bims-kimdis 2024-10-20 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2024–10–20
thirty-one papers selected by
Matías Javier Monsalves Álvarez, Universidad Andrés Bello

Effect of weight-maintaining ketogenic diet on glycemic control and insulin sensitivity in obese T2D subjects.
Investigating the impact of ketogenic diets.
An Exogenous Ketone Ester Slows Tumor Progression in Murine Breast and Renal Cancer Models.
Emerging Roles of Ketone Bodies in Cardiac Fibrosis.
Efficacy, Safety, and Tolerability of a Very Low-Calorie Ketogenic Diet in Women with Obesity and Symptomatic Knee Osteoarthritis: A Pilot Interventional Study.
Exogenous ketones exert antiseizure effects and modulate the gut microbiome and mycobiome in a clinically relevant murine model of epilepsy.
Acute Ketone Monoester Supplementation in Young Adults: Modulating Metabolic and Neurocognitive Functions Across Body Weights.
Short-term intermittent fasting and energy restriction do not impair rates of muscle protein synthesis: A randomised, controlled dietary intervention.
The NLRP3 inflammasome: Mechanisms of activation, regulation, and role in diseases.
Euglycemic diabetic ketoacidosis in a patient with new-onset type 1 diabetes following a ketogenic diet: a potential risk of a dangerous dietary trend.
Targeting ketone body metabolism to treat fatty liver disease.
Regulation of the NLRP3 inflammasome by autophagy and mitophagy.
Metabolic Effects of the SGLT2 Inhibitor Dapagliflozin in Heart Failure Across the Spectrum of Ejection Fraction.
Updated insights into the NLRP3 inflammasome in postoperative cognitive dysfunction: emerging mechanisms and treatments.
Monoamine oxidases: A missing link between mitochondria and inflammation in chronic diseases ?
Ketogenic β-hydroxybutyrate regulates β-hydroxybutyrylation of TCA cycle-associated enzymes and attenuates disease-associated pathologies in Alzheimer's mice.
The ketone body β-hydroxybutyrate ameliorates neurodevelopmental deficits in the GABAergic system of daf-18/PTEN Caenorhabditis elegans mutants.
Serum concentrations of lipids, ketones and acylcarnitines during the postprandial and fasting state: the Postprandial Metabolism (PoMet) study in healthy young adults.
MICU1 and MICU2, two peas in a pod or entirely different fruits?
Comparing the effects of time-restricted eating on glycaemic control in people with type 2 diabetes with standard dietetic practices: A randomised controlled trial.
Integrative study of skeletal muscle mitochondrial dysfunction in a murine pancreatic cancer-induced cachexia model.
Quantification of nutrient fluxes during acute exercise in mice.
Impacts of time-restricted feeding on middle-aged and old mice with obesity.
Analyzing Mitochondrial Calcium Influx in Isolated Mitochondria.
Direct mitochondrial import of lactate supports resilient carbohydrate oxidation.
Skeletal muscle fuel utilisation during exercise: A historical account of the Scandinavian involvement in the 'Zuntz-Chauveau controversy'.
Muscle Oxygen Dynamics Measured by NIRS.
MICUs protect the heart by regulating mitochondrial calcium.
SGLT2 inhibitors and NLRP3 inflammasome: potential target in diabetic kidney disease.
The Oldest of Old Male C57B/6J Mice Are Protected from Sarcopenic Obesity: The Possible Role of Skeletal Muscle Protein Kinase B Expression.
Late-onset primary muscle diseases mimicking sarcopenia.

BMJ Open Diabetes Res Care. 2024 Oct 18. pii: e004199. [Epub ahead of print]12(5):

Effect of weight-maintaining ketogenic diet on glycemic control and insulin sensitivity in obese T2D subjects.

Aurora Merovci, Brittany Finley, Andrea Hansis-Diarte, Sivaram Neppala, Muhammad A Abdul-Ghani, Eugenio Cersosimo, Curtis Triplitt, Ralph A DeFronzo.

   INTRODUCTION: Low carbohydrate ketogenic diets have received renewed interest for the treatment of obesity and type 2 diabetes. These diets promote weight loss, improve glycemic control, and reduce insulin resistance. However, whether the improvements in glycemic control and insulin sensitivity are secondary to the weight loss or result from a direct effect of hyperketonemia is controversial.
RESEARCH DESIGN AND METHODS: 29 overweight obese subjects were randomized to one of three dietary interventions for 10 days: (1) Weight-maintaining standard diet; (2) Weight-maintaining ketogenic diet; (3) Weight-maintaining ketogenic diet plus supplementation with the ketone ester of beta-hydroxybutyrate (β-OH-B), 8 g every 8 hours. At baseline, all subjects had oral glucose tolerance test, 2-step euglycemic insulin clamp (20 mU/m2.min and 60 mU/m2.min) with titrated glucose and indirect calorimetry.
RESULTS: Body weight, fat content, and per cent body fat (DEXA) remained constant over the 10-day dietary intervention period in all three groups. Plasma β-OH-B concentration increased twofold, while carbohydrate oxidation decreased, and lipid oxidation increased demonstrating the expected shifts in substrate metabolism with institution of the ketogenic diet. Glucose tolerance either decreased slightly or remained unchanged in the two ketogenic diet groups. Whole body (muscle), liver, and adipose tissue sensitivity to insulin remained unchanged in all 3 groups, as did the plasma lipid profile and blood pressure.
CONCLUSION: In the absence of weight loss, a low carbohydrate ketogenic diet has no beneficial effect on glucose tolerance, insulin sensitivity, or other metabolic parameters.

Keywords:  Diabetes Mellitus, Type 2; Diet; Ketones; Obesity

DOI:  https://doi.org/10.1136/bmjdrc-2024-004199
Elife. 2024 Oct 18. pii: e103140. [Epub ahead of print]13

Investigating the impact of ketogenic diets.

Nalia Samba, Marie Gendrel.

  Exposure to ketone bodies in early development can reduce neurological impairments in a strain of the nematode C. elegans with PTEN defects.

Keywords:  C. elegans; GABA; brain development; developmental biology; ketone bodies; neurodevelopment; neuroscience

DOI:  https://doi.org/10.7554/eLife.103140
Cancers (Basel). 2024 Oct 04. pii: 3390. [Epub ahead of print]16(19):

An Exogenous Ketone Ester Slows Tumor Progression in Murine Breast and Renal Cancer Models.

Henry Nnaemeka Ogbonna, Zachary Roberts, Nicholas Godwin, Pia Muri, William J Turbitt, Zoey N Swalley, Francesca R Dempsey, Holly R Stephens, Jianqing Zhang, Eric P Plaisance, Lyse A Norian.

   BACKGROUND/OBJECTIVES: Ketone esters (KEs) exhibit promise as anti-cancer agents but their impact on spontaneous metastases remains poorly understood. Although consumption of a ketogenic diet (KD) that is low in carbohydrates and high in fats can lead to KE production in vivo, the restrictive composition of KDs may diminish adherence in cancer patients.
METHODS: We investigated the effects of an exogenous ketone ester-supplemented (eKET), carbohydrate-replete diet on tumor growth, metastasis, and underlying mechanisms in orthotopic models of metastatic breast (4T1-Luc) and renal (Renca-Luc) carcinomas. Mice were randomized to diet after tumor challenge.
RESULTS: Administration of KEs did not alter tumor cell growth in vitro. However, in mice, our eKET diet increased circulating β-hydroxybutyrate and inhibited primary tumor growth and lung metastasis in both models. Body composition analysis illustrated the overall safety of eKET diet use, although it was associated with a loss of fat mass in mice with renal tumors. Immunogenetic profiling revealed divergent intratumoral eKET-related changes by tumor type. In mammary tumors, Wnt and TGFβ pathways were downregulated, whereas in renal tumors, genes related to hypoxia and DNA damage repair were downregulated.
CONCLUSIONS: Thus, our eKET diet exerts potent antitumor and antimetastatic effects in both breast and renal cancer models, albeit with different modes of action and physiologic effects. Its potential as an adjuvant dietary approach for patients with diverse cancer types should be explored further.

