bims-moremu Biomed News
on Molecular regulators of muscle mass
Issue of 2025–01–05
twenty-two papers selected by
Anna Vainshtein, Craft Science Inc.
  1. Physiology of ageing skeletal muscle and the protective effects of exercise.
  2. Excessive BMP3b suppresses skeletal muscle differentiation.
  3. Aerobic plus resistance exercise attenuates skeletal muscle atrophy induced by dexamethasone through the HDAC4/FoxO3a pathway.
  4. Reduced ATP turnover during hibernation in relaxed skeletal muscle.
  5. Altering phosphorylation of dystrophin S3059 to attenuate cancer cachexia.
  6. Pantothenate kinase 4 controls skeletal muscle substrate metabolism.
  7. IL-6 Promotes Muscle Atrophy by Increasing Ubiquitin-Proteasome Degradation of Muscle Regeneration Factors After Cerebral Infarction in Rats.
  8. Higher skeletal muscle mitochondrial oxidative capacity is associated with preserved brain structure up to over a decade.
  9. Cellular Feimin enhances exercise performance by suppressing muscle thermogenesis.
  10. Effects of seven days' fasting on physical performance and metabolic adaptation during exercise in humans.
  11. The role of the circadian timing system in sarcopenia in old age: a scoping review.
  12. Exposure of Young Mice to Atmospherically Relevant PM2.5 Has Sex-Dependent Long-Lasting Impacts on the Skeletal Muscle System.
  13. Cardio-metabolic and cytoskeletal proteomic signatures differentiate stress hypersensitivity in dystrophin-deficient mdx mice.
  14. Molecular basis of Spns1-mediated lysophospholipid transport from the lysosome.
  15. Metabolite mysteries: Decoding age-related muscle fatigue mechanisms at the myofibrillar level.
  16. Gene-editing in patient and humanized-mice primary muscle stem cells rescues dysferlin expression in dysferlin-deficient muscular dystrophy.
  17. Mitochondrial Quality Control: A New Perspective in Skeletal Muscle Dysfunction of Chronic Obstructive Pulmonary Disease.
  18. Histone mark age of human tissues and cell types.
  19. Sex- and endurance training-mediated cardiovascular protection through lipids during exercise.
  20. Hypoxia-induced increase in sphingomyelin synthase 2 aggravates ischemic skeletal muscle inflammation.
  21. Investigating skeletal muscle micro-trauma with time-dependent diffusion and the random permeable barrier model.
  22. Muscle Biopsy Sample Preparation and Proteomics Analysis Based on UHPLC-MS/MS.
  1. J Physiol. 2025 Jan 01.
    Physiology of ageing skeletal muscle and the protective effects of exercise.
    Christopher W Sundberg.
      
    Keywords:  ageing; contractile function; dynapenia; exercise; muscle metabolism; sarcopenia; skeletal muscle
    DOI:  https://doi.org/10.1113/JP287926
  2. Biochem Biophys Res Commun. 2024 Dec 28. pii: S0006-291X(24)01797-2. [Epub ahead of print]746 151261
    Excessive BMP3b suppresses skeletal muscle differentiation.
    Shoichiro Kokabu, Nao Kodama, Aki Miyawaki, Kunikazu Tsuji, Jun Hino, Yusuke Ono, Takuma Matsubara.
      Bone morphogenetic protein (BMP)-3b, also known as growth differentiation factor (GDF)-10, belongs to the transforming growth factor (TGF)-β superfamily. Despite being named a BMP, BMP3b is considered as an intermediate between the TGFβ/activin/myostatin and BMP/GDF subgroups of the TGFβ superfamily. Myoblast differentiation is tightly regulated by various cytokines, including the TGFβ superfamily members. However, despite BMP3b supporting the maintenance of skeletal myofibers, myoblast differentiation induced by BMP3b remains unclear. In this study, BMP3 expression levels in isolated satellites were very low compared to those in the skeletal muscle tissues. We analyzed cardiotoxin-induced muscle regeneration. Intact muscle fiber size was larger in BMP3b null mice than in wild-type mice; however, regenerated muscle fiber size did not differ between the null and wild-type mice. Next, we analyzed the satellite cell-specific BMP3b-overexpressing (BMP3b Tg) mice. Intact fiber size was increased in BMP3b Tg mice. However, regenerating tibialis anterior muscle size was reduced in BMP3b Tg mice compared to that in control mice. BMP3b overexpression in C2C12 cells stimulated Smad2/3 signaling. Moreover, BMP3b overexpression and conditioned medium of BMP3b-expressing Chinese hamster ovary cells strongly suppressed myoblast differentiation by repressing transactivation. Overall, our data suggest that BMP3b is not necessary for muscle regeneration; however, excessive BMP3b interferes with muscle regeneration by suppressing myoblast differentiation.
    Keywords:  Bone morphogenic protein; Differentiation; Regeneration; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.bbrc.2024.151261
  3. Cell Signal. 2024 Dec 26. pii: S0898-6568(24)00557-6. [Epub ahead of print] 111581
    Aerobic plus resistance exercise attenuates skeletal muscle atrophy induced by dexamethasone through the HDAC4/FoxO3a pathway.
    Dehuan Liang, Danni Wang, Xinyue Zheng, Heng Xiang, Sujuan Liu, Chunxia Yu, Jiatong Tian, Jianxiong Ma, Yanmei Niu.
      This study aimed to investigate the underlying mechanisms by which physical exercise mitigates muscle atrophy induced by Dexamethasone (Dex). A muscle atrophy model was established in the mouse C2C12 cell line and 8-week-old mice treated with Dex, with subsequent verification of phenotype and atrogene expression. The potential benefits of combined aerobic and resistance exercise in mitigating muscle atrophy were then examined. To elucidate the involvement of Histone deacetylase 4 (HDAC4) in the protective effects of exercise against muscle loss, a combination of RT-PCR, Western blotting, immunoprecipitation, and immunofluorescence staining techniques were employed. The upregulation of HDAC4 was observed following Dex-induced muscle atrophy in vitro and in vivo. Inhibition of HDAC4 in C2C12 cells resulted in an increase in myotube diameter and fusion index, along with a decrease in the expression of Atrogin-1 and MuRF1. Treatment with Tasquinimod, an HDAC4 inhibitor, effectively prevented muscle wasting and dysfunction in mice induced by Dex. After a 6-week exercise intervention, the Dex-Exercise group exhibited significant improvements in body fat level, hyperinsulinemia, muscle mass and function in comparison to the Dex-Sedentary group. Mechanistically, we discovered that HDAC4 bound to and deacetylated Forkhead box protein O 3a (FoxO3a) within the nucleus, leading to decreased phosphorylation of FoxO3a at Ser 253. This interaction subsequently facilitated the expression of downstream atrogene Atrogin-1 and MuRF1, resulting in muscle atrophy. Conversely, exercise was found to potentially mitigate muscle atrophy by inhibiting the HDAC4/FoxO3a pathway. These findings suggest that HDAC4 may be a potential therapeutic target for exercise to combat Dex-induced muscle atrophy.
    Keywords:  Aerobic plus resistance exercise; Dexamethasone; FoxO3a; HDAC4; Skeletal muscle atrophy
    DOI:  https://doi.org/10.1016/j.cellsig.2024.111581
  4. Nat Commun. 2025 Jan 02. 16(1): 80
    Reduced ATP turnover during hibernation in relaxed skeletal muscle.
    Cosimo De Napoli, Luisa Schmidt, Mauro Montesel, Laura Cussonneau, Samuele Sanniti, Lorenzo Marcucci, Elena Germinario, Jonas Kindberg, Alina Lynn Evans, Guillemette Gauquelin-Koch, Marco Narici, Fabrice Bertile, Etienne Lefai, Marcus Krüger, Leonardo Nogara, Bert Blaauw.
      Hibernating brown bears, due to a drastic reduction in metabolic rate, show only moderate muscle wasting. Here, we evaluate if ATPase activity of resting skeletal muscle myosin can contribute to this energy sparing. By analyzing single muscle fibers taken from the same bears, either during hibernation or in summer, we find that fibers from hibernating bears have a mild decline in force production and a significant reduction in ATPase activity. Single fiber proteomics, western blotting, and immunohistochemical analyses reveal major remodeling of the mitochondrial proteome during hibernation. Furthermore, using bioinformatical approaches and western blotting we find that phosphorylated myosin light chain, a known stimulator of basal myosin ATPase activity, is decreased in hibernating and disused muscles. These results suggest that skeletal muscle limits energy loss by reducing myosin ATPase activity, indicating a possible role for myosin ATPase activity modulation in multiple muscle wasting conditions.
    DOI:  https://doi.org/10.1038/s41467-024-55565-4
  5. Life Sci. 2024 Dec 29. pii: S0024-3205(24)00933-0. [Epub ahead of print] 123343
    Altering phosphorylation of dystrophin S3059 to attenuate cancer cachexia.
    Kristy Swiderski, Jennifer Trieu, Annabel Chee, Timur Naim, Christopher J Brock, