bims-kimdis Biomed News
on Ketones, inflammation and mitochondria in disease
Issue of 2024‒07‒14
27 papers selected by
Matías Javier Monsalves Álvarez, Universidad Andrés Bello
  1. Ketone body metabolism and the NLRP3 inflammasome in Alzheimer's disease.
  2. Long-term use of investigational β-Hydroxybutyrate salts in children with multiple acyl-CoA dehydrogenase or pyruvate dehydrogenase deficiency.
  3. Effects of a Ketogenic Diet on Body Composition in Healthy, Young, Normal-Weight Women: A Randomized Controlled Feeding Trial.
  4. Novel methodology to enrich medium- and short-chain fatty acids in milk fat to improve metabolic health.
  5. Metabolic Effects of Ketogenic Diets: Exploring Whole-Body Metabolism in Connection with Adipose Tissue and Other Metabolic Organs.
  6. Reduced oxidative capacity of skeletal muscle IS NOT an inevitable consequence of adult ageing.
  7. Rebuttal: reduced oxidative capacity of skeletal muscle IS NOT an inevitable consequence of adult ageing.
  8. Ketogenic diet improves chromatin remodeling and rescues mitochondrial dysfunction in ischemic heart disease by regulating PGC-1alpha transcription.
  9. Beta-hydroxybutyrate promotes basal insulin secretion while decreasing glucagon secretion in mouse and human islets.
  10. Integrative effects of resistance training and endurance training on mitochondrial remodeling in skeletal muscle.
  11. Reduced oxidative capacity of skeletal muscle mitochondria is a fundamental consequence of adult ageing.
  12. The Role of Short Chain Fatty Acids in Inflammation and Body Health.
  13. Mitochondrial Adaptation in Skeletal Muscle: Impact of Obesity, Caloric Restriction, and Dietary Compounds.
  14. Lactate promotes fatty acid oxidation by the TCA cycle and mitochondrial respiration in muscles of obese mice.
  15. Epigenetic control of skeletal muscle atrophy.
  16. Intermittent Fasting: Myths, Fakes and Truth on This Dietary Regimen Approach.
  17. Skeletal muscle dysfunction with advancing age.
  18. PINK1 regulated mitophagy is evident in skeletal muscles.
  19. Isolation of Mitochondria from Murine Skeletal Muscle.
  20. Is it Time to Define Obesity by Body Composition and Not Solely Body Mass Index?
  21. Inhibition of NLRP3 inflammasome ameliorates LPS-induced neuroinflammatory injury in mice via PINK1/Parkin pathway.
  22. Exercise as a tool to mitigate metabolic disease.
  23. Sucrose-induced metabolic syndrome differentially affects energy metabolism and fiber phenotype of EDL and soleus muscles during exercise in the rat.
  24. Stop the madness! An urgent call to standardize the assessment of exercise physiology thresholds.
  25. A roadmap for ribosome assembly in human mitochondria.
  26. Effects of Mitoquinone (MitoQ) Supplementation on Aerobic Exercise Performance and Oxidative Damage: A Systematic Review and Meta-analysis.
  27. New insights into the function of the NLRP3 inflammasome in sarcopenia: mechanism and therapeutic strategies.
  1. Immunol Rev. 2024 Jul 11.
    Ketone body metabolism and the NLRP3 inflammasome in Alzheimer's disease.
    Daniel C Shippy, Abigail H Evered, Tyler K Ulland.
      Alzheimer's disease (AD) is a degenerative brain disorder and the most common form of dementia. AD pathology is characterized by senile plaques and neurofibrillary tangles (NFTs) composed of amyloid-β (Aβ) and hyperphosphorylated tau, respectively. Neuroinflammation has been shown to drive Aβ and tau pathology, with evidence suggesting the nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome as a key pathway in AD pathogenesis. NLRP3 inflammasome activation in microglia, the primary immune effector cells of the brain, results in caspase-1 activation and secretion of IL-1β and IL-18. Recent studies have demonstrated a dramatic interplay between the metabolic state and effector functions of immune cells. Microglial metabolism in AD is of particular interest, as ketone bodies (acetone, acetoacetate (AcAc), and β-hydroxybutyrate (BHB)) serve as an alternative energy source when glucose utilization is compromised in the brain of patients with AD. Furthermore, reduced cerebral glucose metabolism concomitant with increased BHB levels has been demonstrated to inhibit NLRP3 inflammasome activation. Here, we review the role of the NLRP3 inflammasome and microglial ketone body metabolism in AD pathogenesis. We also highlight NLRP3 inflammasome inhibition by several ketone body therapies as a promising new treatment strategy for AD.
    Keywords:  Alzheimer's disease; Beta‐hydroxybutyrate; NLRP3 inflammasome; ketone bodies; metabolism; microglia
    DOI:  https://doi.org/10.1111/imr.13365
  2. Mol Genet Metab Rep. 2024 Sep;40 101104
    Long-term use of investigational β-Hydroxybutyrate salts in children with multiple acyl-CoA dehydrogenase or pyruvate dehydrogenase deficiency.
