bims-kimdis 2023-07-16 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2023‒07‒16
thirty-two papers selected by
Matías Javier Monsalves Álvarez

Ketogenic diet alleviates cognitive dysfunction and neuroinflammation in APP/PS1 mice via the Nrf2/HO-1 and NF-κB signaling pathways.
Ketogenic-Mimicking Diet as a Therapeutic Modality for Bipolar Disorder: Biomechanistic Rationale and Protocol for a Pilot Clinical Trial.
A systematic review and meta-regression of exogenous ketone infusion rates and resulting ketosis-A tool for clinicians and researchers.
A randomized, open-label, parallel pilot study investigating metabolic product kinetics of the novel ketone ester, bis-hexanoyl (R)-1,3-butanediol, over one week of ingestion in healthy adults.
The ketogenic diet promotes triacylglycerol recycling in white adipose tissue and uncoupled fat oxidation in brown adipose tissue, but does not reduce adiposity in rats.
Effect of the ketogenic diet on gut microbiome composition and metabolomics in polycystic ovarian syndrome rats induced by letrozole and a high-fat diet.
Ketogenic diet in relapsing multiple sclerosis: Patient perceptions, post-trial diet adherence & outcomes.
A Ketogenic Diet in Combination with Gemcitabine Mitigates Pancreatic Cancer-Associated Cachexia in Male and Female KPC Mice.
Regulation of mitochondrial morphology and cristae architecture by the TLR4 pathway in human skeletal muscle.
The role of mitochondria and mitophagy in cell senescence.
Mitochondrial Dysfunction and Skeletal Muscle Atrophy: Causes, Mechanisms, and Treatment Strategies.
High-Intensity Interval Training Attenuates Impairment in Regulatory Protein Machinery of Mitochondrial Quality Control in Skeletal Muscle of Diet-Induced Obese Mice.
Ketone bodies supplementation restores the barrier function, induces a metabolic switch, and elicits beta-hydroxybutyrate diffusion across a monolayer of iPSC-derived brain microvascular endothelial cells.
MITOCHONDRIAL ROS AND LYTIC PROGRAMMED CELL DEATH IN ACUTE INFLAMMATION.
Increasing autophagy ameliorates all-trans-retinal-activated NLRP3 inflammasomes in human THP-1 macrophages.
Inflammasome in Skeletal Muscle: NLRP3 Is an Inflammatory Cell Stress Component in Inclusion Body Myositis.
Commentary: Inhibitors of mitochondrial respiratory chain in the treatment of type 2 diabetes.
Combined lactic acidosis and ketoacidosis in a female diabetic patient with severe heart failure.
Skeletal Muscle Endogenous Estrogen Production Ameliorates the Metabolic Consequences of a High-Fat Diet in Male Mice.
Mitochondria in cell senescence: A Friend or Foe?
Metabolic Flexibility and Inflexibility: Pathology Underlying Metabolism Dysfunction.
Molecular mechanism of caloric restriction mimetics-mediated neuroprotection of age-related neurodegenerative diseases: an emerging therapeutic approach.
Chasing the right tail: How the ER membrane complex recognizes its substrates.
Effects of mitochondria on postmortem meat quality: characteristic, isolation, energy metabolism, apoptosis and oxygen consumption.
Assessment of metabolic flexibility by measuring maximal fat oxidation during submaximal intensity exercise: Can we improve the analytical procedures?
A partial Drp1 knockout improves autophagy flux independent of mitochondrial function.
SGLT1: A Potential Drug Target for Cardiovascular Disease.
NLRP3 inflammasome activation after ischemic stroke.
Mitochondrial respiratory complex I deficiency inhibits brown adipogenesis by limiting heme regulation of histone demethylation.
Mass spectrometry of the white adipose metabolome in a hibernating mammal reveals seasonal changes in alternate fuels and carnitine derivatives.
Empagliflozin reduces endoplasmic reticulum stress associated TXNIP/NLRP3 activation in tunicamycin-stimulated aortic endothelial cells.
Anti-Inflammatory Activity of Black Soldier Fly Oil Associated with Modulation of TLR Signaling: A Metabolomic Approach.

Neural Regen Res. 2023 Dec;18(12): 2767-2772

Ketogenic diet alleviates cognitive dysfunction and neuroinflammation in APP/PS1 mice via the Nrf2/HO-1 and NF-κB signaling pathways.

Jingwen Jiang, Hong Pan, Fanxia Shen, Yuyan Tan, Shengdi Chen.

  Alzheimer's disease is a progressive neurological disorder characterized by cognitive decline and chronic inflammation within the brain. The ketogenic diet, a widely recognized therapeutic intervention for refractory epilepsy, has recently been proposed as a potential treatment for a variety of neurological diseases, including Alzheimer's disease. However, the efficacy of ketogenic diet in treating Alzheimer's disease and the underlying mechanism remains unclear. The current investigation aimed to explore the effect of ketogenic diet on cognitive function and the underlying biological mechanisms in a mouse model of Alzheimer's disease. Male amyloid precursor protein/presenilin 1 (APP/PS1) mice were randomly assigned to either a ketogenic diet or control diet group, and received their respective diets for a duration of 3 months. The findings show that ketogenic diet administration enhanced cognitive function, attenuated amyloid plaque formation and proinflammatory cytokine levels in APP/PS1 mice, and augmented the nuclear factor-erythroid 2-p45 derived factor 2/heme oxygenase-1 signaling pathway while suppressing the nuclear factor-kappa B pathway. Collectively, these data suggest that ketogenic diet may have a therapeutic potential in treating Alzheimer's disease by ameliorating the neurotoxicity associated with Aβ-induced inflammation. This study highlights the urgent need for further research into the use of ketogenic diet as a potential therapy for Alzheimer's disease.

Keywords:  APP/PS1 mice; Alzheimer’s disease; cognitive impairment; ketogenic diet; neuroinflammation; nuclear factor-erythroid 2-p45 derived factor 2/heme oxygenase-1; nuclear factor-kappa B pathway; therapeutic benefits

DOI:  https://doi.org/10.4103/1673-5374.373715
Nutrients. 2023 Jul 07. pii: 3068. [Epub ahead of print]15(13):

Ketogenic-Mimicking Diet as a Therapeutic Modality for Bipolar Disorder: Biomechanistic Rationale and Protocol for a Pilot Clinical Trial.

Jeffrey L B Bohnen, Travis P Wigstrom, Alexis M Griggs, Stiven Roytman, Rebecca R Paalanen, Hailemicael A Andrews, Nicolaas I Bohnen, Jacob J H Franklin, Melvin G McInnis.

  There is growing interest in the investigation of ketogenic diets as a potential therapy for bipolar disorder. The overlapping pharmacotherapies utilized for both bipolar disorder and seizures suggest that a mechanistic overlap may exist between these conditions, with fasting and the ketogenic diet representing the most time-proven therapies for seizure control. Recently, preliminary evidence has begun to emerge supporting a potential role for ketogenic diets in treating bipolar disorder. Notably, some patients may struggle to initiate a strict diet in the midst of a mood episode or significant life stressors. The key question addressed by this pilot clinical trial protocol is if benefits can be achieved with a less restrictive diet, as this would allow such an intervention to be accessible for more patients. Recent development of so-called ketone esters, that once ingested is converted to natural ketone bodies, combined with low glycemic index dietary changes has the potential to mimic two foundational components of therapeutic ketosis: high levels of ketones and minimal spiking of glucose/insulin. This pilot clinical trial protocol thus aims to investigate the effect of a 'ketogenic-mimicking diet' (combining supplementation of ketone esters with a low glycemic index dietary intervention) on neural network stability, mood, and biomarker outcomes in the setting of bipolar disorder. Positive findings obtained via this pilot clinical trial protocol may support future target engagement studies of ketogenic-mimicking diets or related ketogenic interventions. A lack of positive findings, in contrast, may justify a focus on more strict dietary interventions for future research.