Keywords:  breast cancer; diet; ketone ester; kidney cancer

DOI:  https://doi.org/10.3390/cancers16193390
Am J Physiol Cell Physiol. 2024 Oct 14.

Emerging Roles of Ketone Bodies in Cardiac Fibrosis.

Kellina Maduray, Jingquan Zhong.

  Cardiac fibrosis, characterized by excessive extracellular matrix (ECM) deposition within the myocardium, poses a significant challenge in cardiovascular health, contributing to various cardiac pathologies. Ketone bodies (KBs), particularly β-hydroxybutyrate (β-OHB), have emerged as subjects of interest due to their potential cardioprotective effects. However, their specific influence on cardiac fibrosis remains underexplored. This literature review comprehensively examines the relationship between KBs and cardiac fibrosis, elucidating potential mechanisms through which KBs modulate fibrotic pathways. A multifaceted interplay exists between KBs and key mediators of cardiac fibrosis. While some studies indicate a pro-fibrotic role for KBs, others highlight their potential to attenuate fibrosis and cardiac remodeling. Mechanistically, KBs may regulate fibrotic pathways through modulation of cellular components such as cardiac fibroblasts, macrophages, and lymphocytes, as well as extracellular matrix proteins. Furthermore, the impact of KBs on cellular processes implicated in fibrosis, including oxidative stress, chemokine and cytokine expression, caspase activation, and inflammasome signaling are explored. While conflicting findings exist regarding the effects of KBs on these processes, emerging evidence suggests a predominantly beneficial role in mitigating inflammation and oxidative stress associated with fibrotic remodeling. Overall, this review underscores the importance of elucidating the complex interplay between KB metabolism and cardiac fibrosis. Insights gained have the potential to inform novel therapeutic strategies for managing cardiac fibrosis and associated cardiovascular disorders, highlighting the need for further research in this area.

Keywords:  Cardiac fibrosis; Ketogenic diet; Ketone; Ketone ester; β-hydroxybutyrate

DOI:  https://doi.org/10.1152/ajpcell.00241.2024
Nutrients. 2024 Sep 24. pii: 3236. [Epub ahead of print]16(19):

Efficacy, Safety, and Tolerability of a Very Low-Calorie Ketogenic Diet in Women with Obesity and Symptomatic Knee Osteoarthritis: A Pilot Interventional Study.

Jacopo Ciaffi, Luana Mancarella, Giulia Pederzani, Lucia Lisi, Veronica Brusi, Federica Pignatti, Susanna Ricci, Giorgia Vitali, Cesare Faldini, Francesco Ursini.

   BACKGROUND/OBJECTIVES: Obesity is a major risk factor for knee osteoarthritis (OA), and weight loss is crucial for its management. This pilot study explores the effects of a Very Low-Calorie Ketogenic Diet (VLCKD) in women with obesity and symptomatic knee OA.
METHODS: Women with symptomatic knee OA and obesity, defined as a body mass index (BMI) ≥ 30 kg/m2, were eligible for the VLCKD protocol. The intervention included a ketogenic phase from baseline (T0) to the 8th week (T8), followed by a progressive reintroduction of carbohydrates over the next 12 weeks, ending at the 20th week (T20). Body mass index (BMI), the Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index, the EuroQol 5D (EQ-5D), and the 36-item Short Form Health Survey (SF-36) were assessed at all time points. Generalized estimating equations were used to analyze the association between BMI and patient-reported outcomes across the study period.
RESULTS: Twenty participants started the study, but four discontinued the intervention, with two of these being due to adverse effects. The mean age of the 16 patients who completed the 20-week program was 57.3 ± 5.5 years, and their mean BMI was 40.0 ± 4.8 kg/m2. The mean BMI significantly decreased to 37.5 ± 4.5 at T4, 36.3 ± 4.6 at T8, and 34.8 ± 4.8 at T20 (all p < 0.001 compared to baseline). The total WOMAC score improved from a mean of 43.6 ± 16.9 at T0 to 30.2 ± 12.8 at T4 (p = 0.005) and further to 24.7 ± 10.6 at T8 (p = 0.001) and to 24.8 ± 15.9 at T20 (p = 0.005). The reduction in BMI was significantly correlated with the improvements in WOMAC, EQ-5D, and SF-36 over time. No major adverse effects were observed.
CONCLUSIONS: A 20-week VLCKD in women with obesity and knee OA significantly reduced their weight and improved their outcomes, warranting further research. This trial is registered with number NCT05848544 on ClinicalTrials.gov.

Keywords:  WOMAC; ketogenic diet; ketone bodies; knee; obesity; osteoarthritis; pain

DOI:  https://doi.org/10.3390/nu16193236
Epilepsia. 2024 Oct 16.

Exogenous ketones exert antiseizure effects and modulate the gut microbiome and mycobiome in a clinically relevant murine model of epilepsy.

Chunlong Mu, Mitchell Kesler, Xingyu Chen, Jane Shearer, G Campbell Teskey, Jong M Rho.

   OBJECTIVE: Despite growing interest in the potential use of exogenous ketones for the treatment of epilepsy, their impact on seizures and the gut microbiome and mycobiome remain unclear.
METHODS: Here, we examined the effects of both oral gavage and subcutaneous (SC) injection of a ketone ester (KE) in spontaneously epileptic Kcna1-null (KO) mice that model seminal aspects of human temporal lobe epilepsy. Electroencephalographic recordings and biochemical analyses were performed in KE-treated KO mice. Fecal microbial and fungal communities were profiled to determine whether the antiseizure activity of KE involves changes in the gut microbiome.
RESULTS: We found that exogenous KE administration by SC injection was more effective than oral gavage in terms of rendering antiseizure effects while generating similar degrees of ketonemia. However, reductions in mean daily seizure counts were accompanied by overall alterations in the fecal bacterial microbiome. Either oral or SC injection imposed a greater impact on the microbiome in male than female mice. In males, oral KE decreased Bacteroidota phylum and genera of Ligilactobacillus and Muribaculaceae, whereas SC injection decreased Bacteroides, Lactobacillus, and Lachnospiraceae. The fecal mycobiome was affected by KE injection to a greater degree than by oral gavage, and more in females than in males, as reflected by an increase in Ascomycota and Saccharomyces. Correlation analysis between microbiome and seizure counts revealed that in mice receiving KE injection, the seizure count was positively correlated with an amplicon sequencing variant of Lactobacillus (Spearman rho = .64, p = .03) and tended toward a negative correlation with Saccharomyces (Spearman rho = -.57, p = .057).
SIGNIFICANCE: Our findings demonstrate that exogenous ketone administration alone can induce antiseizure effects equally via different routes of administration, and that they induce differential shifts in both the bacterial microbiome and mycobiome.

Keywords:  epilepsy; ketogenic diet; ketone ester; microbiome; mycobiome

DOI:  https://doi.org/10.1111/epi.18150
Appl Physiol Nutr Metab. 2024 Oct 17.