    Andrew A M Morris, Bernard Cuenoud, Philippe Delerive, Helen Mundy, Bernd C Schwahn.
      Several disorders of energy metabolism have been treated with exogenous ketone bodies. The benefit of this treatment is best documented in multiple acyl-CoA dehydrogenase deficiency (MADD) (MIM#231680). One might also expect ketone bodies to help in other disorders with impaired ketogenesis or in conditions that profit from a ketogenic diet. Here, we report the use of a novel preparation of dextro-β-hydroxybutyrate (D-βHB) salts in two cases of MADD and one case of pyruvate dehydrogenase (PDH) deficiency (MIM#312170). The two patients with MADD had previously been on a racemic mixture of D- and L‑sodium hydroxybutyrate. Patient #1 found D-βHB more palatable, and the change in formulation corrected hypernatraemia in patient #2. The patient with PDH deficiency was on a ketogenic diet but had not previously been given hydroxybutyrate. In this case, the addition of D-βHB improved ketosis. We conclude that NHS101 is a good candidate for further clinical studies in this group of diseases of inborn errors of metabolism.
    Keywords:  Glutaric aciduria II; Ketone bodies; MADD; Pyruvate dehydrogenase deficiency; β-Hydroxybutyrate
    DOI:  https://doi.org/10.1016/j.ymgmr.2024.101104
  3. Nutrients. 2024 Jun 26. pii: 2030. [Epub ahead of print]16(13):
    Effects of a Ketogenic Diet on Body Composition in Healthy, Young, Normal-Weight Women: A Randomized Controlled Feeding Trial.
    Jonas Burén, Michael Svensson, Per Liv, Anna Sjödin.
      This study investigates the effects of a ketogenic low-carbohydrate high-fat (LCHF) diet on body composition in healthy, young, normal-weight women. With the increasing interest in ketogenic diets for their various health benefits, this research aims to understand their impact on body composition, focusing on women who are often underrepresented in such studies. Conducting a randomized controlled feeding trial with a crossover design, this study compares a ketogenic LCHF diet to a Swedish National Food Agency (NFA)-recommended control diet over four weeks. Seventeen healthy, young, normal-weight women adhered strictly to the provided diets, with ketosis confirmed through blood β-hydroxybutyrate concentrations. Dual-energy X-ray absorptiometry (DXA) was utilized for precise body composition measurements. To avoid bias, all statistical analyses were performed blind. The findings reveal that the ketogenic LCHF diet led to a significant reduction in both lean mass (-1.45 kg 95% CI: [-1.90;-1.00]; p < 0.001) and fat mass (-0.66 kg 95% CI: [-1.00;-0.32]; p < 0.001) compared to the control diet, despite similar energy intake and physical activity levels. This study concludes that while the ketogenic LCHF diet is effective for weight loss, it disproportionately reduces lean mass over fat mass, suggesting the need for concurrent strength training to mitigate muscle loss in women following this diet.
    Keywords:  DEXA; carbohydrate restriction; fat-free mass (FFM); female; high-fat diet (HFD); low-carbohydrate diet (LCD); metabolism; saturated fatty acids; sports nutrition; weight reduction
    DOI:  https://doi.org/10.3390/nu16132030
  4. Food Funct. 2024 Jul 09.
    Novel methodology to enrich medium- and short-chain fatty acids in milk fat to improve metabolic health.
    Sally Samsø Mathiasen, Josephine M Kanta, Rikke P Frydenberg, Annemarie Lundsgaard, Zheng Guo, Andreas M Fritzen, Bente Kiens, Lars Wiking, Maximilian Kleinert.
      Dietary short- and medium-chain fatty acids have been shown to elevate circulating ketone bodies and confer metabolic health benefits. Cow milk fat contains these lipids in a balanced mix but in relatively low concentrations. Enriching them could amplify health benefits of dairy products. Here, we used a volatility-based workflow to produce milk fat with a 2-fold enrichment of medium- and short-chain fatty acids (referred to as MSFAT). Our proof-of-concept studies in mice demonstrated that intake of MSFAT increased circulating ketone bodies, reduced blood glucose levels, and suppressed food intake. In humans, ingestion of MSFAT resulted in increased circulating ketone bodies, trended to attenuate (p = 0.07) postprandial glucose excursion, and acutely elevated energy expenditure. Our findings show that milk products enriched with MSFAT may hold significant metabolic advantages.
    DOI:  https://doi.org/10.1039/d4fo00267a
  5. Int J Mol Sci. 2024 Jun 27. pii: 7076. [Epub ahead of print]25(13):
    Metabolic Effects of Ketogenic Diets: Exploring Whole-Body Metabolism in Connection with Adipose Tissue and Other Metabolic Organs.
    Yusra Ahmad, Dong Soo Seo, Younghoon Jang.
      The ketogenic diet (KD) is characterized by minimal carbohydrate, moderate protein, and high fat intake, leading to ketosis. It is recognized for its efficiency in weight loss, metabolic health improvement, and various therapeutic interventions. The KD enhances glucose and lipid metabolism, reducing triglycerides and total cholesterol while increasing high-density lipoprotein levels and alleviating dyslipidemia. It significantly influences adipose tissue hormones, key contributors to systemic metabolism. Brown adipose tissue, essential for thermogenesis and lipid combustion, encounters modified UCP1 levels due to dietary factors, including the KD. UCP1 generates heat by uncoupling electron transport during ATP synthesis. Browning of the white adipose tissue elevates UCP1 levels in both white and brown adipose tissues, a phenomenon encouraged by the KD. Ketone oxidation depletes intermediates in the Krebs cycle, requiring anaplerotic substances, including glucose, glycogen, or amino acids, for metabolic efficiency. Methylation is essential in adipogenesis and the body's dietary responses, with DNA methylation of several genes linked to weight loss and ketosis. The KD stimulates FGF21, influencing metabolic stability via the UCP1 pathways. The KD induces a reduction in muscle mass, potentially involving anti-lipolytic effects and attenuating proteolysis in skeletal muscles. Additionally, the KD contributes to neuroprotection, possesses anti-inflammatory properties, and alters epigenetics. This review encapsulates the metabolic effects and signaling induced by the KD in adipose tissue and major metabolic organs.
    Keywords:  adipose tissue; adipose tissue hormone; cancer cachexia; ketogenic diet; metabolic organ; metabolic signaling
    DOI:  https://doi.org/10.3390/ijms25137076
  6. J Physiol. 2024 Jul 06.
    Reduced oxidative capacity of skeletal muscle IS NOT an inevitable consequence of adult ageing.
    Ian R Lanza, Christopher W Sundberg, Jane A Kent.
      
    Keywords:  ageing; mitochondria; oxidative phosphorylation; skeletal muscle
    DOI:  https://doi.org/10.1113/JP285042
  7. J Physiol. 2024 Jul 06.
    Rebuttal: reduced oxidative capacity of skeletal muscle IS NOT an inevitable consequence of adult ageing.
    Ian R Lanza, Christopher W Sundberg, Jane A Kent.
      
    Keywords:  ageing; mitochondria; muscle; oxidative phosphorylation
    DOI:  https://doi.org/10.1113/JP286695
  8. Vascul Pharmacol. 2024 Jun;pii: S1537-1891(24)00073-9. [Epub ahead of print]155 107348
    Ketogenic diet improves chromatin remodeling and rescues mitochondrial dysfunction in ischemic heart disease by regulating PGC-1alpha transcription.
    Jessica Gambardella, Fahimeh Varzideh, Stanislovas S Jankauskas, Urna Kansakar, Simone Sidoli, Angela Lombardi, Gaetano Santulli.
      
    DOI:  https://doi.org/10.1016/j.vph.2024.107348
  9. Endocrinology. 2024 Jul 06. pii: bqae079. [Epub ahead of print]
    Beta-hydroxybutyrate promotes basal insulin secretion while decreasing glucagon secretion in mouse and human islets.
    Risha Banerjee, Ying Zhu, George P Brownrigg, Renata Moravcova, Jason C Rogalski, Leonard J Foster, James D Johnson, Jelena Kolic.
      Dietary carbohydrates raise blood glucose and limiting carbohydrate intake improves glycemia in patients with type 2 diabetes. Low carbohydrate intake (< 25 g) allows the body to utilize fat as its primary fuel. As a consequence of increased fatty acid oxidation, the liver produces ketones to serve as an alternative energy source. β-Hydroxybutyrate (βHB) is the most abundant ketone. While βHB has a wide range of functions outside of the pancreas, its direct effects on islet cell function remain understudied. We examined human islet secretory response to acute racemic βHB treatment and observed increased insulin secretion at low glucose concentrations (3 mM glucose). Because βHB is a chiral molecule, existing as both R and S forms, we further studied insulin and glucagon secretion following acute treatment with individual βHB enantiomers in human and C57BL6/J mouse islets. We found that acute treatment with R-βHB increased insulin secretion and decreased glucagon secretion at physiological glucose concentrations in both human and mouse islets. Proteomic analysis of human islets treated with R-βHB over 72 h showed altered abundance of proteins that may promote islet cell health and survival. Collectively, our data show that physiological concentrations of βHB influence hormone secretion and signaling within pancreatic islets.
    Keywords:  Beta-hydroxybutyrate; beta cell; glucagon; human islets; insulin
    DOI:  https://doi.org/10.1210/endocr/bqae079
  10. Eur J Appl Physiol. 2024 Jul 09.
    Integrative effects of resistance training and endurance training on mitochondrial remodeling in skeletal muscle.
    Yong-Cai Zhao, Bing-Hong Gao.
      Resistance training activates mammalian target of rapamycin (mTOR) pathway of hypertrophy for strength gain, while endurance training increases peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) pathway of mitochondrial biogenesis benefiting oxidative phosphorylation. The conventional view suggests that resistance training-induced hypertrophy signaling interferes with endurance training-induced mitochondrial remodeling. However, this idea has been challenged because acute leg press and knee extension in humans enhance both muscle hypertrophy and mitochondrial remodeling signals. Thus, we first examined the muscle mitochondrial remodeling and hypertrophy signals with endurance training and resistance training, respectively. In addition, we discussed the influence of resistance training on muscle mitochondria, demonstrating that the PGC-1α-mediated muscle mitochondrial adaptation and hypertrophy occur simultaneously. The second aim was to discuss the integrative effects of concurrent training, which consists of endurance and resistance training sessions on mitochondrial remodeling. The study found that the resistance training component does not reduce muscle mitochondrial remodeling signals in concurrent training. On the contrary, concurrent training has the potential to amplify skeletal muscle mitochondrial biogenesis compared to a single exercise model. Concurrent training involving differential sequences of resistance and endurance training may result in varied mitochondrial biogenesis signals, which should be linked to the pre-activation of mTOR or PGC-1α signaling. Our review proposed a mechanism for mTOR signaling that promotes PGC-1α signaling through unidentified pathways. This mechanism may be account for the superior muscle mitochondrial remodeling change following the concurrent training. Our review suggested an interaction between resistance training and endurance training in skeletal muscle mitochondrial adaptation.
    Keywords:  Concurrent training; Mitochondrial biogenesis; Skeletal muscle
    DOI:  https://doi.org/10.1007/s00421-024-05549-5
  11. J Physiol. 2024 Jul 06.
    Reduced oxidative capacity of skeletal muscle mitochondria is a fundamental consequence of adult ageing.
    David J Marcinek, Luigi Ferrucci.
      
    Keywords:  ageing; magnetic resonance; mitochondria; sarcopenia; skeletal muscle
    DOI:  https://doi.org/10.1113/JP285040
  12. Int J Mol Sci. 2024 Jul 05. pii: 7379. [Epub ahead of print]25(13):
    The Role of Short Chain Fatty Acids in Inflammation and Body Health.
    Yuhang Du, Changhao He, Yongcheng An, Yan Huang, Huilin Zhang, Wanxin Fu, Menglu Wang, Ziyi Shan, Jiamei Xie, Yang Yang, Baosheng Zhao.
      Short chain fatty acids (SCFAs), mainly including acetate, propionate and butyrate, are produced by intestinal bacteria during the fermentation of partially digested and indigestible polysaccharides. SCFAs play an important role in regulating intestinal energy metabolism and maintaining the homeostasis of the intestinal environment and also play an important regulatory role in organs and tissues outside the gut. In recent years, many studies have shown that SCFAs can regulate inflammation and affect host health, and two main signaling mechanisms have also been identified: the activation of G-protein coupled receptors (GPCRs) and inhibition of histone deacetylase (HDAC). In addition, a growing body of evidence highlights the importance of every SCFA in influencing health maintenance and disease development. In this review, we summarized the recent advances concerning the biological properties of SCFAs and their signaling pathways in inflammation and body health. Hopefully, it can provide a systematic theoretical basis for the nutritional prevention and treatment of human diseases.
    Keywords:  gut microbiota; inflammation; metabolic disease; short chain fatty acids; signaling pathways
    DOI:  https://doi.org/10.3390/ijms25137379
  13. Curr Nutr Rep. 2024 Jul 08.
    Mitochondrial Adaptation in Skeletal Muscle: Impact of Obesity, Caloric Restriction, and Dietary Compounds.
    Lauren Jun, Ya-Xiong Tao, Thangiah Geetha, Jeganathan Ramesh Babu.
      PURPOSE OF REVIEW: The global obesity epidemic has become a major public health concern, necessitating comprehensive research into its adverse effects on various tissues within the human body. Among these tissues, skeletal muscle has gained attention due to its susceptibility to obesity-related alterations. Mitochondria are primary source of energy production in the skeletal muscle. Healthy skeletal muscle maintains constant mitochondrial content through continuous cycle of synthesis and degradation. However, obesity has been shown to disrupt this intricate balance. This review summarizes recent findings on the impact of obesity on skeletal muscle mitochondria structure and function. In addition, we summarize the molecular mechanism of mitochondrial quality control systems and how obesity impacts these systems. RECENT FINDINGS: Recent findings show various interventions aimed at mitigating mitochondrial dysfunction in obese model, encompassing strategies including caloric restriction and various dietary compounds. Obesity has deleterious effect on skeletal muscle mitochondria by disrupting mitochondrial biogenesis and dynamics. Caloric restriction, omega-3 fatty acids, resveratrol, and other dietary compounds enhance mitochondrial function and present promising therapeutic opportunities.
    Keywords:  Metabolic disease; Mitochondrial biogenesis; Mitochondrial dynamics; Omega-3 fatty acids; Resveratrol; Skeletal muscle fiber type
    DOI:  https://doi.org/10.1007/s13668-024-00555-7
  14. Am J Physiol Cell Physiol. 2024 Jul 09.
    Lactate promotes fatty acid oxidation by the TCA cycle and mitochondrial respiration in muscles of obese mice.
    Soi-Yi Park, Su-Ryun Jung, Jong-Yeon Kim, Yong-Woon Kim, Hoon-Ki Sung, So-Young Park, Kyung-Oh Doh, Jin-Ho Koh.
      Lower oxidative capacity in skeletal muscles (SKMs) is a prevailing cause of metabolic diseases. Exercise not only enhances the fatty acid oxidation (FAO) capacity of SKMs but also increases lactate levels. Given that lactate may contribute to tricarboxylic acid cycle (TCA) flux and impact monocarboxylate transporter 1 in the SKMs, we hypothesize that lactate can influence glucose and fatty acid (FA) metabolism. To test this hypothesis, we investigated the mechanism underlying lactate-driven FAO regulation in the SKM of mice with diet-induced obesity (DIO). Lactate was administered to DIO mice immediately after exercise over three weeks. We found that increased lactate levels enhanced energy expenditure mediated by fat metabolism during exercise recovery and decreased triglyceride levels in DIO mice SKMs. To determine the lactate-specific effects without exercise, we administered lactate to mice on a high-fat diet (HFD) for eight weeks. Similar to our exercise conditions, lactate increased FAO, TCA cycle activity, and mitochondrial respiration in the SKMs of HFD-fed mice. Additionally, under sufficient FA conditions, lactate increased uncoupling protein-3 abundance via the NADH/NAD+ shuttle. Conversely ATP synthase abundance decreased in the SKMs of HFD mice. Taken together, our results suggest that lactate amplifies the adaptive increase in FAO capacity mediated by the TCA cycle and mitochondrial respiration in SKMs under sufficient FA abundance.
    Keywords:  Exercise; Fatty acid oxidation; Lactate; Mitochondrial respiration; TCA cycle
    DOI:  https://doi.org/10.1152/ajpcell.00060.2024
  15. Cell Mol Biol Lett. 2024 Jul 08. 29(1): 99
    Epigenetic control of skeletal muscle atrophy.
    Wenpeng Liang, Feng Xu, Li Li, Chunlei Peng, Hualin Sun, Jiaying Qiu, Junjie Sun.
      Skeletal muscular atrophy is a complex disease involving a large number of gene expression regulatory networks and various biological processes. Despite extensive research on this topic, its underlying mechanisms remain elusive, and effective therapeutic approaches are yet to be established. Recent studies have shown that epigenetics play an important role in regulating skeletal muscle atrophy, influencing the expression of numerous genes associated with this condition through the addition or removal of certain chemical modifications at the molecular level. This review article comprehensively summarizes the different types of modifications to DNA, histones, RNA, and their known regulators. We also discuss how epigenetic modifications change during the process of skeletal muscle atrophy, the molecular mechanisms by which epigenetic regulatory proteins control skeletal muscle atrophy, and assess their translational potential. The role of epigenetics on muscle stem cells is also highlighted. In addition, we propose that alternative splicing interacts with epigenetic mechanisms to regulate skeletal muscle mass, offering a novel perspective that enhances our understanding of epigenetic inheritance's role and the regulatory network governing skeletal muscle atrophy. Collectively, advancements in the understanding of epigenetic mechanisms provide invaluable insights into the study of skeletal muscle atrophy. Moreover, this knowledge paves the way for identifying new avenues for the development of more effective therapeutic strategies and pharmaceutical interventions.
    Keywords:  Histone modifications; Skeletal muscle atrophy; Ubiquitin–proteasome; epigenetic; m6A
    DOI:  https://doi.org/10.1186/s11658-024-00618-1
  16. Foods. 2024 Jun 21. pii: 1960. [Epub ahead of print]13(13):
    Intermittent Fasting: Myths, Fakes and Truth on This Dietary Regimen Approach.
    Simone Brogi, Rita Tabanelli, Sara Puca, Vincenzo Calderone.
      Intermittent fasting (IF) has been indicated as a valuable alternative to the classical caloric restriction dietary regimen for lowering body weight and preventing obesity-related complications, such as metabolic syndrome and type II diabetes. However, is it effective? In this review article, we analyzed over 50 clinical studies in which IF, conducted by alternate day fasting (ADF) or time-restricted feeding (TRF), was compared with the caloric restriction approach. We evaluated the different roles of IF in treating and preventing human disorders such as metabolic syndrome, type II diabetes, and some types of cancer, as well as the usefulness of IF in reducing body weight and cardiovascular risk factors such as hypertension. Furthermore, we explored the cellular pathways targeted by IF to exert their beneficial effects by activating effector proteins that modulate cell functions and resistance to oxidative stress. In contrast, we investigated concerns regarding human health related to the adoption of IF dietary regimens, highlighting the profound debate surrounding weight loss regimens. We examined and compared several clinical trials to formulate an updated concept regarding IF and its therapeutic potential.
    Keywords:  alternate day fasting (ADF); dietary regimen; intermittent fasting (IF); obesity; time-restricted feeding (TRF)
    DOI:  https://doi.org/10.3390/foods13131960
  17. Clin Sci (Lond). 2024 Jul 17. 138(14): 863-882
    Skeletal muscle dysfunction with advancing age.
    Pardeep Pabla, Eleanor J Jones, Mathew Piasecki, Bethan E Phillips.