Keywords:  ketone ester; ketosis; metabolic psychiatry; metabolism; mitochondria; mood; network stability

DOI:  https://doi.org/10.3390/nu15133068
Front Physiol. 2023 ;14 1202186

A systematic review and meta-regression of exogenous ketone infusion rates and resulting ketosis-A tool for clinicians and researchers.

Kristi L Storoschuk, Thomas R Wood, Brianna J Stubbs.

  Introduction: Ketone bodies such as beta-hydroxybutyrate (BHB) have pleiotropic functional benefits as fuel and signaling metabolites and may have multiple clinical applications. An alternative to inducing ketosis by dietary modification is intravenous delivery of exogenous sources of ketones. It is unknown whether there is a strong relationship between BHB infusion rate and blood BHB concentrations in the published literature; this information is vital for clinical studies investigating therapeutic effects of ketosis. This systematic review aimed to aggregate available data and address this gap. Methods: The PubMed and EMBASE databases were searched, and data were extracted from 23 manuscripts where BHB was infused and maximum and/or steady state BHB levels assessed. Infusion rate was adjusted when racemic BHB was infused but only D-BHB was measured. Results: Using a random effects meta-regression, strong linear relationships between BHB infusion rate and maximal (y = 0.060 + 0.870x, R 2 = 87.2%, p < 0.0001) and steady state (y = -0.022 + 0.849x, R 2 = 86.9%, p < 0.0001) blood BHB concentrations were found. Sensitivity analysis found this relationship was stronger when studies in non-healthy populations were excluded (y = 0.059 + 0.831x, R 2 = 96.3%, p < 0.0001). Conclusion: There is a strong relationship between BHB infusion rate and blood BHB concentrations; the regressions described here can be used by clinicians or researchers to determine ketone delivery required for a target blood concentration.

Keywords:  beta-hydroxybutyrate (BHB); exogenous ketone; infusion; ketones (plasma); pharmacokinetics

DOI:  https://doi.org/10.3389/fphys.2023.1202186
Front Physiol. 2023 ;14 1196535

A randomized, open-label, parallel pilot study investigating metabolic product kinetics of the novel ketone ester, bis-hexanoyl (R)-1,3-butanediol, over one week of ingestion in healthy adults.

Eunice Mah, Traci M Blonquist, Valerie N Kaden, Dawn Beckman, Amy C Boileau, Joshua C Anthony, Brianna J Stubbs.

  Introduction: Bis-hexanoyl (R)-1,3-butanediol (BH-BD) is a novel ketone ester that, when consumed, is hydrolyzed into hexanoic acid (HEX) and (R)-1,3-butanediol (BDO) which are subsequently metabolized into beta-hydroxybutyrate (BHB). Methods: We undertook a randomized, parallel, open-label study in healthy adults (n = 33) to elucidate blood BHB, HEX and BDO concentrations for 8 h following consumption of three different serving sizes (SS) of BH-BD (12.5, 25 and 50 g/day) before (Day 0) and after 7 days of daily BH-BD consumption (Day 7). Results: Maximal concentration and area under the curve of all metabolites increased proportionally to SS and were greatest for BHB followed by BDO then HEX on both Day 0 and 7. Metabolite half-life tended to decrease with increasing SS for BHB and HEX. Time to peak concentration increased with increasing SS for BHB and BDO on both days. In vitro incubation of BH-BD in human plasma demonstrated BH-BD undergoes rapid spontaneous hydrolysis. Conclusion: These results demonstrate that orally ingested BH-BD is hydrolyzed into products that appear in the plasma and undergo conversion to BHB in a SS dependent manner, and that metabolism of BH-BD neither becomes saturated at serving sizes up to 50 g nor displays consistent adaptation after 7 days of daily consumption.

Keywords:  beta-hydroxybutyrate (BHB); exogenous ketone; ketone di-ester; ketone ester; ketones

DOI:  https://doi.org/10.3389/fphys.2023.1196535
J Nutr Biochem. 2023 Jul 06. pii: S0955-2863(23)00145-6. [Epub ahead of print]120 109412

The ketogenic diet promotes triacylglycerol recycling in white adipose tissue and uncoupled fat oxidation in brown adipose tissue, but does not reduce adiposity in rats.

Daniel Da Eira, Shailee Jani, Mateja Stefanovic, Rolando B Ceddia.

  The purpose of this study was to determine whether the weight-reducing and fat burning effects of the ketogenic diet (KD) could be attributed to alterations in the energy dissipating pathways of brown adipose tissue (BAT) uncoupled oxidation, and white adipose tissue (WAT) browning and triacylglycerol (TAG) recycling. To investigate this, male Wistar rats were fed one of the following three diets for either 8 or 16 weeks: a standard chow (SC), a high-fat, sucrose-enriched (HFS) obesogenic diet, or a KD. At the end of the intervention, subcutaneous inguinal (Sc Ing) and epididymal (Epid) fat, and interscapular and aortic BAT (iBAT and aBAT, respectively) were extracted. These tissues were used for the analysis of proteins involved in WAT browning and thermogenesis. Isolated adipocytes from WAT were assayed for basal and isoproterenol (Iso)-stimulated lipolysis and basal and insulin-stimulated lipogenesis, and BAT adipocytes were assayed for the determination of coupled and uncoupled glucose and palmitate oxidation. Adiposity similarly increased in HFS- and KD-fed rats at weeks 8 and 16. However, in HFS-fed animals insulin-stimulated lipogenesis and Iso-stimulated lipolysis were impaired in WAT adipocytes, whereas in KD-fed animals these pathways remained intact. The KD also significantly elevated WAT glycerol kinase levels, and favored TAG recycling under conditions of enhanced lipolysis. In BAT, the KD significantly increased uncoupling protein-1 levels and uncoupled fat oxidation. In summary, the KD preserved insulin sensitivity and lipolytic capacity in WAT and also upregulated energy-dissipating pathways in BAT, but it was not sufficient to prevent an increase in adiposity.

Keywords:  Glycerol kinase; Insulin-stimulated lipogenesis; Lipolysis; PGC-1α; UCP1

DOI:  https://doi.org/10.1016/j.jnutbio.2023.109412
Nutrition. 2023 Jun 08. pii: S0899-9007(23)00156-9. [Epub ahead of print]114 112127

Effect of the ketogenic diet on gut microbiome composition and metabolomics in polycystic ovarian syndrome rats induced by letrozole and a high-fat diet.

Ruye Wang, Ying Zhao, Xiaohong Fang, Chenyun Miao, Ning Ren, Yun Chen, Wei Cheng, Qin Zhang.

