitochondrial ribosomal protein S6 (MRPS6), mitochondrial calcium uniporter dominant negative subunit beta (MCUB) and dihydrolipoamide branched chain transacylase E2 (DBT).
    CONCLUSIONS: In summary, this study identified multiple mitochondria related genes regulated by AMPK in BeWo cells, and among them, three clusters of genes may potentially contribute to altered mitochondrial functions in response to reduced AMPK signaling.
    Keywords:  AMPK; ATP production; RNA‐seq; gene expression; mitochondria; trophoblast
    DOI:  https://doi.org/10.1002/ame2.12475
  41. J Cardiovasc Dev Dis. 2024 Oct 17. pii: 331. [Epub ahead of print]11(10):
    Association of Cardiovascular Risk Factors and Coronary Calcium Burden with Epicardial Adipose Tissue Volume Obtained from PET-CT Imaging in Oncological Patients.
    Carmela Nappi, Andrea Ponsiglione, Carlo Vallone, Roberto Lepre, Luigi Basile, Roberta Green, Valeria Cantoni, Ciro Gabriele Mainolfi, Massimo Imbriaco, Mario Petretta, Alberto Cuocolo.
      Whole-body positron emission tomography (PET)-computed tomography (CT) imaging performed for oncological purposes may provide additional parameters such as the coronary artery calcium (CAC) and epicardial adipose tissue (EAT) volume with cost-effective prognostic information in asymptomatic people beyond traditional cardiovascular risk factors. We evaluated the feasibility of measuring the CAC score and EAT volume in cancer patients without known coronary artery disease (CAD) referred to whole-body 18F-FDG PET-CT imaging, regardless of the main clinical problem. We also investigated the potential relationships between traditional cardiovascular risk factors and CAC with EAT volume. A total of 109 oncological patients without overt CAD underwent whole-body PET-CT imaging with 18F-fluorodeoxyglucose (FDG). Unenhanced CT images were retrospectively viewed for CAC and EAT measurements on a dedicated platform. Overall, the mean EAT volume was 99 ± 49 cm3. Patients with a CAC score ≥ 1 were older than those with a CAC = 0 (p < 0.001) and the prevalence of hypertension was higher in patients with detectable CAC as compared to those without (p < 0.005). The EAT volume was higher in patients with CAC than in those without (p < 0.001). For univariable age, body mass index (BMI), hypertension, and CAC were associated with increasing EAT values (all p < 0.005). However, the correlation between the CAC score and EAT volume was weak, and in multivariable analysis only age and BMI were independently associated with increased EAT (both p < 0.001), suggesting that potential prognostic information on CAC and EAT is not redundant. This study demonstrates the feasibility of a cost-effective assessment of CAC scores and EAT volumes in oncological patients undergoing whole-body 18F-FDG PET-CT imaging, enabling staging cancer disease and atherosclerotic burden by a single test already included in the diagnostic work program, with optimization of the radiation dose and without additional costs.
    Keywords:  PET/CT imaging; coronary artery calcium; coronary artery disease; epicardial adipose tissue
    DOI:  https://doi.org/10.3390/jcdd11100331
  42. Mitochondrial Commun. 2024 ;2 38-47
    Photobleaching and phototoxicity of mitochondria in live cell fluorescent super-resolution microscopy.
    Chia-Hung Lee, Douglas C Wallace, Peter J Burke.
      Photobleaching and phototoxicity can induce detrimental effects on cell viability and compromise the integrity of collected data, particularly in studies utilizing super-resolution microscopes. Given the involvement of multiple factors, it is currently challenging to propose a single set of standards for assessing the potential of phototoxicity. The objective of this paper is to present empirical data on the effects of photobleaching and phototoxicity on mitochondria during super-resolution imaging of mitochondrial structure and function using Airyscan and the fluorescent structure dyes Mitotracker green (MTG), 10-N-nonyl acridine orange (NAO), and voltage dye Tetramethylrhodamine, Ethyl Ester (TMRE). We discern two related phenomena. First, phototoxicity causes a transformation of mitochondria from tubular to spherical shape, accompanied by a reduction in the number of cristae. Second, phototoxicity impacts the mitochondrial membrane potential. Through these parameters, we discovered that upon illumination, NAO is much more phototoxic to mitochondria compared to MTG or TMRE and that these parameters can be used to evaluate the relative phototoxicity of various mitochondrial dye-illumination combinations during mitochondrial imaging.
    Keywords:  Fluorescent dye; Mitochondria; Photobleaching; Phototoxicity; Super-resolution
    DOI:  https://doi.org/10.1016/j.mitoco.2024.03.001
  43. Eur J Pharmacol. 2024 Oct 21. pii: S0014-2999(24)00760-X. [Epub ahead of print]984 177070
    Spatheliachromen mitigates methylglyoxal-induced myotube atrophy by activating Nrf2, inhibiting ubiquitin-mediated protein degradation, and restoring mitochondrial function.
    Yu-Fan Chuang, Lin Cheng, Wan-Hsuan Chang, Szu-Yin Yu, Hung-Te Hsu, Li-Mei An, Chia-Hung Yen, Fang-Rong Chang, Yi-Ching Lo.