      As a result of advances in medical treatments and associated policy over the last century, life expectancy has risen substantially and continues to increase globally. However, the disconnect between lifespan and 'health span' (the length of time spent in a healthy, disease-free state) has also increased, with skeletal muscle being a substantial contributor to this. Biological ageing is accompanied by declines in both skeletal muscle mass and function, termed sarcopenia. The mechanisms underpinning sarcopenia are multifactorial and are known to include marked alterations in muscle protein turnover and adaptations to the neural input to muscle. However, to date, the relative contribution of each factor remains largely unexplored. Specifically, muscle protein synthetic responses to key anabolic stimuli are blunted with advancing age, whilst alterations to neural components, spanning from the motor cortex and motoneuron excitability to the neuromuscular junction, may explain the greater magnitude of function losses when compared with mass. The consequences of these losses can be devastating for individuals, their support networks, and healthcare services; with clear detrimental impacts on both clinical (e.g., mortality, frailty, and post-treatment complications) and societal (e.g., independence maintenance) outcomes. Whether declines in muscle quantity and quality are an inevitable component of ageing remains to be completely understood. Nevertheless, strategies to mitigate these declines are of vital importance to improve the health span of older adults. This review aims to provide an overview of the declines in skeletal muscle mass and function with advancing age, describes the wide-ranging implications of these declines, and finally suggests strategies to mitigate them, including the merits of emerging pharmaceutical agents.
    Keywords:  activity; aging; neuromuscular; physical function; skeletal muscle
    DOI:  https://doi.org/10.1042/CS20231197
  18. Autophagy Rep. 2024 Mar 11. 3(1): 2326402
    PINK1 regulated mitophagy is evident in skeletal muscles.
    Francois Singh, Lea Wilhelm, Alan R Prescott, Kevin Ostacolo, Jin-Feng Zhao, Margret H Ogmundsdottir, Ian G Ganley.
      PINK1, mutated in familial forms of Parkinson's disease, initiates mitophagy following mitochondrial depolarization. However, it is difficult to monitor this pathway physiologically in mice as loss of PINK1 does not alter basal mitophagy levels in most tissues. To further characterize this pathway in vivo, we used mito-QC mice in which loss of PINK1 was combined with the mitochondrial-associated POLGD257A mutation. We focused on skeletal muscle as gene expression data indicates that this tissue has the highest PINK1 levels. We found that loss of PINK1 in oxidative hindlimb muscle significantly reduced mitophagy. Of interest, the presence of the POLGD257A mutation, while having a minor effect in most tissues, restored levels of muscle mitophagy caused by the loss of PINK1. Although our observations highlight that multiple mitophagy pathways operate within a single tissue, we identify skeletal muscle as a tissue of choice for the study of PINK1-dependant mitophagy under basal conditions.
    Keywords:  PINK1; POLG; Parkinson’s; mitophagy; muscle; mutator
    DOI:  https://doi.org/10.1080/27694127.2024.2326402
  19. Methods Mol Biol. 2024 ;2816 77-85
    Isolation of Mitochondria from Murine Skeletal Muscle.
    Li Dong, Xuejun Li, Ang Li, Jianxun Yi, Jingsong Zhou.
      Skeletal muscle is one of the largest tissues in human body. Besides enabling voluntary movements and maintaining body's metabolic homeostasis, skeletal muscle is also a target of many pathological conditions. Mitochondria occupy 10-15% volume of a muscle myofiber and regulate many cellular processes, which often determine the fate of the cell. Isolation of mitochondria from skeletal muscle provides opportunities for various multi-omics studies with a focus on mitochondria in biomedical research field. Here we describe a protocol to efficiently isolate mitochondria with high quality and purity from skeletal muscle of mice using Nycodenz density gradient ultracentrifugation.
    Keywords:  Mitochondria isolation; Nycodenz density gradient ultracentrifugation; Skeletal muscle
    DOI:  https://doi.org/10.1007/978-1-0716-3902-3_8
  20. J Clin Endocrinol Metab. 2024 Jul 12. pii: dgae473. [Epub ahead of print]
    Is it Time to Define Obesity by Body Composition and Not Solely Body Mass Index?
    Eugene Lucas, Louis J Aronne.
      
    Keywords:  Anti-Obesity Medications; Body Composition Assessments; Muscle Mass; Obesity; Protein; Strength Assessments
    DOI:  https://doi.org/10.1210/clinem/dgae473
  21. Neuropharmacology. 2024 Jul 06. pii: S0028-3908(24)00232-6. [Epub ahead of print]257 110063
    Inhibition of NLRP3 inflammasome ameliorates LPS-induced neuroinflammatory injury in mice via PINK1/Parkin pathway.
    Ao Wang, Guangshang Zhong, Mengjiao Ying, Zhuling Fang, Ying Chen, Haojie Wang, Chunjing Wang, Changqing Liu, Yu Guo.