  OBJECTIVES: The ketogenic diet (KD) is recommended to improve polycystic ovary syndrome (PCOS); however, its mechanisms of action are unclear. We aimed to study the effects and mechanisms of action of the KD on the gut microbiome and metabolites in PCOS rats and determine whether the sex hormone regulatory effects are related to modulations of the gut microbiota and metabolites.METHODS: PCOS was induced with a high-fat diet and letrozole in the rats. A KD was fed to rats for 8 wk, serum samples were collected for biochemical analysis, and the rats' fecal samples were subjected to 16S ribosomal RNA sequencing and metabolomic analysis.
RESULTS: Feeding with a KD for 8 wk suppressed body weight gain, decreased luteinizing hormone and androgen levels, and improved insulin levels. Furthermore, the KD reversed the dysregulation of the gut microbiota in PCOS rats by adjusting the ratio of firmicutes and bacteroidetes. Also, the KD was involved in hormonal metabolic pathways by reducing the levels of some metabolites (such as testosterone and 7α-hydroxytestosterone) that are closely related to gut microbes.
CONCLUSIONS: The KD improved the clinical phenotype and insulin resistance in PCOS rats and altered the composition of the gut microbiome and metabolites, which were associated with androgen metabolism, representing a potential mechanism for mediating the effects of the KD on sex hormone metabolism in PCOS. However, our study found contradictory effects of KD on the gut microbiome in PCOS, which need further research.

Keywords:  Insulin resistance; Intestinal microbiota; Metabolites; Polycystic ovary syndrome; Steroid hormone biosynthesis pathway

DOI:  https://doi.org/10.1016/j.nut.2023.112127
Clin Nutr. 2023 Jul 04. pii: S0261-5614(23)00214-5. [Epub ahead of print]42(8): 1427-1435

Ketogenic diet in relapsing multiple sclerosis: Patient perceptions, post-trial diet adherence & outcomes.

Emma Wetmore, Diana Lehner-Gulotta, Brian Florenzo, Brenda Banwell, A G Christina Bergqvist, Rachael Coleman, Mark Conaway, Myla D Goldman, J Nicholas Brenton.

  BACKGROUND: Ketogenic diets (KDs) are safe and tolerable in people with multiple sclerosis (MS). While many patient-reported and clinical benefits are noted, the sustainability of these diets outside of a clinical trial is unknown.AIMS: Evaluate patient perceptions of the KD following intervention, determine the degree of adherence to KDs post-trial, and examine what factors increase the likelihood of KD continuation following the structured diet intervention trial.
METHODS: Sixty-five subjects with relapsing MS previously enrolled into a 6-month prospective, intention-to-treat KD intervention. Following the 6-month trial, subjects were asked to return for a 3-month post-study follow-up, at which time patient reported outcomes, dietary recall, clinical outcome measures, and laboratory values were repeated. In addition, subjects completed a survey to evaluate sustained and attenuated benefits following completion of the intervention phase of the trial.
RESULTS: Fifty-two subjects (81%) returned for the 3-month post-KD intervention visit. Twenty-one percent reported continued adherence to a strict KD and an additional 37% reported adhering to a liberalized, less restrictive form of the KD. Those subjects with greater reductions in body mass index (BMI) and fatigue at 6-months on-diet were more likely to continue on KD following trial completion. Using intention-to-treat analysis, patient-reported and clinical outcomes at 3-months post-trial remained significantly improved from baseline (pre-KD), though the degree of improvement was slightly attenuated relative to outcomes at 6-months on KD. Regardless of diet type following the KD intervention, dietary patterns shifted toward greater protein and polyunsaturated fats and less carbohydrate/added sugar consumption.
CONCLUSIONS: Following the 6-month KD intervention study, the majority of subjects elected to continue on KD, though many pursued a more liberal limit for carbohydrate restriction. Those who experienced a greater reduction in BMI or fatigue were more likely to continue with strict KD. The 6-month KD intervention induced persistent changes to dietary habits in the months following study completion.
TRIAL REGISTRATION INFORMATION: Registered on Clinicaltrials.gov under registration number NCT03718247, posted on Oct 24, 2018. First patient enrollment date: Nov 1, 2018. Link: https://clinicaltrials.gov/ct2/show/NCT03718247?term=NCT03718247&draw=2&rank=1.

Keywords:  Autoimmune; Dietary; Modified atkins; Neuroimmunology; Obesity

DOI:  https://doi.org/10.1016/j.clnu.2023.06.029
Int J Mol Sci. 2023 Jun 28. pii: 10753. [Epub ahead of print]24(13):

A Ketogenic Diet in Combination with Gemcitabine Mitigates Pancreatic Cancer-Associated Cachexia in Male and Female KPC Mice.

Natalia E Cortez, Suraj Pathak, Cecilia Rodriguez Lanzi, Brian V Hong, Ryman Crone, Rasheed Sule, Fangyi Wang, Shuai Chen, Aldrin V Gomes, Keith Baar, Gerardo G Mackenzie.

  Cancer-associated cachexia (CAC) is a critical contributor to pancreatic ductal adenocarcinoma (PDAC) mortality. Thus, there is an urgent need for new strategies to mitigate PDAC-associated cachexia; and the exploration of dietary interventions is a critical component. We previously observed that a ketogenic diet (KD) combined with gemcitabine enhances overall survival in the autochthonous LSL-KrasG12D/+; LSL-Trp53 R172H/+; Pdx1-Cre (KPC) mouse model. In this study, we investigated the effect and cellular mechanisms of a KD in combination with gemcitabine on the maintenance of skeletal muscle mass in KPC mice. For this purpose, male and female pancreatic tumor-bearing KPC mice were allocated to a control diet (CD), a KD, a CD + gemcitabine (CG), or a KD + gemcitabine (KG) group. We observed that a KD or a KG-mitigated muscle strength declined over time and presented higher gastrocnemius weights compared CD-fed mice. Mechanistically, we observed sex-dependent effects of KG treatment, including the inhibition of autophagy, and increased phosphorylation levels of eIF2α in KG-treated KPC mice when compared to CG-treated mice. Our data suggest that a KG results in preservation of skeletal muscle mass. Additional research is warranted to explore whether this diet-treatment combination can be clinically effective in combating CAC in PDAC patients.

Keywords:  cachexia; cancer-associated cachexia; gemcitabine; ketogenic diet; pancreatic cancer

DOI:  https://doi.org/10.3390/ijms241310753
Front Cell Dev Biol. 2023 ;11 1212779

Regulation of mitochondrial morphology and cristae architecture by the TLR4 pathway in human skeletal muscle.

Mauricio Castro-Sepulveda, Mauro Tuñón-Suárez, Giovanni Rosales-Soto, Ronald Vargas-Foitzick, Louise Deldicque, Hermann Zbinden-Foncea.

  In skeletal muscle (SkM), a reduced mitochondrial elongate phenotype is associated with several metabolic disorders like type 2 diabetes mellitus (T2DM). However, the mechanisms contributing to this reduction in mitochondrial elongate phenotype in SkM have not been fully elucidated. It has recently been shown in a SkM cell line that toll-like receptor 4 (TLR4) contributes to the regulation of mitochondrial morphology. However, this has not been investigated in human SkM. Here we found that in human SkM biopsies, TLR4 protein correlated negatively with Opa1 (pro-mitochondrial fusion protein). Moreover, the incubation of human myotubes with LPS reduced mitochondrial size and elongation and induced abnormal mitochondrial cristae, which was prevented with the co-incubation of LPS with TAK242. Finally, T2DM myotubes were found to have reduced mitochondrial elongation and mitochondrial cristae density. Mitochondrial morphology, membrane structure, and insulin-stimulated glucose uptake were restored to healthy levels in T2DM myotubes treated with TAK242. In conclusion, mitochondrial morphology and mitochondrial cristae seem to be regulated by the TLR4 pathway in human SkM. Those mitochondrial alterations might potentially contribute to insulin resistance in the SkM of patients with T2DM.