       BACKGROUND: Methylglyoxal (MGO) is a potent precursor of glycative stress that leads to oxidative stress and muscle atrophy in diabetes. Spatheliachromen (FPATM-20), derived from Ficus pumila var. awkeotsang, exhibited potential antioxidant activity.
    PURPOSE: This study aimed to evaluate the potential impact and underlying mechanisms of FPATM-20 on MGO-induced myotube atrophy and mitochondrial dysfunction in mouse skeletal C2C12 myotubes.
    METHODS: Atrophic and antioxidant factors were evaluated using immunofluorescence, enzyme-linked immunosorbent assay, and western blotting. Mitochondrial function was assessed using the ATP assay and Seahorse Cell Mito Stress Test. The glycogen content was determined using periodic acid-Schiff staining. Molecular docking was performed to determine the interaction between FPATM-20 and Keap1.
    RESULTS: In myotubes treated with MGO, FPATM-20 activated the Nrf2 pathway, reduced ROS levels, enhanced antioxidant defense, and increased glycogen content. FPATM-20 improved myotube viability and size, upregulated myosin heavy chain (MyHC) expression, modulated ubiquitin-proteasome molecules (nuclear FoxO3a, atrogin-1, MuRF-1, and p62/SQSTM1), and inhibited apoptosis (Bax/Bcl-2 ratio and cleaved caspase 3). Moreover, FPATM-20 restored mitochondrial function, including mitochondrial membrane potential, mitochondrial oxygen consumption rate, and mitochondrial biogenesis pathway (nuclear PGC-1α/TFAM/FNDC5). The inhibition of Nrf2 with ML385 reversed the effects of FPATM-20 on MGO. Furthermore, molecular docking confirmed the binding of FPATM-20 to Keap1, a suppressor of Nrf2, showing the crucial role of Nrf2 in protective effects.
    CONCLUSIONS: FPATM-20 protects myotubes from MGO toxicity by activating the Nrf2 antioxidant defense, reducing protein degradation and apoptosis, and enhancing mitochondrial function. Thus, FPATM-20 may be a novel agent for preventing skeletal muscle atrophy.
    Keywords:  Methylglyoxal; Mitochondrial function; Myotube atrophy; Nrf2; Oxidative stress; Spatheliachromen
    DOI:  https://doi.org/10.1016/j.ejphar.2024.177070
  44. JACC Basic Transl Sci. 2024 Sep;9(9): 1085-1087
    "Circulating Inflammation" and the Plasma Proteome in Heart Failure With Preserved Ejection Fraction.
    Thomas M Vondriska, David J Lefer.
      
    Keywords:  African Americans; genomics; heart failure with preserved left ventricular ejection fraction; proteomics
    DOI:  https://doi.org/10.1016/j.jacbts.2024.07.004
  45. Heart Fail Rev. 2024 Oct 23.
    The sympathetic nervous system in heart failure with preserved ejection fraction.
    Joshua W-H Chang, Rohit Ramchandra.
      The sympathetic nervous system (SNS) is a major mediator of cardiovascular physiology during exercise in healthy people. However, its role in heart failure with preserved ejection fraction (HFpEF), where exercise intolerance is a cardinal symptom, has remained relatively unexplored. The present review summarizes and critically explores the currently limited data on SNS changes in HFpEF patients with a particular emphasis on caveats of the data and the implications for its subsequent interpretation. While direct measurements of SNS activity in HFpEF patients is scarce, modest increases in resting levels of muscle sympathetic nerve activity are apparent, although this may be due to the co-morbidities associated with the syndrome rather than HFpEF per se. In addition, despite some evidence for dysfunctional sympathetic signaling in the heart, there is no clear evidence for elevated cardiac sympathetic nerve activity. The lack of a compelling prognostic benefit with use of β-blockers in HFpEF patients also suggests a lack of sympathetic hyperactivity to the heart. Similarly, while renal and splanchnic denervation studies have been performed in HFpEF patients, there is no concrete evidence that the sympathetic nerves innervating these organs exhibit heightened activity. Taken together, the totality of data suggests limited evidence for elevated sympathetic nerve activity in HFpEF and that any SNS perturbations that do occur are not universal to all HFpEF patients. Finally, how the SNS responds during exertion in HFpEF patients remains unknown and requires urgent investigation.
    Keywords:  Autonomic; Diastolic; Exercise; HFpEF; Heart failure; Sympathetic
    DOI:  https://doi.org/10.1007/s10741-024-10456-0
  46. Am J Physiol Endocrinol Metab. 2024 Oct 23.
    Endothelial Beta 1 Integrins are Necessary for Microvascular Function and Glucose Uptake.
    Nathan C Winn, Deborah A Roby, Penn Mason McClatchey, Ian M Williams, Deanna P Bracy, Michelle N Bedenbaugh, Louise Lantier, Erin Plosa, Ambra Pozzi, Roy Zent, David H Wasserman.