      Parkinson's disease (PD) is characterized by the severe loss of dopaminergic neurons in the substantia nigra pars compacta, leading to motor dysfunction. The onset of PD is often accompanied by neuroinflammation and α-Synuclein aggregation, and extensive research has focused on the activation of microglial NLRP3 inflammasomes in PD, which promotes the death of dopaminergic neurons. In this study, a model of cerebral inflammatory response was constructed in wild-type and Parkin＋/－ mice through bilateral intraventricular injection of LPS. LPS-induced activation of the NLRP3 inflammasome in wild-type mice promotes the progression of PD. The use of MCC950 in wild mice injected with LPS induces activation of Parkin/PINK and improves autophagy, which in turn improves mitochondrial turnover. It also inhibits LPS-induced inflammatory responses, improves motor function, protects dopaminergic neurons, and inhibits microglia activation. Furthermore, Parkin＋/－ mice exhibited motor dysfunction, loss of dopaminergic neurons, activation of the NLRP3 inflammasome, and α-Synuclein aggregation beginning at an early age. Parkin ± mice exhibited more pronounced microglia activation, greater NLRP3 inflammasome activation, more severe autophagy dysfunction, and more pronounced motor dysfunction after LPS injection compared to wild-type mice. Notably, the use of MCC950 in Parkin ± mice did not ameliorate NLRP3 inflammasome activation, autophagy dysfunction, or α-synuclein aggregation. Thus, MCC950 can only exert its effects in the presence of Parkin/PINK1, and targeting Parkin-mediated NLRP3 inflammasome activation is expected to be a potential therapeutic strategy for Parkinson's disease.
    Keywords:  MCC950; NLRP3 inflammasome; Parkin; Parkinson's disease; α-Synuclein
    DOI:  https://doi.org/10.1016/j.neuropharm.2024.110063
  22. Am J Physiol Cell Physiol. 2024 Jul 09.
    Exercise as a tool to mitigate metabolic disease.
    Joao Victor Esteves, Kristin I Stanford.
      Metabolic diseases, notably obesity and type 2 diabetes, have reached alarming proportions and constitute a significant global health challenge, emphasizing the urgent need for effective preventive and therapeutic strategies. In contrast, exercise training emerges as a potent intervention, exerting numerous positive effects on metabolic health through adaptations to the metabolic tissues. Here, we reviewed the major features of our current understanding with respect to the intricate interplay between metabolic diseases and key metabolic tissues, including adipose tissue, skeletal muscle, and liver, describing some of the main underlying mechanisms driving pathogenesis, as well as the role of exercise to combat and treat obesity and metabolic disease.
    Keywords:  Exercise; adipose tissue; insulin resistance; metabolism; skeletal muscle
    DOI:  https://doi.org/10.1152/ajpcell.00144.2024
  23. Physiol Rep. 2024 Jul;12(13): e16126
    Sucrose-induced metabolic syndrome differentially affects energy metabolism and fiber phenotype of EDL and soleus muscles during exercise in the rat.
    Rodríguez-Correa Eduardo, Carvajal Karla.
      Molecular mechanisms associated to improvement of metabolic syndrome (MetS) during exercise are not fully elucidated. MetS was induced in 250 g male Wistar rats by 30% sucrose in drinking water. Control rats receiving tap water were controls, both groups received solid standard diet. After 14 weeks, an endurance exercised group, and a sedentary were formed for 8 weeks. The soleus and extensor digitorum longus (EDL) muscles were dissected to determine contractile performance, expression of myosin heavy chain isoforms, PGC1α, AMPKα2, NFATC1, MEF2a, SIX1, EYA1, FOXO1, key metabolic enzymes activities. Exercise mildly improved MetS features. MetS didn't alter the contractile performance of the muscles. Exercise didn't altered expression of PGC1α, NFATC1, SIX1 and EYA1 on MetS EDL whereas NFATC1 increased in soleus. Only citrate synthase was affected by MetS on the EDL and this was partially reverted by exercise. Soleus α-ketoglutarate dehydrogenase activity was increased by exercise but MetS rendered the muscle resistant to this effect. MetS affects mostly the EDL muscle, and endurance exercise only partially reverts this. Soleus muscle seems more resilient to MetS. We highlight the importance of studying both muscles during MetS, and their metabolic remodeling on the development and treatment of MetS by exercise.
    Keywords:  exercise; metabolic syndrome; metabolism; myosin; skeletal muscle
    DOI:  https://doi.org/10.14814/phy2.16126
  24. J Physiol. 2024 Jul 07.
    Stop the madness! An urgent call to standardize the assessment of exercise physiology thresholds.
    Isaac A Chavez-Guevara, Jørn W Helge, Francisco J Amaro-Gahete.
      
    Keywords:  cardiopulmonary exercise testing; methods; reliability
    DOI:  https://doi.org/10.1113/JP287084
  25. Nat Struct Mol Biol. 2024 Jul 11.
    A roadmap for ribosome assembly in human mitochondria.
    Elena Lavdovskaia, Elisa Hanitsch, Andreas Linden, Martin Pašen, Venkatapathi Challa, Yehor Horokhovskyi, Hanna P Roetschke, Franziska Nadler, Luisa Welp, Emely Steube, Marleen Heinrichs, Mandy Mong-Quyen Mai, Henning Urlaub, Juliane Liepe, Ricarda Richter-Dennerlein.