Keywords:  Lipopolysaccharide; TAK242; mitochondrial dynamics; mitochondrial nanotunnels; skeletal muscle function; type 2 diabetes

DOI:  https://doi.org/10.3389/fcell.2023.1212779
Adv Protein Chem Struct Biol. 2023 ;pii: S1876-1623(23)00043-3. [Epub ahead of print]136 93-115

The role of mitochondria and mitophagy in cell senescence.

Tayyab Ali, Fatma Hussain, Haroon Ur Rashid Kayani, Muhammad Naeem, Fozia Anjum.

  Mitochondrial malfunction and cell senescence have been defined as the hallmarks of aging. Cell senescence leads to the loss of health allied with aging. While deciphering the complex association between mitochondria and cellular senescence, it is observed that senescence has a two-faced nature being beneficial and hazardous. This duality of cellular senescence is associated with circumstantial aspects. During the process of cellular senescence, dysfunctional mitochondria are accumulated, the efficiency of the oxidative phosphorylation process declines along with the enhanced synthesis of reactive oxygen species. It is suggested that reduction in the negative consequences of senescence throughout old age might be accomplished by targeting the mitochondria as all roads lead towards mitochondria. It is unclear how perturbation of mitophagy in senescence results in the accumulation of mitochondria, impairment of mitochondrial biogenesis and onset of diseases. Understanding this complex interplay will bring about a long yet healthy lifespan. But definitely casual and specific players contribute in the initiation and conservation of the cell senescence. Variations in metabolism, quality control and dynamics of mitochondria are observed during cell aging process. Several On-target and Off-target mechanisms can also cause side effects in cellular senescence. Translational research of these mechanisms may lead to effective clinical interventions. This chapter reviews the role of mitochondria, homeostatic mechanisms and mitophagy as drivers and effectors of cell senescence along with multiple signalling pathways that lead to the initiation, maintenance, induction and suppression of cellular aging process during health and disease.

Keywords:  Autophagy; Cell senescence; Mitophagy; Signaling pathways

DOI:  https://doi.org/10.1016/bs.apcsb.2023.03.001
Mitochondrion. 2023 Jul 12. pii: S1567-7249(23)00066-1. [Epub ahead of print]

Mitochondrial Dysfunction and Skeletal Muscle Atrophy: Causes, Mechanisms, and Treatment Strategies.

Gokhan Burcin Kubat, Esmaa Bouhamida, Oner Ulger, Ibrahim Turkel, Gaia Pedriali, Daniela Ramaccini, Ozgur Ekinci, Berkay Ozerklig, Ozbeyen Atalay, Simone Patergnani, Beyza Nur Sahin, Giampaolo Morciano, Meltem Tuncer, Elena Tremoli, Paolo Pinton.

  Skeletal muscle, which accounts for approximately 40% of total body weight, is one of the most dynamic and plastic tissues in the human body and plays a vital role in movement, posture and force production. More than just a component of the locomotor system, skeletal muscle functions as an endocrine organ capable of producing and secreting hundreds of bioactive molecules. Therefore, maintaining healthy skeletal muscles is crucial for supporting overall body health. Various pathological conditions, such as prolonged immobilization, cachexia, aging, drug-induced toxicity, and cardiovascular diseases (CVDs), can disrupt the balance between muscle protein synthesis and degradation, leading to skeletal muscle atrophy. Mitochondrial dysfunction is a major contributing mechanism to skeletal muscle atrophy, as it plays crucial roles in various biological processes, including energy production, metabolic flexibility, maintenance of redox homeostasis, and regulation of apoptosis. In this review, we critically examine recent knowledge regarding the causes of muscle atrophy (disuse, cachexia, aging, etc.) and its contribution to CVDs. Additionally, we highlight the mitochondrial signaling pathways involvement to skeletal muscle atrophy, such as the ubiquitin-proteasome system, autophagy and mitophagy, mitochondrial fission-fusion, and mitochondrial biogenesis. Furthermore, we discuss current strategies, including exercise, mitochondria-targeted antioxidants, in vivo transfection of PGC-1α, and the potential use of mitochondrial transplantation as a possible therapeutic approach.

Keywords:  Skeletal muscle atrophy; cardiovascular diseases; exercise; mitochondria; mitochondrial transplantation

DOI:  https://doi.org/10.1016/j.mito.2023.07.003
bioRxiv. 2023 Jun 29. pii: 2023.06.28.546902. [Epub ahead of print]

High-Intensity Interval Training Attenuates Impairment in Regulatory Protein Machinery of Mitochondrial Quality Control in Skeletal Muscle of Diet-Induced Obese Mice.

James B Tincknell, Benjamin Kugler, Haley Spicuzza, Huimin Yan, Tongjian You, Kai Zou.

Mitochondrial quality control processes are essential in governing mitochondrial integrity and function. The purpose of the study was to examine the effects of 10 weeks of HIIT on the regulatory protein machinery of skeletal muscle mitochondrial quality control and whole-body glucose homeostasis in diet-induced obese mice. Male C57BL/6 mice were randomly assigned to a low-fat diet (LFD) or high-fat diet (HFD) group. After 10 weeks, HFD-fed mice were divided into sedentary and HIIT (HFD+HIIT) groups and remained on HFD for another 10 weeks (n=9/group). Graded exercise test, glucose and insulin tolerance tests, mitochondrial respiration and regulatory protein markers of mitochondrial quality control processes were determined by immunoblots. Ten weeks of HIIT enhanced ADP-stimulated mitochondrial respiration in diet-induced obese mice (P < 0.05) but did not improve whole-body insulin sensitivity. Importantly, the ratio of Drp1(Ser 616 ) over Drp1(Ser 637 ) phosphorylation, an indicator of mitochondrial fission, was attenuated in HFD-HIIT compared to HFD (-35.7%, P < 0.05). Regarding autophagy, skeletal muscle p62 content was lower in HFD group than LFD group (-35.1%, P < 0.05), however, such reduction was disappeared in HFD+HIIT group. In addition, LC3B II/I ratio was higher in HFD than LFD group (15.5%, P < 0.05) but was ameliorated in HFD+HIIT group (-29.9%, P < 0.05). Overall, our study demonstrated that 10 weeks of HIIT was effective in improving skeletal muscle mitochondrial respiration and the regulatory protein machinery of mitochondrial quality control in diet-induced obese mice through the alterations of mitochondrial fission protein Drp1 activity and p62/LC3B-mediated regulatory machinery of autophagy.

DOI: https://doi.org/10.1101/2023.06.28.546902
Microvasc Res. 2023 Jul 10. pii: S0026-2862(23)00111-5. [Epub ahead of print] 104585

Ketone bodies supplementation restores the barrier function, induces a metabolic switch, and elicits beta-hydroxybutyrate diffusion across a monolayer of iPSC-derived brain microvascular endothelial cells.

Pervaiz Iqra, Mehta Yash, Sherill Kinzie, Patel Dhavalkumar, Al-Ahmad Abraham Jacob.

  Glucose constitutes the main source of energy for the central nervous system (CNS), its entry occurring at the blood-brain barrier (BBB) via the presence of glucose transporter 1 (GLUT1). However, under food intake restrictions, the CNS can utilize ketone bodies (KB) as an alternative source of energy. Notably, the relationship between the BBB and KBs and its effect on their glucose metabolism remains poorly understood. In this study, we investigated the effect of glucose deprivation on the brain endothelium in vitro, and supplementation with KBs using induced pluripotent stem cell (iPSC)-derived brain microvascular endothelial cell-like cells (iBMECs). Glucose-free environment significantly decreased cell metabolic activity and negatively impacted the barrier function. In addition, glucose deprivation did not increase GLUT1 expression but also resulted in a decrease in glucose uptake and glycolysis. Supplementation of glucose-deprived iBMECs monolayers with KB showed no improvement and even worsened upon treatment with acetoacetate. However, under a hypoglycemic condition in the presence of KBs, we noted a slight improvement of the barrier function, with no changes in glucose uptake. Notably, hypoglycemia and/or KB pre-treatment elicited a saturable beta-hydroxybutyrate diffusion across iBMECs monolayers, such diffusion occurred partially via an MCT1-dependent mechanism. Taken together, our study highlights the importance of glucose metabolism and the reliance of the brain endothelium on glucose and glycolysis for its function, such dependence is unlikely to be covered by KBs supplementation. In addition, KB diffusion at the BBB appeared induced by KB pre-treatment and appears to involve an MCT1-dependent mechanism.

Keywords:  Blood-brain barrier; Glycolysis; Ketone bodies; Stem cells; β-Hydroxybutyrate

DOI:  https://doi.org/10.1016/j.mvr.2023.104585
Antioxid Redox Signal. 2023 Jul 14.

MITOCHONDRIAL ROS AND LYTIC PROGRAMMED CELL DEATH IN ACUTE INFLAMMATION.

Sergio Rius-Pérez, Salvador Pérez, Michel Toledano, Juan Sastre.

SIGNIFICANCE: Redox signaling through mitochondrial reactive oxygen species (ROS) has a key role in several mechanisms of regulated cell death, necroptosis, ferroptosis, pyroptosis, and apoptosis, thereby decisively contributing to inflammatory disorders. The role of mitochondrial ROS in apoptosis has been extensively addressed, but their involvement in necrotic-like regulated cell death has just started to be elucidated, providing novel insights into the pathophysiology of acute inflammation.CRITICAL ISSUES: Mitochondrial ROS trigger positive feedback loops leading to lytic regulated cell death in conjunction with the necrosome, the inflammasome, glutathione depletion, and glutathione peroxidase 4 deficiency.
RECENT ADVANCES: p53 together with mitochondrial ROS drive necroptosis in acute inflammation through downregulation of sulfiredoxin and peroxiredoxin 3. Mitochondrial hydroorotate dehydrogenase is a key redox system in the regulation of ferroptosis. In addition, a non-canonical pathway, which generates mitochondrial ROS through the Ragulator-Rag complex and acts via mTORC1 to promote gasdermin D oligomerization, triggers pyroptosis.
FUTURE DIRECTIONS: The precise mechanism of membrane rupture in ferroptosis and the contribution of mitochondrial ROS to ferroptosis in inflammatory disorders are still unclear, which will need further research. Mitochondrial antioxidants may provide promising therapeutic approaches towards acute inflammatory disorders. However, establishing doses and windows of action will be required to optimize their therapeutic potential, and to avoid potential adverse side effects linked to blockade of beneficial mitochondrial ROS adaptive signaling.

DOI: https://doi.org/10.1089/ars.2022.0209
Am J Transl Res. 2023 ;15(6): 4380-4389

Increasing autophagy ameliorates all-trans-retinal-activated NLRP3 inflammasomes in human THP-1 macrophages.

Qingqing Xia, Jie Li, Lingmin Zhang, Yingying Zhou, Zaixing Yang, Jing Xie.

OBJECTIVE: Severe inflammation, mediated by innate immune sensors, can be observed in the retina and is considered to play an important role in the pathogenesis of retinal degeneration caused by all-trans-retinal (atRAL). However, the underlying mechanism thereof remains elusive. This study investigated the effects of atRAL on the macrophage cell line THP-1 and determined the underlying signaling pathway through pharmacological and genetical manipulation.METHODS: The cytotoxicity of atRAL in THP-1 macrophage cells was assessed using the cell counting kit-8 (CCK-8) assay, and mature IL-1β was detected by enzyme-linked immunosorbent assay (ELISA). We measured levels of NLRP3 and cleaved caspase-1 by western blotting to evaluate the activation of NLRP3 inflammasomes. Oxidative stress was validated by measuring mitochondria-associated reactive oxygen species (ROS) with MitoSOXTM Red staining. Autophagy was assessed with the LC3BII turnover assay and tandem mCherry-eGFP-LC3B fluorescence microscopy.
RESULTS: The maturation and release of IL-1β were regulated by the activation of the NLRP3 inflammasome. Mitochondria-associated ROS were involved in the regulation of NLRP3 inflammasome activation and caspase-1 cleavage. In addition, atRAL functionally activated autophagy in THP-1 cells, and atRAL-induced NLRP3 inflammasome activation was suppressed by autophagy.
CONCLUSIONS: atRAL activates both the NLRP3 inflammasome and autophagy in THP-1 cells, and the increasing level of autophagy leads to the inhibition of excessive NLRP3 inflammasome activation. These findings shed new light on the pathogenesis of age-related retinal degeneration.

Keywords: All-trans-retinal; NLRP3 inflammasome; age-related macular degeneration; autophagy; reactive oxygen species
Int J Mol Sci. 2023 Jun 26. pii: 10675. [Epub ahead of print]24(13):

Inflammasome in Skeletal Muscle: NLRP3 Is an Inflammatory Cell Stress Component in Inclusion Body Myositis.

Karsten Kummer, Imke Bertram, Sabrina Zechel, Daniel B Hoffmann, Jens Schmidt.

  Inclusion body myositis (IBM) is a chronic, mostly treatment-resistant, inflammatory myopathy with a pathology that centers around specific interactions between inflammation and protein accumulation. The study aimed to identify the inflammasome as a key event in the complex network of pathomechanisms. Regulation of the inflammasome was assessed in a well-established pro-inflammatory cell culture model using human myoblasts and primary human myotubes. By quantitative PCR, western blot and immunocytochemistry, inflammasome markers including NLRP3 were assessed in muscle cells exposed to the cytokines IL-1β and IFN-γ. The data were corroborated by analysis of muscle biopsies from patients with IBM compared to other myositis subtypes. In the cell culture model of IBM, the NLRP3 inflammasome was significantly overexpressed, as evidenced by western blot (p = 0.03) and quantitative PCR (p < 0.01). Target genes that play a role in inflammasome assembly, T-cell migration, and MHC-I expression (p = 0.009) were highly co-upregulated. NLRP3 was significantly overexpressed in muscle biopsies from IBM samples compared to disease controls (p = 0.049), including other inflammatory myopathies. Due to the extraordinary features of the pathogenesis and the pronounced upregulation of NLRP3 in IBM, the inflammasome could serve as a key molecule that drives the inflammatory cascade as well as protein accumulation in the muscle. These data can be useful for future therapeutic developments.

Keywords:  NLRC5; NLRP3; inclusion body myositis; inflammasome; muscle inflammation

DOI:  https://doi.org/10.3390/ijms241310675
Acta Pharm Sin B. 2023 Jun;13(6): 2807-2808

Commentary: Inhibitors of mitochondrial respiratory chain in the treatment of type 2 diabetes.

Jianping Ye.



Keywords:  Berberine; Insulin sensitization; Metformin; Mitochondrial inhibitors; Mitochondrial overheating; Mitochondrial respiration; Type 2 diabetes

DOI:  https://doi.org/10.1016/j.apsb.2023.03.016
Cardiovasc Endocrinol Metab. 2023 Sep;12(3): e0287

Combined lactic acidosis and ketoacidosis in a female diabetic patient with severe heart failure.

Desire Nzomessi, Emmanuelle Massie, Karim Gariani, Raphael Giraud, Philippe Meyer.