Acute Ketone Monoester Supplementation in Young Adults: Modulating Metabolic and Neurocognitive Functions Across Body Weights.

Qian Yu, Ka Kit Wong, On Kei Lei, Paulo Armada-da-Silva, Zongze Wu, Jinlei Nie, Qingde Shi, Zhaowei Kong.

This study investigated the acute effects of ketone monoester on metabolic and neurocognitive indicators and underlying metabolism-brain-cognition interactions among young adults of healthy weight (HW) and those with overweight/obesity (OW). Forty participants were divided into two groups: HW (n = 20, age 23.80±3.96 years, body mass index [BMI] 21.49±1.80 kg/m²) and OW (n = 20, age 22.00±2.13 years, BMI 28.23±3.48 kg/m²). Each participant completed two trials (ketone monoester vs. placebo, 395 mg/kg dose) in a randomized order. Metabolic indicators (blood beta-hydroxybutyrate [BHB] and glucose) and neurocognitive function (causal density via functional near-infrared spectroscopy and cognitive interference via the Stroop task) were measured at baseline, 30 minutes, and 90 minutes post-supplementation. A chain mediation model was constructed to test the indirect effects of BHB level on cognitive interference through mediators like blood glucose and causal density. In the linear mixed models, significant effects were observed for trial (β = -0.92, 0.20, -0.04, 25.53) and assessment time (β = 0.50, -0.14, 0.09, -62.88) in BHB, glucose, causal density, and cognitive interference (p < 0.05), but not for group factors. Compared to OW, the effects of ketone monoester on prefrontal connectomes were more enduring in the HW (p < 0.05). Elevated BHB level improved cognitive function through decreasing glucose level and increasing causal density, with estimate of -0.63. Acute ketone monoester supplementation elevated levels of blood BHB and prefrontal connectomes and decreased levels of glucose and cognitive interference, regardless of weight status. Elevated blood BHB enhanced cognitive function through multi-tiered neurometabolic pathways.

DOI: https://doi.org/10.1139/apnm-2024-0229
Clin Nutr. 2024 Sep 26. pii: S0261-5614(24)00345-5. [Epub ahead of print]43(11): 174-184

Short-term intermittent fasting and energy restriction do not impair rates of muscle protein synthesis: A randomised, controlled dietary intervention.

Imre W K Kouw, Evelyn B Parr, Michael J Wheeler, Bridget E Radford, Rebecca C Hall, Joan M Senden, Joy P B Goessens, Luc J C van Loon, John A Hawley.

   BACKGROUND: Intermittent fasting (IF) is an effective energy restricted dietary strategy to reduce body and fat mass and improve metabolic health in individuals with either an overweight or obese status. However, dietary energy restriction may impair muscle protein synthesis (MPS) resulting in a concomitant decline in lean body mass. Due to periods of prolonged fasting combined with irregular meal intake, we hypothesised that IF would reduce rates of MPS compared to an energy balanced diet with regular meal patterns.
AIMS: We assessed the impact of a short-term, ten days, alternate day fasting or a continuous energy restricted diet to a control diet on integrated rates of skeletal MPS in middle-aged males with overweight or obesity.
METHODS: Twenty-seven middle-aged males with overweight or obesity (age: 44.6 ± 5.4 y; BMI: 30.3 ± 2.6 kg/m2) consumed a three-day lead-in diet, followed by a ten-day controlled dietary intervention matched for protein intake, as alternate day fasting (ADF: 62.5 energy (En)%, days of 25 En% alternated with days of 100 En% food ingestion), continuous energy restriction (CER: 62.5 En%), or an energy balanced, control diet (CON: 100 En%). Deuterated water (D2O) methodology with saliva, blood, and skeletal muscle sampling were used to assess integrated rates of MPS over the ten-day intervention period. Secondary measures included fasting plasma glucose, insulin, and gastrointestinal hormone concentrations, continuous glucose monitoring, and assessment of body composition.
RESULTS: There were no differences in daily rates of MPS between groups (ADF: 1.18 ± 0.13, CER: 1.13 ± 0.16, and CON: 1.18 ± 0.18 %/day, P > 0.05). The reductions in body mass were greater in ADF and CER compared to CON (P < 0.001). Lean and fat mass were decreased by a similar magnitude across groups (main time effect, P < 0.001; main group effect, P > 0.05). Fasting plasma leptin concentrations decreased in ADF and CER (P < 0.001), with no differences in fasting plasma glucose or insulin concentrations between groups.
CONCLUSION: Short-term alternate day fasting does not lower rates of MPS compared to continuous energy restriction or an energy balanced, control diet with matched protein intake. The prolonged effects of IF and periods of irregular energy and protein intake patterns on muscle mass maintenance remain to be investigated. This trial was registered under Australian New Zealand Clinical Trial Registry (https://www.anzctr.org.au), identifier no. ACTRN12619000757112.

Keywords:  Chrono-nutrition; Dietary protein; Energy restriction; Intermittent fasting; Muscle mass; Muscle protein synthesis

DOI:  https://doi.org/10.1016/j.clnu.2024.09.034
Int Rev Immunol. 2024 Oct 14. 1-14

The NLRP3 inflammasome: Mechanisms of activation, regulation, and role in diseases.

Mina Dadkhah, Mohammadreza Sharifi.

  Because of numerous stress signals, intracellular protein complexes are called inflammasomes. They function as catalysts for the proteolytic transformation of pro-interleukin into the active form of interleukin. Inflammasomes can promote a type of cell death process known as pyroptosis. The NLRP3 inflammasome, comprised of the NLRP3 protein, procaspase-1, and ASC, tightly regulates inflammation. The NLRP3 inflammasome is activated by a variety of stimuli, and several molecular and cellular events, such as ion influx, mitochondrial dysfunction, reactive oxygen species production, and lysosomal damage have been shown to trigger its activation. Inflammation plays a major role in almost all types of human diseases. The NLRP3 inflammasome has been the most widely studied and plays an important pathogenic role in various inflammatory pathologies. This review briefly presents the basic features of NLRP3 inflammasome and their mechanisms of activation and regulation. In addition, recent studies report the role of NLRP3 inflammasome in several diseases have been summarized.

Keywords:  Immune regulators; NLRP3; inflammasome; inflammation; inflammatory diseases

DOI:  https://doi.org/10.1080/08830185.2024.2415688
Arch Endocrinol Metab. 2024 ;68 e230229

Euglycemic diabetic ketoacidosis in a patient with new-onset type 1 diabetes following a ketogenic diet: a potential risk of a dangerous dietary trend.

Burcak Cavnar Helvaci, Beril Turan Erdogan, Didem Ozdemir, Oya Topaloglu, Bekir Cakir.