      Microvascular insulin delivery to myocytes is rate limiting for the onset of insulin-stimulated muscle glucose uptake. The structural integrity of capillaries of the microvasculature is regulated, in part, by a family of transmembrane adhesion receptors known as integrins, which are composed of an α and β subunit. The integrin β1 (itgb1) subunit is highly expressed in endothelial cells (EC). EC itgb1 is necessary for the formation of capillary networks during embryonic during development and its knockdown blunts the reactive hyperemia that manifests during ischemia reperfusion. We investigated the contribution of EC itgb1 in microcirculatory function and glucose uptake with emphasis in skeletal muscle. We hypothesized that loss of EC itgb1 would impair microvascular hemodynamics and glucose uptake during insulin stimulation, creating 'delivery'-mediated insulin resistance. An itgβ1 knockdown mouse model was developed to avoid lethality of embryonic gene knockout and the deteriorating health resulting from early post-natal inducible gene deletion. Mice with (itgb1fl/flSCLcre) and without (itgb1fl/fl) tamoxifen inducible stem cell leukemia cre recombinase (SLCcre) expression at 10 days post cre induction had comparable exercise tolerance and pulmonary and cardiac functions. Using robust in vivo experimental platforms (i.e., intravital microscopy and hyperinsulinemic-euglycemic clamp), we show that itgb1fl/flSCLcre mice compared to itgb1fl/fl littermates have, i) deficits in capillary flow rate, flow heterogeneity, and capillary density; ii) impaired insulin-stimulated glucose uptake despite sufficient transcapillary insulin efflux; and iii) reduced insulin-stimulated glucose uptake due to perfusion-limited glucose delivery. Thus, EC itgb1 is necessary for microcirculatory function and to meet the metabolic challenge of insulin stimulation.
    Keywords:  Endothelial; Glucose uptake; Integrin; Microcirculation; Skeletal muscle
    DOI:  https://doi.org/10.1152/ajpendo.00322.2024
  47. J Physiol. 2024 Oct 24.
    Atrial cardiomyopathy resulting from loss of plakophilin-2 expression: Response to adrenergic stimulation and implications for the exercise response.
    Kavya Phadke, Sergio D'Anna, Estefania Torres Vega, Junhua Xiao, Xianming Lin, Mingliang Zhang, Joseph Sall, Feng-Xia Liang, David S Park, Marina Cerrone, Alicia Lundby, Mario Delmar, Chantal J M van van Opbergen.
      Atrial arrhythmias occur in 20-40% of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) and are associated with an increased risk of sustained ventricular arrhythmias and inappropriate implantable cardioverter-defibrillator shocks. The pathophysiology of atrial arrhythmias in ARVC remains unclear. Most cases of gene-positive ARVC are linked to pathogenic variants in the desmosomal gene plakophilin-2 (PKP2). Here, we test the hypothesis that loss of PKP2 expression leads to pro-arrhythmic changes in atrial cardiomyocytes. Atrial cells/tissue were obtained from a cardiac-specific, tamoxifen-activated model of PKP2 deficiency (PKP2cKO). By contrast to PKP2cKO ventricular myocytes, PKP2cKO atrial cardiomyocytes presented no significant differences in intracellular calcium (Ca2+ i) transient dynamics, sarcoplasmic reticulum load or action potential morphology. PKP2cKO atrial cardiomyocytes showed elevated reactive oxygen species levels, increased frequency and amplitude of Ca2+ sparks, and increased diastolic [Ca2+]i compared to control; the latter two parameters were further increased by isoproterenol exposure and reversed by exposure to ryanodine receptor blocker dantrolene. We speculate that these isoproterenol-dependent effects may impact on the exercise-related atrial arrhythmia risk in ARVC patients. Despite absence of changes in Ca2+ i transient dynamics, PKP2cKO atrial cardiomyocytes showed enhanced sarcomere shortening and impaired sarcomere relaxation. Orthogonal transcriptomic analysis of human(GTEx) and PKP2cKO atrial tissue led to identification of 41 transcripts depending on PKP2 expression. Biochemical follow-up confirmed reduced abundance of sarcomeric protein myosin binding protein C, potentially playing a role in cellular shortening and relaxation changes observed. Our findings provide novel insights into the role of PKP2 in atrial myocardium with potential implications to therapeutic management of atrial fibrillation in patients with PKP2-related ARVC. KEY POINTS: Atrial arrhythmias occur in a large group of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), a cardiac disease mostly caused by pathogenic variants in the desmosomal gene plakophilin-2 (PKP2). Exercise is considered to be an independent risk factor for arrhythmias consequent to PKP2 deficiency. We show that loss of PKP2 expression affects cellular calcium handling and electrophysiology differently in left atrial vs. ventricular myocardium and causes extensive atrial fibrosis. PKP2-deficient atrial cardiomyocytes present increased spontaneous sarcoplasmic reticulum calcium release events, further enhanced by isoproterenol exposure and reversible by a ryanodine receptor blocker (dantrolene). In addition, PKP2-deficient atrial myocytes exhibit impaired relaxation and enhanced sarcomere shortening, most probably related to reduced abundance of myosin binding protein C. We speculate that cellular effects reported upon isoproterenol impact on the exercise-related atrial arrhythmia risk in ARVC patients. We further propose that therapeutic approaches aimed at mitigating ventricular damage may be effective to treat the atrial disease in ARVC.
    Keywords:  adrenergic stimulation; arrhythmogenic right ventricular cardiomyopathy; atrial fibrillation; oxidative stress; plakophilin‐2; ryanodine receptor
    DOI:  https://doi.org/10.1113/JP286985
  48. Quant Imaging Med Surg. 2024 Oct 01. 14(10): 7612-7624
    The value of blood flow velocity and pressure gradient in differentiating patients with different types of heart failure.