  SGLT2i are now recommended in a wide spectrum of indications including type 2 diabetes (T2DM), heart failure, and chronic kidney disease. This medication class is now available in combination with metformin, which is still a fundamental treatment in patients with T2DM. Despite excellent proven safety profile for both drugs, the expanding use of these agents in clinical practice may lead to an increased incidence of rare side effects, like metformin-associated lactic acidosis (MALA) and euglycemic diabetic ketoacidosis (EDKA), which can be life-threatening. A 58-year-old woman with T2DM and severe heart failure treated by metformin and empagliflozin developed progressive EDKA triggered by fasting that was also complicated by severe acute renal failure and MALA. She was successfully treated with intermittent hemodialysis. This case report highlights the importance of the recognition of rare, but very serious adverse effects due to combined metformin and SGLT2i therapy.

Keywords:  SGLT2-inhibitors; case report; ketoacidosis; lactic acidosis; metformin

DOI:  https://doi.org/10.1097/XCE.0000000000000287
Endocrinology. 2023 Jul 08. pii: bqad105. [Epub ahead of print]

Skeletal Muscle Endogenous Estrogen Production Ameliorates the Metabolic Consequences of a High-Fat Diet in Male Mice.

Christian A Unger, Ahmed K Aladhami, Marion C Hope, William E Cotham, Kendall W Nettles, Deborah J Clegg, Kandy T Velázquez, Reilly T Enos.

  AIMS: The role of skeletal muscle estrogen and its ability to mitigate the negative impact of a high-fat diet (HFD) on obesity-associated metabolic impairments is unknown. To address this, we developed a novel mouse model to determine the role of endogenous estrogen (E2) production in males in skeletal muscle via inducible, skeletal-muscle-specific aromatase overexpression (SkM-Arom↑).METHODS: Male SkM-Arom↑ mice and littermate controls were fed a HFD for 14 weeks prior to induction of SkM-Arom↑ for a period of 6.5 weeks. Glucose tolerance, insulin action, adipose tissue inflammation, and body composition were assessed. Indirect calorimetry and behavioral phenotyping experiments were performed using metabolic cages. Liquid chromatography-mass spectrometry was used to determine circulating and tissue (skeletal muscle, hepatic, and adipose) E2 and testosterone concentrations.
RESULTS: SkM-Arom↑ significantly increased E2 in skeletal muscle, circulation, the liver, and adipose tissue. SkM-Arom↑ ameliorated high fat diet induced hyperglycemia, hyperinsulinemia, impaired glucose tolerance, adipose tissue inflammation, and reduced hepatic lipid accumulation without causing skeletal muscle hypertrophy.
CONCLUSION: Enhanced skeletal muscle aromatase activity in male mice induces weight loss, improves metabolic and inflammatory outcomes and mitigates the negative effects of a HFD. Additionally, our data demonstrate for the first time skeletal muscle E2 has anabolic effects on the musculoskeletal system.

Keywords:  Skeletal muscle; aromatase; estrogen; metabolism; obesity

DOI:  https://doi.org/10.1210/endocr/bqad105
Adv Protein Chem Struct Biol. 2023 ;pii: S1876-1623(23)00040-8. [Epub ahead of print]136 35-91

Mitochondria in cell senescence: A Friend or Foe?

Qian Chen, Lindon Young, Robert Barsotti.

  Cell senescence denotes cell growth arrest in response to continuous replication or stresses damaging DNA or mitochondria. Mounting research suggests that cell senescence attributes to aging-associated failing organ function and diseases. Conversely, it participates in embryonic tissue maturation, wound healing, tissue regeneration, and tumor suppression. The acute or chronic properties and microenvironment may explain the double faces of senescence. Senescent cells display unique characteristics. In particular, its mitochondria become elongated with altered metabolomes and dynamics. Accordingly, mitochondria reform their function to produce more reactive oxygen species at the cost of low ATP production. Meanwhile, destructed mitochondrial unfolded protein responses further break the delicate proteostasis fostering mitochondrial dysfunction. Additionally, the release of mitochondrial damage-associated molecular patterns, mitochondrial Ca2+ overload, and altered NAD+ level intertwine other cellular organelle strengthening senescence. These findings further intrigue researchers to develop anti-senescence interventions. Applying mitochondrial-targeted antioxidants reduces cell senescence and mitigates aging by restoring mitochondrial function and attenuating oxidative stress. Metformin and caloric restriction also manifest senescent rescuing effects by increasing mitochondria efficiency and alleviating oxidative damage. On the other hand, Bcl2 family protein inhibitors eradicate senescent cells by inducing apoptosis to facilitate cancer chemotherapy. This review describes the different aspects of mitochondrial changes in senescence and highlights the recent progress of some anti-senescence strategies.

Keywords:  Bcl2 family protein inhibitors; Caloric restriction; Cell senescence; Metabolic reprograming; Metformin; Mitochondria-targeted antioxidants; Mitochondrial damage-associated molecular patterns; Mitochondrial unfolded protein responses; NAD(+); Reactive oxygen species

DOI:  https://doi.org/10.1016/bs.apcsb.2023.02.019
J Clin Med. 2023 Jul 03. pii: 4453. [Epub ahead of print]12(13):

Metabolic Flexibility and Inflexibility: Pathology Underlying Metabolism Dysfunction.

Marni E Shoemaker, Zachary M Gillen, David H Fukuda, Joel T Cramer.

Metabolic flexibility can be defined as the ability of the skeletal muscle to adjust its utilization of substrate pathways [...].

DOI: https://doi.org/10.3390/jcm12134453
Biogerontology. 2023 Jul 10.

Molecular mechanism of caloric restriction mimetics-mediated neuroprotection of age-related neurodegenerative diseases: an emerging therapeutic approach.

Apoorv Sharma, Abhishek Kumar Singh.

  Aging-induced neurodegenerative diseases (NDs) are significantly increasing health problem worldwide. It has been well documented that oxidative stress is one of the potential causes of aging and age-related NDs. There are no drugs for the treatment of NDs, therefore there is an immediate necessity for the development of strategies/treatments either to prevent or cure age-related NDs. Caloric restriction (CR) and intermittent fasting have been considered as effective strategies in increasing the healthspan and lifespan, but it is difficult to adhere to these routines strictly, which has led to the development of calorie restriction mimetics (CRMs). CRMs are natural compounds that provide similar molecular and biochemical effects of CR, and activate autophagy process. CRMs have been reported to regulate redox signaling by enhancing the antioxidant defense systems through activation of the Nrf2 pathway, and inhibiting ROS generation through attenuation of mitochondrial dysfunction. Moreover, CRMs also regulate redox-sensitive signaling pathways such as the PI3K/Akt and MAPK pathways to promote neuronal cell survival. Here, we discuss the neuroprotective effects of various CRMs at molecular and cellular levels during aging of the brain. The CRMs are envisaged to become a cornerstone of the pharmaceutical arsenal against aging and age-related pathologies.

Keywords:  Aging; Autophagy; Caloric restriction mimetics (CRMs); Neurodegenerative disorders; Neuroprotection; Redox signaling

DOI:  https://doi.org/10.1007/s10522-023-10045-y
J Cell Biol. 2023 08 07. pii: e202306035. [Epub ahead of print]222(8):

Chasing the right tail: How the ER membrane complex recognizes its substrates.

Doron Rapaport, Johannes M Herrmann.