Euglycemic diabetic ketoacidosis (DKA) is a rare complication of diabetes mellitus (DM) characterized by metabolic acidosis, ketosis, and blood glucose levels < 250 mg/dL. The prevalence of euglycemic DKA is increasing with the popularity of ketogenic (low-carbohydrate) diets. We present herein the case of a patient with newly diagnosed type 1 DM who developed euglycemic DKA following a ketogenic diet. A 22-year-old woman presented to the emergency department with malaise, fatigue, nausea, and vomiting. She had no family history of DM. She had consulted her primary care physician 2 weeks before due to hair loss, numbness, and tingling sensation in her fingertips. Her fasting blood glucose was 205 mg/dL at that time. Reluctant to use medication to control her blood glucose levels, she started a ketogenic diet. On admission, she was conscious, oriented, cooperative, and tachycardic. Her body mass index was 17.6 kg/m2. Laboratory tests showed fasting blood glucose of 86 mg/dL, glycated hemoglobin of 10.3%, and elevated insulin levels. Ketone levels in urine and blood were high, indicating ketosis. High anion-gap metabolic acidosis was detected, with a pH of 7.10 and serum bicarbonate level of 12 mEq/L. A diagnosis of new-onset DM and euglycemic DKA was established. She was treated with a modified DKA protocol that included intravenous dextrose-containing serum as fluid therapy, and intravenous insulin infusion was delayed until blood glucose levels increased above 250 mg/dL. The development of euglycemic DKA in our patient was attributed to severe carbohydrate restriction. This case underscores the importance of considering dietary risk factors, particularly ketogenic diets, in the management of DM.

DOI: https://doi.org/10.20945/2359-4292-2023-0229
J Pharm Pharm Sci. 2024 ;27 13375

Targeting ketone body metabolism to treat fatty liver disease.

Sora Kwon, Reshani Jeyaratnam, Kyoung-Han Kim.

  Metabolic dysfunction-associated steatotic liver disease (MASLD) is a metabolic disorder marked by excessive accumulation of lipids within the liver. If untreated, this condition can progress to metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, cirrhosis, and ultimately, hepatocellular carcinoma (HCC). Given the liver's pivotal role in glucose and fatty acid metabolism, disruptions in these processes are commonly observed in MASLD. Ketone bodies, crucial energy metabolites primarily produced in the liver, are also closely related to the progression of MASLD. Recent studies have demonstrated that disrupted ketogenesis not only accompanies MASLD, but may also play a causal role in its development and progression. Moreover, activation of the ketogenic pathway has been suggested as a promising strategy for reducing excessive hepatic fat accumulation. This review focuses on the regulation of ketogenesis in MASLD, emphasizing the significance of dietary and pharmacological interventions as potential therapeutic approaches to treat fatty liver disease.

Keywords:  MASLD; dietary interventions; ketogenesis; ketone bodies; pharmacological interventions

DOI:  https://doi.org/10.3389/jpps.2024.13375
Immunol Rev. 2024 Oct 17.

Regulation of the NLRP3 inflammasome by autophagy and mitophagy.

Suman Gupta, Suzanne L Cassel, Fayyaz S Sutterwala, Jargalsaikhan Dagvadorj.

  The NLRP3 inflammasome is a multiprotein complex that upon activation by the innate immune system drives a broad inflammatory response. The primary initial mediators of this response are pro-IL-1β and pro-IL-18, both of which are in an inactive form. Formation and activation of the NLRP3 inflammasome activates caspase-1, which cleaves pro-IL-1β and pro-IL-18 and triggers the formation of gasdermin D pores. Gasdermin D pores allow for the secretion of active IL-1β and IL-18 initiating the organism-wide inflammatory response. The NLRP3 inflammasome response can be beneficial to the host; however, if the NLRP3 inflammasome is inappropriately activated it can lead to significant pathology. While the primary components of the NLRP3 inflammasome are known, the precise details of assembly and activation are less well defined and conflicting. Here, we discuss several of the proposed pathways of activation of the NLRP3 inflammasome. We examine the role of subcellular localization and the reciprocal regulation of the NLRP3 inflammasome by autophagy. We focus on the roles of mitochondria and mitophagy in activating and regulating the NLRP3 inflammasome. Finally, we detail the impact of pathologic NLRP3 responses in the development and manifestations of pulmonary disease.

Keywords:  NLRP3; caspase‐1; inflammasome; lung injury; mitochondria

DOI:  https://doi.org/10.1111/imr.13410
Circ Heart Fail. 2024 Oct 18. e011980

Metabolic Effects of the SGLT2 Inhibitor Dapagliflozin in Heart Failure Across the Spectrum of Ejection Fraction.

Senthil Selvaraj, Shachi Patel, Andrew J Sauer, Robert W McGarrah, Philip Jones, Lydia Coulter Kwee, Sheryl L Windsor, Olga Ilkayeva, Michael J Muehlbauer, Christopher B Newgard, Barry A Borlaug, Dalane W Kitzman, Sanjiv J Shah, Kenneth B Margulies, Mansoor Husain, Silvio E Inzucchi, Darren K McGuire, David E Lanfear, Ali Javaheri, Guillermo Umpierrez, Robert J Mentz, Kavita Sharma, Mikhail N Kosiborod, Svati H Shah.

   BACKGROUND: Mechanisms of benefit with SGLT2is (sodium-glucose cotransporter-2 inhibitors) in heart failure (HF) remain incompletely characterized. Dapagliflozin alters ketone and fatty acid metabolism in HF with reduced ejection fraction though similar effects have not been observed in HF with preserved ejection fraction. We explore whether metabolic effects of SGLT2is vary across the left ventricular ejection fraction spectrum and their relationship with cardiometabolic end points in 2 randomized trials of dapagliflozin in HF.
METHODS: Metabolomic profiling of 61 metabolites was performed in 527 participants from DEFINE-HF (Dapagliflozin Effects on Biomarkers, Symptoms and Functional Status in Patients With HF With Reduced Ejection Fraction) and PRESERVED-HF (Dapagliflozin in PRESERVED Ejection Fraction HF; 12-week, placebo-controlled trials of dapagliflozin in HF with reduced ejection fraction and HF with preserved ejection fraction, respectively). Linear regression was used to assess changes in principal components analysis-defined metabolite factors with treatment from baseline to 12 weeks, as well as the relationship between changes in metabolite clusters and HF-related end points.
RESULTS: The mean age was 66±11 years, 43% were female, and 33% were self-identified as Black. Two principal components analysis-derived metabolite factors (which were comprised of ketone and short-/medium-chain acylcarnitines) increased with dapagliflozin compared with placebo. Ketosis (defined as 3-hydroxybutyrate >500 μM) was achieved in 4.5% with dapagliflozin versus 1.2% with placebo (P=0.03). There were no appreciable treatment effects on amino acids, including branched-chain amino acids. Increases in several acylcarnitines were consistent across LVEF (Pinteraction>0.10), whereas the ketogenic effect diminished at higher LVEF (Pinteraction=0.01 for 3-hydroxybutyrate). Increases in metabolites reflecting mitochondrial dysfunction (particularly long-chain acylcarnitines) and aromatic amino acids and decreases in branched-chain amino acids were associated with worse HF-related outcomes in the overall cohort, with consistency across treatment and LVEF.
CONCLUSIONS: SGLT2is demonstrate common (fatty acid) and distinct (ketogenic) metabolic signatures across the LVEF spectrum. Changes in key pathways related to fatty acid and amino acid metabolism are associated with HF-related end points and may serve as therapeutic targets across HF subtypes.
REGISTRATION: URL: https://www.clinicaltrials.gov; Unique Identifiers: NCT03030235 and NCT02653482.

Keywords:  fatty acid; heart failure; ketone bodies; metabolomics; quality of life

DOI:  https://doi.org/10.1161/CIRCHEARTFAILURE.124.011980
Front Aging Neurosci. 2024 ;16 1480502

Updated insights into the NLRP3 inflammasome in postoperative cognitive dysfunction: emerging mechanisms and treatments.

Tian Wang, Guangwei Sun, Bingdong Tao.