      Mitochondria contain dedicated ribosomes (mitoribosomes), which synthesize the mitochondrial-encoded core components of the oxidative phosphorylation complexes. The RNA and protein components of mitoribosomes are encoded on two different genomes (mitochondrial and nuclear) and are assembled into functional complexes with the help of dedicated factors inside the organelle. Defects in mitoribosome biogenesis are associated with severe human diseases, yet the molecular pathway of mitoribosome assembly remains poorly understood. Here, we applied a multidisciplinary approach combining biochemical isolation and analysis of native mitoribosomal assembly complexes with quantitative mass spectrometry and mathematical modeling to reconstitute the entire assembly pathway of the human mitoribosome. We show that, in contrast to its bacterial and cytosolic counterparts, human mitoribosome biogenesis involves the formation of ribosomal protein-only modules, which then assemble on the appropriate ribosomal RNA moiety in a coordinated fashion. The presence of excess protein-only modules primed for assembly rationalizes how mitochondria cope with the challenge of forming a protein-rich ribonucleoprotein complex of dual genetic origin. This study provides a comprehensive roadmap of mitoribosome biogenesis, from very early to late maturation steps, and highlights the evolutionary divergence from its bacterial ancestor.
    DOI:  https://doi.org/10.1038/s41594-024-01356-w
  26. Sports Med Open. 2024 Jul 09. 10(1): 77
    Effects of Mitoquinone (MitoQ) Supplementation on Aerobic Exercise Performance and Oxidative Damage: A Systematic Review and Meta-analysis.
    Oliver Gonzalo-Skok, Rafael A Casuso.
      BACKGROUND: Contracting skeletal muscle produces reactive oxygen species (ROS) originating from both mitochondrial and cytosolic sources. The use of non-specific antioxidants, such as vitamins C and E, during exercise has produced inconsistent results in terms of exercise performance. Consequently, the effects of the mitochondrial-targeted coenzyme Q10, named Mitoquinone (MitoQ) on exercise responses are currently under investigation.METHODS: In this study, we conducted a meta-analysis to quantitatively synthesize research assessing the impact of MitoQ on aerobic endurance performance and exercise-induced oxidative damage. PubMed, Web of Science, and SCOPUS databases were used to select articles from inception to January 16th of 2024. Inclusion criteria were MitoQ supplementation must be compared with a placebo group, showing acute exercise responses in both; for crossover designs, at least 14 d of washout was needed, and exercise training can be concomitant to MitoQ or placebo supplementation if the study meets the other inclusion criteria points. The risk of bias was evaluated through the Critical Appraisal Checklist (JBI).
    RESULTS: We identified eight studies encompassing a total sample size of 188 subjects. Our findings indicate that MitoQ supplementation effectively reduces exercise-induced oxidative damage (SMD: -1.33; 95% CI: -2.24 to -0.43). Furthermore, our findings indicate that acute and/or chronic MitoQ supplementation does not improve endurance exercise performance (SMD: -0.50; 95% CI: -1.39 to 0.40) despite reducing exercise-induced oxidative stress. Notably, our sensitivity analysis reveals that MitoQ may benefit subjects with peripheral artery disease (PAD) in improving exercise tolerance.
    CONCLUSION: While MitoQ effectively reduces exercise-induced oxidative damage, no evidence suggests that aerobic exercise performance is enhanced by either acute or chronic MitoQ supplementation. However, acute MitoQ supplementation may improve exercise tolerance in subjects with PAD. Future research should investigate whether MitoQ supplementation concurrent with exercise training (e.g., 4-16 weeks) alters adaptations induced by exercise alone and using different doses.
    Keywords:  Ergogenic; Mitochondria; Oxidative Stress; Training
    DOI:  https://doi.org/10.1186/s40798-024-00741-5
  27. Metabolism. 2024 Jul 05. pii: S0026-0495(24)00199-9. [Epub ahead of print] 155972
    New insights into the function of the NLRP3 inflammasome in sarcopenia: mechanism and therapeutic strategies.
    Yunyi Zou, Xiangbin Tang, Siyuan Yang, Zhanglin Chen, Bin Liu, Zuoqiong Zhou, Xiyang Peng, Changfa Tang.
      Sarcopenia is one of the most common skeletal muscle disorders and is characterized by infirmity and disability. While extensive research has focused on elucidating the mechanisms underlying the progression of sarcopenia, further comprehensive insights into its pathogenesis are necessary to identify new preventive and therapeutic approaches. The involvement of inflammasomes in sarcopenia is widely recognized, with particular emphasis on the NLRP3 (NLR family pyrin domain containing 3) inflammasome. In this review, we aim to elucidate the underlying mechanisms of the NLRP3 inflammasome and its relevance in sarcopenia of various etiologies. Furthermore, we highlight interventions targeting the NLRP3 inflammasome in the context of sarcopenia and discuss the current limitations of our knowledge in this area.
    Keywords:  Inflammasome; NLRP3; Sarcopenia
    DOI:  https://doi.org/10.1016/j.metabol.2024.155972
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