Tail-anchored proteins are tethered to membranes of the ER, mitochondria, and peroxisomes. In this issue, Pleiner and colleagues (2023. J. Cell Biol.https://doi.org/10.1083/jcb.202212007) show that the ER membrane complex (EMC) uses an inbuilt charge-dependent selectivity filter to specifically insert ER tail-anchored proteins according to their topology signals and to prevent the misincorporation of mitochondrial proteins.

DOI: https://doi.org/10.1083/jcb.202306035
Crit Rev Food Sci Nutr. 2023 Jul 15. 1-24

Effects of mitochondria on postmortem meat quality: characteristic, isolation, energy metabolism, apoptosis and oxygen consumption.

Bo Zou, Fei Jia, Lin Ji, Xingmin Li, Ruitong Dai.

  Meat quality holds significant importance for both consumers and meat producers. Various factors influence meat quality, and among them, mitochondria play a crucial role. Recent studies have indicated that mitochondria can sustain their functions and viability for a certain duration in postmortem muscles. Consequently, mitochondria have an impact on oxygen consumption, energy metabolism, and apoptotic processes, which in turn affect myoglobin levels, oxidative stress, meat tenderness, fat oxidation, and protein oxidation. Ultimately, these factors influence the color, tenderness, and flavor of meat. However, there is a dearth of comprehensive summaries addressing the effects of mitochondria on postmortem muscle physiology and meat quality. Therefore, this review aims to describe the characteristics of muscle mitochondria and their potential influence on muscle. Additionally, a suitable method for isolating mitochondria is presented. Lastly, the review emphasizes the regulation of oxygen consumption, energy metabolism, and apoptosis by postmortem muscle mitochondria, and provides an overview of relevant research and recent advancements. The ultimate objective of this review is to elucidate the underlying mechanisms through which mitochondria impact meat quality.

Keywords:  Mitochondria; color; meat tenderness; oxidative phosphorylation; reactive oxygen species

DOI:  https://doi.org/10.1080/10408398.2023.2235435
Sports Med Health Sci. 2023 Jun;5(2): 156-158

Assessment of metabolic flexibility by measuring maximal fat oxidation during submaximal intensity exercise: Can we improve the analytical procedures?

Isaac A Chávez-Guevara.

  Assessment of maximal fat oxidation rate (MFO) during a submaximal exercise test has been employed by many studies to investigate the differences in metabolic flexibility (MetFlex) across several populations. Nevertheless, many incorrect assumptions and methodological limitations exist in the procedures employed by previous studies, which might lead to misinterpretation of the reported findings. Considering the data retrieved from 19 trained men (Age: [27 ± 4] years; %Body fat: [16.4 ± 4.5]%; maximal oxygen consumption: [55.8 ± 5.3] mL·kg-1·min-1) who performed a graded exercise test over a motor-driven treadmill, this opinion paper shows that MFO alone does not perfectly capture the MetFlex in response to submaximal intensity exercise and recommend a novel index that considers both fat oxidation and energy expenditure modifications for an accurate examination of MetFlex.

Keywords:  Energy metabolism; Exercise test; Indirect calorimetry; Methods

DOI:  https://doi.org/10.1016/j.smhs.2023.02.001
bioRxiv. 2023 Jun 29. pii: 2023.06.29.547095. [Epub ahead of print]

A partial Drp1 knockout improves autophagy flux independent of mitochondrial function.

Rebecca Z Fan, Carolina Sportelli, Yanhao Lai, Said Salehe, Jennifer R Pinnell, Jason R Richardson, Shouqing Luo, Kim Tieu.

Dynamin-related protein 1 (Drp1) is typically known for its role in mitochondrial fission. A partial inhibition of this protein has been reported to be protective in experimental models of neurodegenerative diseases. The protective mechanism has been attributed primarily to improved mitochondrial function. Herein, we provide evidence showing that a partial Drp1-knockout improves autophagy flux independent of mitochondria. First, we characterized in cell and animal models that at low non-toxic concentrations, manganese (Mn), which causes parkinsonian-like symptoms in humans, impaired autophagy flux but not mitochondrial function and morphology. Furthermore, nigral dopaminergic neurons were more sensitive than their neighbouring GABAergic counterparts. Second, in cells with a partial Drp1-knockdown and Drp1 +/- mice, autophagy impairment induced by Mn was significantly attenuated. This study demonstrates that autophagy is a more vulnerable target than mitochondria to Mn toxicity. Furthermore, improving autophagy flux is a separate mechanism conferred by Drp1 inhibition independent of mitochondrial fission.

DOI: https://doi.org/10.1101/2023.06.29.547095
Drug Des Devel Ther. 2023 ;17 2011-2023

SGLT1: A Potential Drug Target for Cardiovascular Disease.

Mengnan Zhao, Na Li, Hong Zhou.

  SGLT1 and SGLT2 are the two main members of the sodium-glucose cotransporters (SGLTs), which are mainly responsible for glucose reabsorption in the body. In recent years, many large clinical trials have shown that SGLT2 inhibitors have cardiovascular protection for diabetic and non-diabetic patients independent of lowering blood glucose. However, SGLT2 was barely detected in the hearts of humans and animals, while SGLT1 was highly expressed in myocardium. As SGLT2 inhibitors also have a moderate inhibitory effect on SGLT1, the cardiovascular protection of SGLT2 inhibitors may be due to SGLT1 inhibition. SGLT1 expression is associated with pathological processes such as cardiac oxidative stress, inflammation, fibrosis, and cell apoptosis, as well as mitochondrial dysfunction. The purpose of this review is to summarize the protective effects of SGLT1 inhibition on hearts in various cell types, including cardiomyocytes, endothelial cells, and fibroblasts in preclinical studies, and to highlight the underlying molecular mechanisms of protection against cardiovascular diseases. Selective SGLT1 inhibitors could be considered a class of drugs for cardiac-specific therapy in the future.

Keywords:  SGLT1 inhibitor; cardioprotection; heart failure; molecular mechanism; sodium glucose cotransporter 1

DOI:  https://doi.org/10.2147/DDDT.S418321
Behav Brain Res. 2023 Jul 11. pii: S0166-4328(23)00296-6. [Epub ahead of print]452 114578

NLRP3 inflammasome activation after ischemic stroke.

Ping-Ping Han, Yu Han, Xin-Ya Shen, Zhen-Kun Gao, Xia Bi.

  Cerebral ischemia is a pathological condition resulting from the cessation or reduction of blood supply to the cerebral arteries. Neurological deficits that are clinically relevant can arise as a result of brain damage. The etiology of stroke is multifaceted and intricate, with the inflammatory response being a crucial component that warrants significant attention. Following a cerebrovascular accident, the levels of interleukin-1 beta and interleukin-18 within the central nervous system escalate due to the activation of the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 inflammasome. The inflammation is aggravated by the subsequent occurrence of pyroptosis. The mechanisms that activate the NLRP3 inflammasome pyroptosis signaling pathway axis are described in this article. In addition, we go over how pyroptosis interacts with other processes for regulated cell death. In addition, specific NLRP3 inflammasome pathway inhibitors are identified, which offer new approaches to preventing ischemic brain injury.

Keywords:  Inflammation; Ischemic stroke; NLRP3 inflammasome; NLRP3 inflammasome inhibitor; Pyroptosis

DOI:  https://doi.org/10.1016/j.bbr.2023.114578
Mitochondrion. 2023 Jul 12. pii: S1567-7249(23)00067-3. [Epub ahead of print]

Mitochondrial respiratory complex I deficiency inhibits brown adipogenesis by limiting heme regulation of histone demethylation.

Jingjing Liu, Wen Lu, Dongyue Yan, Junyuan Guo, Li Zhou, Bimin Shi, Xiong Su.