    Jiaxuan Guo, Xiuzheng Yue, Wenying Liang, Lirong Ma, Xiao Sun, Huairong Zhang, Li Zhu.
       Background: Patients with different types of heart failure (HF) exhibit varying rates of blood flow through cardiac chambers and pressure gradients across the aortic valve, attributed to differing degrees of myocardial contractility. Assessment of these dynamics offers insights into early HF diagnosis. This study aimed to analyze left ventricular outflow tract (LVOT) blood flow parameters, specifically peak blood flow velocity and pressure gradient derived from four-dimensional flow cardiovascular magnetic resonance (4D flow CMR), and to evaluate 4D flow CMR's utility in distinguishing HF types.
    Methods: This prospective cross-sectional study recruited 115 HF patients from January 2019 to May 2022 at the General Hospital of Ningxia Medical University, classified by the New York Heart Association Cardiac Function Classification of Heart Failure as class II-IV, alongside a control group (n=30). Participants underwent cardiovascular magnetic resonance (CMR), including 4D flow. HF patients were categorized into heart failure with reduced ejection fraction (HFrEF, n=55), heart failure with mildly reduced ejection fraction (HFmrEF, n=30), and heart failure with preserved ejection fraction (HFpEF, n=30), based on ejection fraction. The cardiac functional parameters and aortic valve flow indices were measured using Circle Cardiovascular Imaging. LVOT 4D flow data were obtained 3 mm below the junction of the aortic valve leaflets, assessing peak velocities above and below the valve. Differences in cardiac function and blood flow parameters between groups were analyzed using one-way analysis of variance (ANOVA). The accuracy of these parameters in identifying subgroups was assessed using the receiver operating characteristic (ROC) curve.
    Results: Analysis of conventional cardiac function parameters revealed that left ventricular ejection fraction (LVEF) was significantly lower in the HFrEF and HFmrEF groups compared to the HFpEF and control groups (P<0.01). Additionally, end-diastolic volume and end-systolic volume were significantly higher in the HFrEF and HFmrEF groups than in the HFpEF and control groups (P<0.01). However, there were no significant differences in cardiac function parameters between the HFpEF and control groups (P>0.05). Significant differences were observed in aortic valve peak pressure gradients (Supra-APGmax) among the four study groups (5.01±1.09 vs. 6.23±2.94 vs. 7.63±1.81 vs. 8.89±2.97 mmHg, P<0.05). Aortic valve peak velocities in the HFrEF group differed significantly from the HFpEF and control groups (111.31±12.05 cm/s vs. 137.2±16 vs. 147.15±24.55 cm/s, P<0.001). The ROC curve for the pressure gradient below the aortic valve had an area under the curve (AUC) of 0.728 [95% confidence interval (CI): 0.591-0.864, P=0.002], with an optimal threshold of 4.72 mmHg (sensitivity: 0.8, specificity: 0.7, Youden index: 0.5).
    Conclusions: HF patients exhibit reduced pressure gradients across the aortic valve during systole, indicative of altered intracardiac blood flow dynamics. Combining aortic valve velocities and pressure gradients can aid in distinguishing different types of HF, including HFpEF patients.
    Keywords:  Heart failure (HF); cardiovascular magnetic resonance (CMR); four-dimensional flow (4D flow); left ventricular outflow tract (LVOT)
    DOI:  https://doi.org/10.21037/qims-24-311
  49. Endocrinology. 2024 Oct 24. pii: bqae141. [Epub ahead of print]
    Targeted deletion of Fibroblast Growth Factor-23 rescues metabolic dysregulation of diet-induced obesity in female mice.
    Min Young Park, Chia-Ling Tu, Luce Perie, Narendra Verma, Tamires Duarte Afonso Serdan, Farnaz Shamsi, Sue Shapses, Sean Heffron, Begona Gamallo-Lana, Adam C Mar, José O Alemán, Elisabetta Mueller, Wenhan Chang, Despina Sitara.
      Fibroblast Growth Factor-23 (FGF23) is a bone secreted protein widely recognized as a critical regulator of skeletal and mineral metabolism. However, little is known about non-skeletal production of FGF23 and its role in tissues other than bone. Growing evidence indicates that circulating FGF23 levels rise with high fat diet (HFD) and they are positively correlated with body mass index (BMI) in humans. In the present study, we show for the first time that increased circulating FGF23 levels in obese humans correlate with increased expression of adipose Fgf23 and both positively correlate with BMI. To understand the role of adipose-derived Fgf23, we generated adipocyte-specific Fgf23 knockout mice (AdipoqFgf23Δfl/Δfl) using the Adiponectin (Adipoq)-Cre driver, which targets mature white, beige, and brown adipocytes. Our data show that targeted ablation of Fgf23 in adipocytes prevents HFD-fed female mice from gaining body weight and fat mass while preserving lean mass, but has no effect on male mice, indicating the presence of sexual dimorphism. These effects are observed in the absence of changes in food and energy intake. Adipose Fgf23 inactivation also prevents dyslipidemia, hyperglycemia, and hepatic steatosis in female mice. Moreover, these changes are associated with decreased respiratory exchange ratio (RER) and increased brown fat Ucp1 expression in KO mice compared to HFD-fed control mice (Fgf23fl/fl). In conclusion, this is the first study highlighting that targeted inactivation of Fgf23 is a promising therapeutic strategy for weight loss and lean mass preservation in humans.