  Postoperative cognitive dysfunction (POCD) poses a significant threat to patients undergoing anesthesia and surgery, particularly elderly patients. It is characterized by diminished cognitive functions post surgery, such as impaired memory and decreased concentration. The potential risk factors for POCD include age, surgical trauma, anesthetic type, and overall health condition; however, the precise mechanisms underlying POCD remain elusive. Recent studies suggest that neuroinflammation might be a primary pathogenic factor. NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasomes are implicated in exacerbating POCD by promoting the release of inflammatory factors and proteins that initiate pyroptosis, further influencing the disease process. The regulation of NLRP3 inflammasome activity, including its activation and degradation, is tightly controlled through multiple pathways and mechanisms. In addition, autophagy, a protective mechanism, regulates the NLRP3 inflammasome to control the progression of POCD. This review reviews recent findings on the role of the NLRP3 inflammasome in POCD pathogenesis and discusses therapeutic strategies aimed at reducing NLRP3 sources, inhibiting cellular pyroptosis, and enhancing autophagy.

Keywords:  NLRP3; POCD; autophagy; autophagy POCD; inflammasomes; neuroinflammation; pyroptosis

DOI:  https://doi.org/10.3389/fnagi.2024.1480502
Redox Biol. 2024 Oct 11. pii: S2213-2317(24)00371-9. [Epub ahead of print]77 103393

Monoamine oxidases: A missing link between mitochondria and inflammation in chronic diseases ?

Lise Beucher, Claudie Gabillard-Lefort, Olivier R Baris, Jeanne Mialet-Perez.

  The role of mitochondria spans from the regulation of the oxidative phosphorylation, cell metabolism and survival/death pathways to a more recently identified function in chronic inflammation. In stress situations, mitochondria release some pro-inflammatory mediators such as ATP, cardiolipin, reactive oxygen species (ROS) or mitochondrial DNA, that are believed to participate in chronic diseases and aging. These mitochondrial Damage-Associated Molecular Patterns (mito-DAMPs) can modulate specific receptors among which TLR9, NLRP3 and cGAS-STING, triggering immune cells activation and sterile inflammation. In order to counter the development of chronic diseases, a better understanding of the underlying mechanisms of low grade inflammation induced by mito-DAMPs is needed. In this context, monoamine oxidases (MAO), the mitochondrial enzymes that degrade catecholamines and serotonin, have recently emerged as potent regulators of chronic inflammation in obesity-related disorders, cardiac diseases, cancer, rheumatoid arthritis and pulmonary diseases. The role of these enzymes in inflammation embraces their action in both immune and non-immune cells, where they regulate monoamines levels and generate toxic ROS and aldehydes, as by-products of enzymatic reaction. Here, we discuss the more recent advances on the role and mechanisms of action of MAOs in chronic inflammatory diseases.

Keywords:  Chronic diseases; DAMPs; Inflammation; Mitochondria; Monoamine oxidases; Oxidative stress

DOI:  https://doi.org/10.1016/j.redox.2024.103393
Aging Cell. 2024 Oct 16. e14368

Ketogenic β-hydroxybutyrate regulates β-hydroxybutyrylation of TCA cycle-associated enzymes and attenuates disease-associated pathologies in Alzheimer's mice.

Wanhong Han, Bingchang Zhang, Wenpeng Zhao, Wentao Zhao, Jiawei He, Xiansheng Qiu, Liang Zhang, Xiuyan Wang, Yong Wang, Hanwen Lu, Yaya Zhang, Yuanyuan Xie, Yanyan Geng, Wujie Zhao, Qionghui Huang, Yun-Wu Zhang, Zhanxiang Wang.

  Lysine β-hydroxybutyrylation (Kbhb) is a post-translational modification that has recently been found to regulate protein functions. However, whether and how protein Kbhb modification participates in Alzheimer's disease (AD) remains unknown. Herein, we carried out 4D label-free β-hydroxybutylation quantitative proteomics using brain samples of 8-month-old and 2-month-old APP/PS1 AD model mice and wild-type (WT) controls. We identified a series of tricarboxylic acid (TCA) cycle-associated enzymes including citrate synthase (CS) and succinate-CoA ligase subunit alpha (SUCLG1), whose Kbhb modifications were decreased in APP/PS1 mice at pathological stages. Sodium β-hydroxybutyrate (Na-β-OHB) treatment markedly increased Kbhb modifications of CS and SUCLG1 and their enzymatic activities, leading to elevated ATP production. We further found that Kbhb modifications at lysine 393 site in CS and at lysine 81 site in SUCLG1 were crucial for their enzymatic activities. Finally, we found that β-OHB levels were decreased in the brain of APP/PS1 mice at pathological stages. While ketogenic diet not only significantly increased β-OHB levels, Kbhb modifications and enzymatic activities of CS and SUCLG1, and ATP production, but also dramatically attenuated β-amyloid plaque pathologies and microgliosis in APP/PS1 mice. Together, our findings indicate the importance of protein Kbhb modification for maintaining normal TCA cycle and ATP production and provide a novel molecular mechanism underlying the beneficial effects of ketogenic diet on energy metabolism and AD intervention.

Keywords:  Alzheimer's disease; TCA cycle; citrate synthase; ketogenic diet; succinate‐CoA ligase subunit alpha; β‐Hydroxybutyrylation

DOI:  https://doi.org/10.1111/acel.14368
Elife. 2024 Oct 18. pii: RP94520. [Epub ahead of print]13

The ketone body β-hydroxybutyrate ameliorates neurodevelopmental deficits in the GABAergic system of daf-18/PTEN Caenorhabditis elegans mutants.

Sebastián Giunti, María Gabriela Blanco, María José De Rosa, Diego Rayes.

  A finely tuned balance between excitation and inhibition (E/I) is essential for proper brain function. Disruptions in the GABAergic system, which alter this equilibrium, are a common feature in various types of neurological disorders, including autism spectrum disorders (ASDs). Mutations in Phosphatase and Tensin Homolog (PTEN), the main negative regulator of the phosphatidylinositol 3-phosphate kinase/Akt pathway, are strongly associated with ASD. However, it is unclear whether PTEN deficiencies can differentially affect inhibitory and excitatory signaling. Using the Caenorhabditis elegans neuromuscular system, where both excitatory (cholinergic) and inhibitory (GABAergic) inputs regulate muscle activity, we found that daf-18/PTEN mutations impact GABAergic (but not cholinergic) neurodevelopment and function. This selective impact results in a deficiency in inhibitory signaling. The defects observed in the GABAergic system in daf-18/PTEN mutants are due to reduced activity of DAF-16/FOXO during development. Ketogenic diets (KGDs) have proven effective for disorders associated with E/I imbalances. However, the mechanisms underlying their action remain largely elusive. We found that a diet enriched with the ketone body β-hydroxybutyrate during early development induces DAF-16/FOXO activity, therefore improving GABAergic neurodevelopment and function in daf-18/PTEN mutants. Our study provides valuable insights into the link between PTEN mutations and neurodevelopmental defects and delves into the mechanisms underlying the potential therapeutic effects of KGDs.

Keywords:  C. elegans; GABA; developmental biology; excitation/inhibition balance; ketone bodies; neurodevelopment; neuroscience

DOI:  https://doi.org/10.7554/eLife.94520
Br J Nutr. 2024 Oct 18. 1-11

Serum concentrations of lipids, ketones and acylcarnitines during the postprandial and fasting state: the Postprandial Metabolism (PoMet) study in healthy young adults.

Åslaug Matre Anfinsen, Vilde Haugen Myklebust, Christina Osland Johannesen, Jacob Juel Christensen, Johnny Laupsa-Borge, Jutta Dierkes, Ottar Nygård, Adrian McCann, Hanne Rosendahl-Riise, Vegard Lysne.

  To improve the interpretation and utilisation of blood lipids, ketones and acylcarnitine concentrations as biomarkers in clinical assessments, more information is needed on their dynamic alterations in response to dietary intake and fasting. The aim of this intervention study was to characterise the changes in serum lipid, ketone and acylcarnitine concentrations 24 h after a standardised breakfast meal. Thirty-four healthy subjects (eighteen males and sixteen females) aged 20-30 years were served a breakfast meal (∼500 kcal, 36 E% fat, 46 E% carbohydrates, 16 E% protein, 2E% fibre), after which they consumed only water for 24 h. Blood samples were drawn before and at thirteen standardised timepoints after the meal. Metabolite concentrations were plotted as a function of time since the completion of the breakfast meal. Results demonstrated that concentrations of HDL-cholesterol and LDL-cholesterol decreased until ∼2 h (-4 % for both), while TAG concentrations peaked at 3 h (+27 %). Acetoacetate and β-hydroxybutyrate were highest 24 h after the meal (+433 and +633 %, respectively). Acetylcarnitine, butyrylcarnitine, hexanoylcarnitine, octanoylcarnitine, decanoylcarnitine and dodecanoylcarnitine reached the lowest values at 60 min (decreases ranging from -47 to -70 %), before increasing and peaking at 24 h after the meal (increases ranging from +86 to +120 %). Our findings suggest that distinguishing between fasting and non-fasting blood samples falls short of capturing the dynamics in lipid, ketone, carnitine and acylcarnitine concentrations. To enhance the utility of serum acylcarnitine analyses, we strongly recommend accounting for the specific time since the last meal at the time of blood sampling.

Keywords:  Acylcarnitines; Biomarkers; Carnitine; Epidemiology; Fasting; Metabolism; Metabolites; Metabolomics; Postprandial response

DOI:  https://doi.org/10.1017/S0007114524001934
Cell Calcium. 2024 Oct 08. pii: S0143-4160(24)00117-9. [Epub ahead of print]124 102959

MICU1 and MICU2, two peas in a pod or entirely different fruits?

Jiuzhou Huo, Jeffery D Molkentin.

Fluctuations in mitochondrial matrix Ca2+ plays a critical role in matching energy production to cellular demand through direct effects on oxidative phosphorylation and ATP production. Disruption in mitochondrial Ca2+ homeostasis, particularly under pathological conditions such as ischemia or heart failure, can lead to mitochondrial dysfunction, energy deficit, and eventually death of cardiomyocytes. The primary channel regulating acute mitochondrial Ca2+ influx is the mitochondrial Ca2+ uniporter (mtCU), which is regulated by the mitochondrial Ca2+ uptake (MICU) proteins that were examined here.

DOI: https://doi.org/10.1016/j.ceca.2024.102959
Diabetes Res Clin Pract. 2024 Oct 14. pii: S0168-8227(24)00803-9. [Epub ahead of print] 111893

Comparing the effects of time-restricted eating on glycaemic control in people with type 2 diabetes with standard dietetic practices: A randomised controlled trial.

Evelyn B Parr, Bridget E Radford, Rebecca C Hall, Nikolai Steventon-Lorenzen, Steve A Flint, Zoe Siviour, Connie Plessas, Shona L Halson, Leah Brennan, Imre W K Kouw, Rich D Johnston, Brooke L Devlin, John A Hawley.

   AIMS: To test the efficacy of time-restricted eating (TRE) in comparison to dietitian-led individualised dietary guidance to improve HbA1c in people with Type 2 diabetes mellitus.
METHODS: In a parallel groups design, 51 adults (35-65 y) with Type 2 diabetes mellitus and overweight/obesity (HbA1c ≥6.5 % (48 mmol/mol), BMI ≥25-≤40 kg/m2) commenced a six-month intervention. Following baseline, participants were randomised to TRE (1000-1900 h) or DIET (individualised dietetic guidance) with four consultations over four months. Changes in HbA1c (primary), body composition, and self-reported adherence (secondary) were analysed using linear mixed models. A non-inferiority margin of 0.3 % (4 mmol/mol) HbA1c was set a priori.
RESULTS: Forty-three participants (56 ± 8 y, BMI: 33 ± 5 kg/m2, HbA1c: 7.6 ± 0.8 %) completed the intervention. HbA1c was reduced (P = 0.002; TRE: -0.4 % (-5 mmol/mol), DIET: -0.3 % (-4 mmol/mol)) with no group or interaction effects; TRE was non-inferior to DIET (-0.11 %, 95 %CI: -0.50 % to 0.28 %). Body mass reduced in both groups (TRE: -1.7 kg; DIET: -1.2 kg) via ∼900 kJ/d spontaneous energy reduction (P < 0.001). Self-reported adherence was higher in TRE versus DIET (P < 0.001).
CONCLUSIONS: When individualised dietary guidance is not available, effective, and/or suitable, TRE may be an alternative dietary strategy to improve glycaemic control in people with Type 2 diabetes mellitus.

Keywords:  Blood glucose; Chrono-nutrition; Continuous glucose monitoring; Dietitian; Eating window; HbA1c

DOI:  https://doi.org/10.1016/j.diabres.2024.111893
Elife. 2024 Oct 18. pii: RP93312. [Epub ahead of print]13

Integrative study of skeletal muscle mitochondrial dysfunction in a murine pancreatic cancer-induced cachexia model.

Tristan Gicquel, Fabio Marchiano, Gabriela Reyes-Castellanos, Stephane Audebert, Luc Camoin, Bianca H Habermann, Benoit Giannesini, Alice Carrier.

  Pancreatic ductal adenocarcinoma (PDAC), the most common pancreatic cancer, is a deadly cancer, often diagnosed late and resistant to current therapies. PDAC patients are frequently affected by cachexia characterized by muscle mass and strength loss (sarcopenia) contributing to patient frailty and poor therapeutic response. This study assesses the mechanisms underlying mitochondrial remodeling in the cachectic skeletal muscle, through an integrative exploration combining functional, morphological, and omics-based evaluation of gastrocnemius muscle from KIC genetically engineered mice developing autochthonous pancreatic tumor and cachexia. Cachectic PDAC KIC mice exhibit severe sarcopenia with loss of muscle mass and strength associated with reduced muscle fiber's size and induction of protein degradation processes. Mitochondria in PDAC atrophied muscles show reduced respiratory capacities and structural alterations, associated with deregulation of oxidative phosphorylation and mitochondrial dynamics pathways. Beyond the metabolic pathways known to be altered in sarcopenic muscle (carbohydrates, proteins, and redox), lipid and nucleic acid metabolisms are also affected. Although the number of mitochondria per cell is not altered, mitochondrial mass shows a twofold decrease and the mitochondrial DNA threefold, suggesting a defect in mitochondrial genome homeostasis. In conclusion, this work provides a framework to guide toward the most relevant targets in the clinic to limit PDAC-induced cachexia.

Keywords:  cachexia; cancer biology; energy metabolism; mitochondria; mouse; muscle wasting; pancreatic cancer

DOI:  https://doi.org/10.7554/eLife.93312
Cell Metab. 2024 Oct 11. pii: S1550-4131(24)00374-7. [Epub ahead of print]

Quantification of nutrient fluxes during acute exercise in mice.