  Mitochondrial functions play a crucial role in determining the metabolic and thermogenic status of brown adipocytes. Increasing evidence reveals that the mitochondrial oxidative phosphorylation (OXPHOS) system plays an important role in brown adipogenesis, but the mechanistic insights are limited. Herein, we explored the potential metabolic mechanisms leading to OXPHOS regulation of brown adipogenesis in pharmacological and genetic models of mitochondrial respiratory complex I deficiency. OXPHOS deficiency inhibits brown adipogenesis through disruption of the brown adipogenic transcription circuit without affecting ATP levels. Neither blockage of calcium signaling nor antioxidant treatment can rescue the suppressed brown adipogenesis. Metabolomics analysis revealed a decrease in levels of tricarboxylic acid cycle intermediates and heme. Heme supplementation specifically enhances respiratory complex I activity without affecting complex II and partially reverses the inhibited brown adipogenesis by OXPHOS deficiency. Moreover, the regulation of brown adipogenesis by the OXPHOS-heme axis may be due to the suppressed histone methylation status by increasing histone demethylation. In summary, our findings identified a heme-sensing retrograde signaling pathway that connects mitochondrial OXPHOS to the regulation of brown adipocyte differentiation and metabolic functions.

Keywords:  brown adipocytes; differentiation; heme; histone methylation; oxidative phosphorylation

DOI:  https://doi.org/10.1016/j.mito.2023.07.004
Front Physiol. 2023 ;14 1214087

Mass spectrometry of the white adipose metabolome in a hibernating mammal reveals seasonal changes in alternate fuels and carnitine derivatives.

Frazer I Heinis, Sophie Alvarez, Matthew T Andrews.

  Mammalian hibernators undergo substantial changes in metabolic function throughout the seasonal hibernation cycle. We report here the polar metabolomic profile of white adipose tissue isolated from active and hibernating thirteen-lined ground squirrels (Ictidomys tridecemlineatus). Polar compounds in white adipose tissue were extracted from five groups representing different timepoints throughout the seasonal activity-torpor cycle and analyzed using hydrophilic interaction liquid chromatography-mass spectrometry in both the positive and negative ion modes. A total of 224 compounds out of 660 features detected after curation were annotated. Unsupervised clustering using principal component analysis revealed discrete clusters representing the different seasonal timepoints throughout hibernation. One-way analysis of variance and feature intensity heatmaps revealed metabolites that varied in abundance between active and torpid timepoints. Pathway analysis compared against the KEGG database demonstrated enrichment of amino acid metabolism, purine metabolism, glycerophospholipid metabolism, and coenzyme A biosynthetic pathways among our identified compounds. Numerous carnitine derivatives and a ketone that serves as an alternate fuel source, beta-hydroxybutyrate (BHB), were among molecules found to be elevated during torpor. Elevated levels of the BHB-carnitine conjugate during torpor suggests the synthesis of beta-hydroxybutyrate in white adipose mitochondria, which may contribute directly to elevated levels of circulating BHB during hibernation.

Keywords:  HILIC-MS; ground squirrels; hibernation; hypothermia; metabolomics; polar metabolites; white adipose

DOI:  https://doi.org/10.3389/fphys.2023.1214087
Naunyn Schmiedebergs Arch Pharmacol. 2023 Jul 08.

Empagliflozin reduces endoplasmic reticulum stress associated TXNIP/NLRP3 activation in tunicamycin-stimulated aortic endothelial cells.

Marc-Antoine Campeau, Richard L Leask.

  Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have proven to be of therapeutic significance for cardiovascular diseases beyond the treatment of type 2 diabetes. Recent studies have demonstrated the beneficial effects of SGLT2i on endothelial cell (EC) dysfunction, but the underlying cellular mechanisms remain to be clarified. In this study, we sought to understand the effect of empagliflozin (EMPA; Jardiance®) on cell homeostasis and endoplasmic reticulum (ER) stress signaling. ER stress was induced by tunicamycin (Tm) in human abdominal aortic ECs treated with EMPA over 24 h. Tm-induced ER stress caused increases in the protein expression of thioredoxin interacting protein (TXNIP), NLR-family pyrin domain-containing protein 3 (NLRP3), C/EBP homologous protein (CHOP), and in the ratio of phospho-eIF2α/eIF2α. EMPA (50-100 µM) resulted in a dampened downstream activation of ER stress as seen by the reduced expression of CHOP and TXNIP/NLRP3 in a dose-dependent manner. Nuclear factor erythroid 2-related factor 2 (nrf2) translocation was also attenuated in EMPA-treated ECs. These results suggest that EMPA improves redox signaling under ER stress which in turn attenuates the activation of TXNIP/NLRP3.

Keywords:  Empagliflozin (EMPA); Endoplasmic reticulum stress (ER stress); NLR-family pyrin domain-containing 3 (NLRP3); Nuclear factor erythroid 2-related factor 2 (nrf2); Sodium/glucose cotransporter 2 (SGLT2) inhibitor; Sotagliflozin (SOTA); Thioredoxin interacting protein (TXNIP)

DOI:  https://doi.org/10.1007/s00210-023-02607-1
Int J Mol Sci. 2023 Jun 25. pii: 10634. [Epub ahead of print]24(13):

Anti-Inflammatory Activity of Black Soldier Fly Oil Associated with Modulation of TLR Signaling: A Metabolomic Approach.

Hadas Richter, Ofer Gover, Betty Schwartz.

  Dietary intervention in the treatment of ulcerative colitis involves, among other things, modifications in fatty acid content and/or profile. For example, replacing saturated long chain fatty acids with medium chain fatty acids (MCFAs) has been reported to ameliorate inflammation. The Black Soldier Fly Larvae's (BSFL) oil is considered a sustainable dietary ingredient rich in the MCFA C12:0; however, its effect on inflammatory-related conditions has not been studied until now. Thus, the present study aimed to investigate the anti-inflammatory activity of BSFL oil in comparison to C12:0 using TLR4- or TLR2-activated THP-1 and J774A.1 cell lines and to assess its putative protective effect against dextran sulfate sodium (DSS)-induced acute colitis in mice. BSFL oil and C12:0 suppressed proinflammatory cytokines release in LPS-stimulated macrophages; however, only BSFL oil exerted anti-inflammatory activity in Pam3CSK4-stimulated macrophages. Transcriptome analysis provided insight into the possible role of BSFL oil in immunometabolism switch, involving mTOR signaling and an increase in PPAR target genes promoting fatty acid oxidation, exhibiting a discrepant mode of action compared to C12:0 treatment, which mainly affected cholesterol biosynthesis pathways. Additionally, we identified anti-inflammatory eicosanoids, oxylipins, and isoprenoids in the BSFL oil that may contribute to an orchestrated anti-inflammatory response. In vivo, a BSFL oil-enriched diet (20%) ameliorated the clinical signs of colitis, as indicated by improved body weight recovery, reduced colon shortening, reduced splenomegaly, and an earlier phase of secretory IgA response. These results indicate the novel beneficial use of BSFL oil as a modulator of inflammation.

Keywords:  Pam3CSK4; Toll-like receptor (TLR); black soldier fly larvae (BSFL); dextran sulfate sodium (DSS)-induced colitis; lipopolysaccharides (LPS); macrophage; mammalian target of rapamycin (mTOR); medium chain fatty acid (MCFA) C12:0; peroxisome proliferator-activated receptor (PPAR); proinflammatory cytokine

DOI:  https://doi.org/10.3390/ijms241310634