    Keywords:  FGF23; adipose tissue; high fat diet; lipid metabolism; obesity
    DOI:  https://doi.org/10.1210/endocr/bqae141
  50. Redox Biol. 2024 Oct 17. pii: S2213-2317(24)00377-X. [Epub ahead of print]77 103399
    Binding of α-synuclein to ACO2 promotes progressive mitochondrial dysfunction in Parkinson's disease models.
    Jie Jiao, Ge Gao, Junge Zhu, Chaodong Wang, Lei Liu, Hui Yang.
      The accumulation of α-synuclein (α-syn), a key protein in Parkinson's disease (PD), contributes to progressive neuronal damage associated with mitochondrial dysfunction and interactions with various proteins. However, the precise mechanism by which α-syn affects energy metabolism remains unclear. In our study, we used human α-syn (hα-syn) transgenic mice, which exhibit progressive neuronal decline. Through an immunoprecipitation assay specific to hα-syn, we identified an enzyme in the mitochondrial tricarboxylic acid (TCA) cycle as a binding partner-mitochondrial aconitase 2 (ACO2), which converts citrate to isocitrate. Hα-syn increasingly interacted with ACO2 in mitochondria as mice aged, correlating with a progressive decrease in ACO2 activity. The overexpression of ACO2 and the addition of isocitrate, a downstream metabolite of ACO2, were observed to alleviate hα-syn-induced mitochondrial dysfunction and cytotoxicity. Furthermore, we designed an interfering peptide to block the interaction between ACO2 and hα-syn, which showed therapeutic effects in reducing hα-syn toxicity in vitro and in vivo. Our research establishes a direct link between α-syn and the TCA cycle and identifies ACO2 as a promising therapeutic target for improving mitochondrial function and reducing α-syn neurotoxicity in PD.
    Keywords:  Interfering peptides; Mitochondrial aconitase 2; Mitochondrial damage; Parkinson's disease; α-Synuclein
    DOI:  https://doi.org/10.1016/j.redox.2024.103399
  51. J Nutr. 2024 Oct 21. pii: S0022-3166(24)01112-X. [Epub ahead of print]
    Identification of genetic polymorphisms associated with interindividual variability of vitamin A concentration in adipose tissue of healthy male adults.
    Mark Pretzel Zumaraga, Charles Desmarchelier, Beatrice Gleize, Marion Nowicki, Djaffar Ould-Ali, Jean-François Landrier, Patrick Borel.
       BACKGROUND: Adipose tissue vitamin A (VA), i.e. mainly retinol (RET) and its esters, comes from preformed VA and proVA carotenoids present in our food. Adipose tissue VA acts as hormonal cue maintaining essential aspects of adipocyte biology which includes fat mobilization and catabolism, energy balance and glucose homeostasis, and it is thus of particular interest to study its determinants, including genetic ones. Hence, this study aimed to identify genetic variations associated with adipose tissue VA concentration.
    METHODS: Forty-two healthy male adults received, in a randomized crossover design, 3 test meals. Periumbilical adipose tissue samples were collected on 6 occasions, i.e. at fast and 8h after consumption of each meal. RET concentration was measured in both plasma and the adipose tissue following saponification. Participants were genotyped using whole-genome microarrays. A total of 1305 SNPs in or near 27 candidate genes were included for univariate analysis. Partial least squares regression (PLS) was carried out to find the best combination of SNPs associated with the interindividual variability in adipose tissue RET concentration.
    RESULTS: Adipose tissue RET concentration was not associated with plasma RET concentrations (r=-0.184, p=0.28). Interindividual variability of adipose tissue RET concentration was high (CV=62%). Twenty-nine SNPs were significantly (p<0.05) associated with adipose tissue RET concentration and a PLS regression model identified 16 SNPs as explanatory variables of this concentration. The SNPs were in or near PPARG, RXRA, STRA6, CD36, FFAR4, ALDH1A1, MGLL, DGAT2, and PKD1L2.
    CONCLUSION: A combination of 16 SNPs has been associated with the interindividual of adipose tissue VA concentration in humans.
    CLINICAL TRIAL REGISTRY: ClinicalTrials.gov registration number NCT02100774.
    Keywords:  adipocyte; nutrigenetics; retinol; single nucleotide polymorphisms
    DOI:  https://doi.org/10.1016/j.tjnut.2024.10.035
  52. Yi Chuan. 2024 Oct;46(10): 860-870
    Screening and analysis of GULP1 downstream target genes based on transcriptomic sequencing.
    Xin Wen, Jin Mei, Mei-Yu Qian, Yi-Dan Jiang, Juan Wang, Shi-Bo Xu, Cui-Zhe Wang, Jun Zhang.