Jessie Axsom, Tara TeSlaa, Won Dong Lee, Qingwei Chu, Alexis Cowan, Marc R Bornstein, Michael D Neinast, Caroline R Bartman, Megan C Blair, Kristina Li, Chelsea Thorsheim, Joshua D Rabinowitz, Zoltan Arany.

  Despite the known metabolic benefits of exercise, an integrated metabolic understanding of exercise is lacking. Here, we use in vivo steady-state isotope-labeled infusions to quantify fuel flux and oxidation during exercise in fasted, fed, and exhausted female mice, revealing several novel findings. Exercise strongly promoted glucose fluxes from liver glycogen, lactate, and glycerol, distinct from humans. Several organs spared glucose, a process that broke down in exhausted mice despite concomitant hypoglycemia. Proteolysis increased markedly, also divergent from humans. Fatty acid oxidation dominated during fasted exercise. Ketone production and oxidation rose rapidly, seemingly driven by a hepatic bottleneck caused by gluconeogenesis-induced cataplerotic stress. Altered fuel consumption was observed in organs not directly involved in muscle contraction, including the pancreas and brown fat. Several futile cycles surprisingly persisted during exercise, despite their energy cost. In sum, we provide a comprehensive, integrated, holistic, and quantitative accounting of metabolism during exercise in an intact organism.

Keywords:  TCA cycle; circulating metabolites; energy metabolism; exercise; in vivo flux quantification; isotope tracing; skeletal muscle

DOI:  https://doi.org/10.1016/j.cmet.2024.09.010
J Physiol. 2024 Oct 15.

Impacts of time-restricted feeding on middle-aged and old mice with obesity.

Yueze Yang, Dexi Liu.

  Time-restricted feeding is known to ameliorate obesity in young mice. However, evaluation of its effect in old age is still lacking. The current work aims to investigate the effects of time-restricted feeding on treating pre-existing obesity in old animals. The study utilized middle-aged and old high fat diet-induced obese mice and subjected them to 8 h daily time-restricted feeding. Aged obese mice did not lose fat mass but lost lean mass after 8 weeks of treatment. In addition, time-restricted feeding reduced adiposity in brown adipose tissue, reversed excessive hepatic lipid accumulation, and improved glucose homeostasis in middle-aged and old obese mice. Mechanistic studies show that these metabolic benefits were mediated by transcriptional downregulation of essential genes responsible for hepatic adipogenesis and adipose tissue chronic inflammation. These results demonstrate that time-restricted feeding improves metabolic health and has beneficial effects in combating diet-induced obesity in aged obese mice. KEY POINTS: Contrary to in young obese mice, in old obese mice time-restricted feeding did not significantly reduce body fat but decreased lean mass. Time-restricted feeding reduced adipose tissue inflammation, reversed fatty liver, and improved glucose homeostasis in aged mice with diet-induced obesity. Time-restricted feeding is effective in improving metabolic homeostasis in aged mice, but less effective in terms of reducing obesity. Future studies should investigate the underlying mechanism of how ageing impaired intermittent fasting induced fat loss.

Keywords:  ageing; fatty liver; insulin resistance; intermittent fasting; obesity; time‐restricted feeding

DOI:  https://doi.org/10.1113/JP285462
Methods Mol Biol. 2025 ;2861 155-164

Analyzing Mitochondrial Calcium Influx in Isolated Mitochondria.

Nasab Ghazal, Jennifer Q Kwong.

  Mitochondria play a crucial role in Ca2+ signaling and homeostasis and can contribute to shaping the cytosolic Ca2+ landscape as well as regulate a variety of pathways including energy production and cell death. Dysregulation of mitochondrial Ca2+ homeostasis promotes pathologies including neurodegenerative diseases, cardiovascular disorders, and metabolic syndromes. The significance of mitochondria to Ca2+ signaling and regulation underscores the value of methods to assess mitochondrial Ca2+ import. Here we present a plate reader-based method using the Ca2+-sensitive fluorescent probe calcium green-5 N to measure mitochondrial Ca2+ import in isolated cardiac mitochondria. This technique can be expanded to measure Ca2+ uptake in mitochondria isolated from other tissue types and from cultured cells.

Keywords:  Calcium; Heart; Mitochondria; Mitochondrial permeability transition pore; Signaling; Uniporter

DOI:  https://doi.org/10.1007/978-1-0716-4164-4_12
bioRxiv. 2024 Oct 08. pii: 2024.10.07.617073. [Epub ahead of print]

Direct mitochondrial import of lactate supports resilient carbohydrate oxidation.

Ahmad A Cluntun, Joseph R Visker, Jesse N Velasco-Silva, Marisa J Lang, Luis Cedeño-Rosario, Thirupura S Shankar, Rana Hamouche, Jing Ling, Ji Eon Kim, Ashish G Toshniwal, Hayden K Low, Corey N Cunningham, James Carrington, Jonathan Leon Catrow, Quentinn Pearce, Mi-Young Jeong, Alex J Bott, Álvaro J Narbona-Pérez, Claire E Stanley, Qing Li, David R Eberhardt, Jeffrey T Morgan, Tarun Yadav, Chloe E Wells, Dinesh K A Ramadurai, Wojciech I Swiatek, Dipayan Chaudhuri, Jeffery D Rothstein, Deborah M Muoio, Joao A Paulo, Steven P Gygi, Steven A Baker, Sutip Navankasattusas, James E Cox, Katsuhiko Funai, Stavros G Drakos, Jared Rutter, Gregory S Ducker.

Lactate is the highest turnover circulating metabolite in mammals. While traditionally viewed as a waste product, lactate is an important energy source for many organs, but first must be oxidized to pyruvate for entry into the tricarboxylic acid cycle (TCA cycle). This reaction is thought to occur in the cytosol, with pyruvate subsequently transported into mitochondria via the mitochondrial pyruvate carrier (MPC). Using 13 C stable isotope tracing, we demonstrated that lactate is oxidized in the myocardial tissue of mice even when the MPC is genetically deleted. This MPC-independent lactate import and mitochondrial oxidation is dependent upon the monocarboxylate transporter 1 (MCT1/ Slc16a1 ). Mitochondria isolated from the myocardium without MCT1 exhibit a specific defect in mitochondrial lactate, but not pyruvate, metabolism. The import and subsequent mitochondrial oxidation of lactate by mitochondrial lactate dehydrogenase (LDH) acts as an electron shuttle, generating sufficient NADH to support respiration even when the TCA cycle is disrupted. In response to diverse cardiac insults, animals with hearts lacking MCT1 undergo rapid progression to heart failure with reduced ejection fraction. Thus, the mitochondrial import and oxidation of lactate enables carbohydrate entry into the TCA cycle to sustain cardiac energetics and maintain myocardial structure and function under stress conditions.

DOI: https://doi.org/10.1101/2024.10.07.617073
Exp Physiol. 2024 Oct 18.

Skeletal muscle fuel utilisation during exercise: A historical account of the Scandinavian involvement in the 'Zuntz-Chauveau controversy'.

Ronan M G Berg.

DOI: https://doi.org/10.1113/EP092156
Adv Exp Med Biol. 2024 ;1463 347-351

Muscle Oxygen Dynamics Measured by NIRS.

Ryotaro Kime, Tasuki Endo, Shun Takagi, Takafumi Hamaoka.

  Near-infrared spectroscopy (NIRS) has been used to measure skeletal muscle oxidative function for more than 30 years. Several indicators evaluate muscle oxidative function using NIRS during exercise, such as deoxygenation rate at the start of exercise (Deoxy-rate), changes in deoxygenation during exercise (ΔDeoxy), and reoxygenation speed after exercise (T1/2 reoxy, reoxy rate). Previous studies have reported that these muscle NIRS indicators are significantly correlated with muscle fibre type, phosphocreatine recovery rate, and peak oxygen uptake. In addition, muscle NIRS indicators have been applied to the study of a number of chronic health conditions, including patients with ischaemic heart failure. Recently, wearable NIRS devices monitor muscle function continuously and freely in the field, and we predict that NIRS devices will be widely applied to our lifestyles more than ever before. However, there are some critical problems with measuring muscle oxidative function using NIRS devices. We have previously reported that subcutaneous adipose tissue thickness (SATT) greatly influences the light pathlength and makes it difficult to quantify tissue deoxygenation, especially in the measurements of muscle deoxygenation from the skin surface. The effects of SATT need to, therefore, be corrected when using NIRS devices, especially when comparing differences in sex, age, and trainability, as the subjects' SATT could differ significantly. In addition, we have more recently reported that assuming constant mean pathlength (MPL) in NIRS leads to an inaccurate interpretation of muscle deoxygenation, since there are greater changes in MPL during incremental cycling exercise, especially at shorter wavelengths in the NIRS region. In this mini-review, we will summarise the indicators of muscle oxidative function using NIRS and the challenges of using an NIRS apparatus, especially during exercise.

Keywords:  Muscle NIRS indicator; Muscle oxidative function; Reoxygenation speed; Subcutaneous adipose tissue thickness (SATT); Wearable NIRS device

DOI:  https://doi.org/10.1007/978-3-031-67458-7_56
Trends Pharmacol Sci. 2024 Oct 14. pii: S0165-6147(24)00209-8. [Epub ahead of print]

MICUs protect the heart by regulating mitochondrial calcium.

Ulas Ozkurede, Shanmugasundaram Pakkiriswami, Julia C Liu.

  Regulation of mitochondrial calcium uptake by the mitochondrial calcium uniporter (mtCU) complex is crucial for heart function. In a recent study, Hasan et al. demonstrated that mitochondrial calcium uptake (MICU)1 and MICU2, regulatory subunits of the complex, help maintain calcium homeostasis in cardiac mitochondria, providing potential targets for therapies aimed at improving mitochondrial function in heart disease.

Keywords:  EMRE; MCU; MICU1; MICU2; calcium; heart; mitochondria

DOI:  https://doi.org/10.1016/j.tips.2024.09.010
J Bras Nefrol. 2024 Oct-Dec;46(4):pii: S0101-28002024000400402. [Epub ahead of print]46(4): e20230187

SGLT2 inhibitors and NLRP3 inflammasome: potential target in diabetic kidney disease.

Paulo André Bispo Machado Júnior, André Lass, Bruna Isadora Pilger, Raphaella Fornazari, Thyago Proença de Moraes, Ricardo Aurino Pinho.

Diabetic kidney disease (DKD) remains the leading cause of chronic kidney disease (CKD) worldwide. The pathogenesis of DKD is influenced by functional, histopathological, and immune mechanisms, including NLRP3 inflammasome activity and oxidative stress. The sodium-glucose cotransporter 2 inhibitors (SGLT2i) have shown metabolic benefits and the ability to slow the progression of DKD in several clinical studies over the years. Recent studies suggest that the antidiabetic activity also extends to inhibition of the inflammatory response, including modulation of the NLRP3 inflammasome, reduction of pro-inflammatory markers and reduction of oxidative stress. Here we review the efficacy of SGLT2i in the treatment of CKD and discuss the role of the inflammatory response in the development of DKD, including its relationship to the NLRP3 inflammasome and oxidative stress.

DOI: https://doi.org/10.1590/2175-8239-JBN-2023-0187en
Int J Mol Sci. 2024 Sep 24. pii: 10278. [Epub ahead of print]25(19):

The Oldest of Old Male C57B/6J Mice Are Protected from Sarcopenic Obesity: The Possible Role of Skeletal Muscle Protein Kinase B Expression.

Thomas H Reynolds, Noa Mills, Dakembay Hoyte, Katy Ehnstrom, Alex Arata.

  The impact of aging on body composition and glucose metabolism is not well established in C57BL/6J mice, despite being a common pre-clinical model for aging and metabolic research. The purpose of this study was to examine the effect of advancing age on body composition, in vivo glucose metabolism, and skeletal muscle AKT expression in young (Y: 4 months old, n = 7), old (O: 17-18 months old, n = 10), and very old (VO: 26-27 month old, n = 9) male C57BL/6J mice. Body composition analysis, assessed by nuclear magnetic resonance, demonstrated O mice had a significantly greater fat mass and body fat percentage when compared to Y and VO mice. Furthermore, VO mice had a significantly greater lean body mass than both O and Y mice. We also found that the VO mice had greater AKT protein levels in skeletal muscle compared to O mice, an observation that explains a portion of the increased lean body mass in VO mice. During glucose tolerance (GT) testing, blood glucose values were significantly lower in the VO mice when compared to the Y and O mice. No age-related differences were observed in insulin tolerance (IT). We also assessed the glucose response to AMPK activation by 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR). The change in blood glucose following AICAR administration was significantly reduced in VO mice compared to Y and AG mice. Our findings indicate that lean body mass and AKT2 protein expression in muscle are significantly increased in VO mice compared to O mice. The increase in AKT2 likely plays a role in the greater lean body mass observed in the oldest of old mice. Finally, despite the increased GT, VO mice appear to be resistant to AMPK-mediated glucose uptake.

Keywords:  aging; body composition; glucose metabolism; protein kinase B; skeletal muscle

DOI:  https://doi.org/10.3390/ijms251910278
Geriatr Gerontol Int. 2024 Oct 14.

Late-onset primary muscle diseases mimicking sarcopenia.

Satoshi Yamashita.

  Sarcopenia is an age-related loss of skeletal muscle mass, strength, and function that causes various health problems. In contrast, late-onset primary myopathies, which occur in the older population, are caused by a variety of factors, including genetic mutations, autoimmune processes, and metabolic abnormalities. Although sarcopenia and primary myopathy are two distinct disease processes, their symptoms can overlap, making differentiation challenging. The diagnostic criteria for sarcopenia have evolved over time, and various criteria have been proposed by expert groups. Late-onset primary muscle diseases such as inclusion body myositis, sporadic late-onset nemaline myopathy, muscular dystrophies, distal myopathies, myofibrillar myopathies, metabolic myopathies, and mitochondrial myopathies share common pathogenic mechanisms with sarcopenia, further complicating the diagnostic process. Appropriate clinical evaluation, including detailed history-taking, physical examination, and diagnostic testing, is essential for accurate diagnosis and management. Treatment approaches, including exercise, nutritional support, and disease-specific therapies, must be tailored to the characteristics of each disease. Despite these differences, sarcopenia and primary myopathies require careful consideration in the clinical setting for proper diagnosis and management. This review outlines the evolution of diagnostic criteria and diagnostic items for sarcopenia, late-onset primary myopathies that should be differentiated from sarcopenia, common pathomechanisms, and diagnostic algorithms to properly differentiate primary myopathies. Geriatr Gerontol Int 2024; ••: ••-••.

Keywords:  inclusion body myositis; late‐onset primary myopathies; muscular dystrophy; sarcopenia; sporadic late‐onset nemaline myopathy

DOI:  https://doi.org/10.1111/ggi.15000