      GULP1 is an engulfment adaptor protein containing a phosphotyrosine-binding (PTB) domain, and existing studies have shown that it can promote glucose uptake in 3T3-L1 adipocytes. To further explore key metabolically related differential genes downstream of GULP1, this study conducted transcriptome analysis on adipocytes and skeletal muscle cells overexpressing GULP1. Subsequently, abnormally expressed genes were subjected to bioinformatic analysis, and real-time fluorescent quantitative PCR (qRT-PCR) was used for mutual validation with transcriptome sequencing. The results indicated that, with a threshold of P < 0.05 and |Log2FoldChange| ≥ 1 for screening differentially expressed genes, compared with control cells, there were 278 upregulated and 263 downregulated genes in adipocytes overexpressing GULP1. Metabolism-related GO (Gene Ontology) terms included cholesterol biosynthetic process, cholesterol metabolic process, response to lipopolysaccharide, lipid metabolic process, etc. A total of 52 metabolically related differentially expressed genes were enriched in 10 KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways, with lipid metabolism being highly enriched. In skeletal muscle cells overexpressing GULP1, there were 280 upregulated and 302 downregulated genes, with metabolism-related GO terms including hormone metabolic process, response to lipopolysaccharide, one-carbon metabolic process, etc. A total of 86 metabolically related differentially expressed genes were enriched in 10 KEGG pathways, with amino acid metabolism, lipid metabolism, and carbohydrate metabolism being highly enriched. GULP1's biological functions are extensive, including lipid metabolism and oncology. This study, through transcriptomics and bioinformatic analysis, identified key metabolically related differential genes downstream of GULP1, obtained metabolically related differential genes and signaling pathways after GULP1 overexpression, providing important theoretical basis for future research on GULP1 downstream target genes.
    Keywords:  GULP1; bioinformatic; differentially expressed gene; metabolism; transcriptome
    DOI:  https://doi.org/10.16288/j.yczz.24-221
  53. Front Cell Dev Biol. 2024 ;12 1475603
    Mitochondrial non-energetic function and embryonic cardiac development.
    Jingxian Shi, Yuxi Jin, Sha Lin, Xing Li, Donghui Zhang, Jinlin Wu, Yan Qi, Yifei Li.
      The initial contraction of the heart during the embryonic stage necessitates a substantial energy supply, predominantly derived from mitochondrial function. However, during embryonic heart development, mitochondria influence beyond energy supplementation. Increasing evidence suggests that mitochondrial permeability transition pore opening and closing, mitochondrial fusion and fission, mitophagy, reactive oxygen species production, apoptosis regulation, Ca2+ homeostasis, and cellular redox state also play critical roles in early cardiac development. Therefore, this review aims to describe the essential roles of mitochondrial non-energetic function embryonic cardiac development.
    Keywords:  ROS; cardiac development; embryo; mitochondria; non-energetic function
    DOI:  https://doi.org/10.3389/fcell.2024.1475603
  54. Appetite. 2024 Oct 18. pii: S0195-6663(24)00520-8. [Epub ahead of print]203 107716
    Effects of overnight-fasted versus fed-state exercise on the components of energy balance and interstitial glucose across four days in healthy adults.
    I Podestá D, A K Blannin, G A Wallis.
      Exercise is an essential component of body mass management interventions. Overnight-fasted exercise (FASTex) acutely enhances fat oxidation compared with fed exercise (FEDex). However, consistent FASTex training does not typically further enhance body mass loss, suggesting the induction of energy compensation responses. The present study aimed to test the effects of FASTex or FEDex on the components of energy balance (i.e., energy intake (EI), energy expenditure (EE), and appetite) and interstitial glucose metrics across four days.
    METHODS: Twelve (10 men, 2 women) healthy, physically active participants (age 22.6 + 1.2 years (mean ± SD); BMI 22.5 ± 2.8 kg ⋅ m-2) were studied twice, across four days, after a 75-min run either FASTex or FEDex. Daily EI was obtained after subtracting leftovers from the provided food. Daily fasting appetite was measured by visual analogue scales. Activity- and total- EE (AEE & TEE, respectively) were estimated by combining heart rate and accelerometry. Continuous glucose monitoring was used to capture daily interstitial glucose metrics and Likert scales were utilised to quantify fatigue, stress, sleep quality, and muscle soreness levels.
    RESULTS: No differences between conditions were observed for EI (FASTex = 15.0 ± 0.1 vs FEDex = 15.0 ± 0.4 MJ⋅day-1; p = 0.865), AEE (FASTex = 7.6 ± 1.1 vs FEDex 7.8 ± 1.3 MJ⋅day-1; p = 0.223) and TEE (FASTex = 15.9 ± 3.4 vs 14.9 ± 4.5 MJ⋅day-1; p = 0.136). Additionally, no condition effects for appetite (p > 0.05) and interstitial glucose (p = 0.074) were observed.
    CONCLUSION: FASTex did not differ from FEDex in the response of components of energy balance or interstitial glucose across four days, suggesting that both exercise approaches could be used interchangeably.
    Keywords:  Appetite; Carbohydrate; Continuous glucose monitoring; Energy expenditure; Energy intake
    DOI:  https://doi.org/10.1016/j.appet.2024.107716
  55. Cell Signal. 2024 Oct 18. pii: S0898-6568(24)00453-4. [Epub ahead of print]124 111478
    Sirt1-mediated deacetylation of PGC-1α alleviated hepatic steatosis in type 2 diabetes mellitus via improving mitochondrial fatty acid oxidation.
    Jiale Pang, Longxiang Yin, Wenjie Jiang, Haiyan Wang, Qian Cheng, Zhenzhou Jiang, Yanjuan Cao, Xia Zhu, Baojing Li, Sitong Qian, Xiaoxing Yin, Tao Wang, Qian Lu, Tingting Yang.
      Being activated by deacetylation, peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) has become an important regulator of metabolic-related diseases. The activation of Sirtuin 1 (Sirt1) by resveratrol was likely to deacetylate PGC-1α. However, the role of deacetylated PGC-1α in the alleviation of activated Sirt1 on type 2 diabetes mellitus (T2DM)-related fatty liver disease (FLD) remained unexplored. The aim of this study was to investigate the potential impact of Sirt1-mediated deacetylation of PGC-1α on T2DM-associated FLD and its underlying mechanisms. Our findings revealed that, along with the decreased Sirt1, the levels of acetylated PGC-1α were up-regulated in hepatocytes co-stimulated with high glucose (HG) and free fatty acids (FFA). Down-regulated Sirt1 inactivated PGC-1α by inhibiting its deacetylation, while activating Sirt1 improved hepatic injury by reducing lipid droplet accumulation through the deacetylation of PGC-1α. However, the beneficial effects of Sirt1 activation on hepatic steatosis were inhibited by PGC-1α antagonist in vitro. Mechanistically, activating Sirt1 enhanced mitochondrial function by promoting PGC-1α activity, thereby facilitating hepatic fatty acid oxidation (FAO). In conclusion, Sirt1-mediated deacetylation of PGC-1α mitigated hepatic lipotoxicity by enhancing mitochondrial FAO, which contributed to the restoration of mitochondrial function in T2DM. The activation of Sirt1-mediated PGC-1α deacetylation might represent a promising therapeutic approach for T2DM-associated FLD.
    Keywords:  Mitochondrial FAO; PGC-1α deacetylation; Sirt1 activation; T2DM-associated FLD
    DOI:  https://doi.org/10.1016/j.cellsig.2024.111478
  56. Free Radic Biol Med. 2024 Oct 19. pii: S0891-5849(24)00998-5. [Epub ahead of print]
    Role of ferroptosis in mitochondrial damage in diabetic retinopathy.
    Pooja Malaviya, Jay Kumar, Renu A Kowluru.
      Diabetic retinopathy is driven by oxidative stress-mitochondrial damage. Activation of ROS producing cytosolic NADPH oxidase 2 (Nox2) in diabetes precedes retinal mitochondrial damage, initiating a vicious cycle of free radicals. Elevated ROS levels peroxidize membrane lipids increasing damaging lipid peroxides (LPOs). While glutathione peroxidase 4 (GPx4) neutralizes LPOs, an imbalance in its generation-neutralization leads to ferroptosis, which is characterized by increased LPOs, free iron and decreased GPx4 activity. Mitochondria are rich in polyunsaturated fatty acids and iron and have mitochondrial isoform of GPx4. Our aim was to investigate mitochondrial ferroptosis in diabetic retinopathy, focusing on Nox2 mediated ROS production. Using human retinal endothelial cells, incubated in 5mM or 20mM D-glucose for 12 to 96 hours, with or without Nox2 inhibitors (100μM apocynin, 5μM EHop-016 or 5μM Gp91 ds-tat), or ferroptosis inhibitors (1μM ferrostatin-1, 50μM deferoxamine) or activator (0.1μM RSL3), cytosolic and mitochondrial ROS, LPOs, iron, GPx4 activity, mitochondrial integrity (membrane permeability, oxygen consumption rate, mtDNA copy numbers) and cell death were quantified. High glucose significantly increased ROS, LPOs and iron levels and inhibited GPx4 activity in cytosol, and while Nox2 and ferroptosis inhibitors prevented glucose-induced increase in ferroptosis markers, mitochondrial damage and cell death, RSL3, further worsened them. Furthermore, high glucose also increased ferroptosis markers in the mitochondria, which followed their increase in the cytosol, suggesting a role of cytosolic ROS in mitochondrial ferroptosis. Thus, targeting Nox2-ferroptosis should help break down the self-perpetuating vicious cycle of free radicals, initiated by the damaged mitochondria, and could provide novel therapeutics to prevent/retard the development of diabetic retinopathy.
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.10.296
  57. Food Chem. 2024 Oct 15. pii: S0308-8146(24)03297-7. [Epub ahead of print]464(Pt 1): 141647
    Insight into the oxidation mechanism of coconut globulin by atmospheric cold plasma focusing on side chain amino acids.
    Yang Chen, Tong Li, Tian Li, Yangchao Luo, Weimin Zhang.
      Atmospheric cold plasma (ACP), a novel non-thermal processing technology, generates active substances that stimulate protein oxidation in protein-based foods. Nevertheless, the precise mechanism through which ACP initiates amino acid oxidation on protein side chains remains ambiguous. This study primarily aimed to elucidate the mechanism of ACP-induced oxidation of coconut globulin, focusing on the process of amino acid oxidation. Analysis of protein oxidation products indicated a positive correlation between the extent of protein oxidation and the voltage and duration of ACP treatment. By analyzing the composition of amino acids and active ingredients, the study identified that the most significant changes amino acids were methionine, cysteine, and arginine, and •OH was the primary free radicals. The findings from oxidation kinetics and dynamic simulation indicated that •OH predominantly oxidized methionine, followed by L-cysteine and L-arginine. These results offer theoretical framework for understanding protein oxidation by ACP and suggest potential applications in protein-based food.
    Keywords:  Active species; Arginine; Cysteine; Free radical; Methionine
    DOI:  https://doi.org/10.1016/j.foodchem.2024.141647
  58. Mol Biol Rep. 2024 Oct 19. 51(1): 1071
    Differential expression of nuclear-derived mitochondrial succinate dehydrogenase genes in metabolically active buffalo tissues.
    E M Sadeesh, Anuj Malik, Madhuri S Lahamge, Pratiksha Singh.
       BACKGROUND: Buffaloes are crucial to agriculture, yet mitochondrial biology in these animals is less studied compared to humans and laboratory animals. This research examines tissue-specific variations in mitochondrial succinate dehydrogenase (SDH) gene expression across buffalo kidneys, hearts, brains, and ovaries. Understanding these variations sheds light on mitochondrial energy metabolism and its impact on buffalo health and productivity, revealing insights into enzyme regulation and potential improvements in livestock management.
    MATERIALS AND METHODS: RNA-seq data from buffalo kidney, heart, brain, and ovary tissues were reanalyzed to explore mitochondrial SDH gene expression. The expression of SDH subunits (SDHA, SDHB, SDHC, SDHD) and assembly factors (SDHAF1, SDHAF2, SDHAF3, SDHAF4) was assessed using a log2 fold-change threshold of + 1 for up-regulated and - 1 for down-regulated transcripts, with significance set at p < 0.05. Hierarchical clustering and differential expression analyses were performed to identify tissue-specific expression patterns and regulatory mechanisms, while Gene Ontology and KEGG pathway analyses were conducted to uncover functional attributes and pathway enrichments across different tissues.
    RESULTS: Reanalysis of RNA-seq data from different tissues of healthy female buffaloes revealed distinct expression patterns for SDH subunits and assembly factors. While SDHA, SDHB, and SDHC showed variable expression across tissues, SDHAF2, SDHAF3, and SDHAF4 exhibited tissue-specific profiles. Significant up-regulation of SDHA, SDHB, and several assembly factors was observed in specific tissue comparisons, with fewer down-regulated transcripts. Gene ontology and KEGG pathway analyses linked the up-regulated transcripts to mitochondrial ATP synthesis and the respiratory electron transport chain. Notably, tissue-specific variations in mitochondrial function were particularly evident in the ovary.
    CONCLUSION: This study identifies distinct SDH gene expression patterns in buffalo tissues, highlighting significant down-regulation of SDHA, SDHB, SDHC, and assembly factors in the ovary. These findings underscore the critical role of mitochondria in tissue-specific energy production and metabolic regulation, suggest potential metabolic adaptations, and emphasize the importance of mitochondrial complex II. The insights gained offer valuable implications for improving feed efficiency and guiding future research and therapies for energy metabolism disorders.
    Keywords:   SDH expression; Buffalo tissues; Energy production; Metabolic insights; Mitochondria
    DOI:  https://doi.org/10.1007/s11033-024-10022-9
  59. Diagnostics (Basel). 2024 Oct 10. pii: 2260. [Epub ahead of print]14(20):
    Sex Differences in Fat Distribution and Muscle Fat Infiltration in the Lower Extremity: A Retrospective Diverse-Ethnicity 7T MRI Study in a Research Institute Setting in the USA.
    Talon Johnson, Jianzhong Su, Johnathan Andres, Anke Henning, Jimin Ren.
      Background: Fat infiltration in skeletal muscle is related to declining muscle strength, whereas excess subcutaneous fat is implicated in the development of metabolic diseases. Methods: Using multi-slice axial T2-weighted (T2w) MR images, this retrospective study characterized muscle fat infiltration (MFI) and fat distribution in the lower extremity of 107 subjects (64M/43F, age 11-79 years) with diverse ethnicities (including White, Black, Latino, and Asian subjects). Results: MRI data analysis shows that MFI, evaluated by the relative intensities of the pixel histogram profile in the calf muscle, tends to increase with both age and BMI. However, statistical significance was found only for the age correlation in women (p < 0.002), and the BMI correlation in men (p = 0.04). Sex disparities were also seen in the fat distribution, which was assessed according to subcutaneous fat thickness (SFT) and the fibula bone marrow cross-sectional area (BMA). SFT tends to decrease with age in men (p < 0.01), whereas SFT tends to increase with BMI only in women (p < 0.01). In contrast, BMA tends to increase with age in women (p < 0.01) and with BMI in men (p = 0.04). Additionally, MFI is positively correlated with BMA but not with SFT, suggesting that compromised bone structure may contribute to fat infiltration in the surrounding skeletal muscle. Conclusions: The findings of this study highlight a sex factor affecting MFI and fat distribution, which may offer valuable insights into effective strategies to prevent and treat MFI in women versus men.
    Keywords:  MRI; aging; bone marrow; fat infiltration; obesity; skeletal muscle; subcutaneous fat
    DOI:  https://doi.org/10.3390/diagnostics14202260
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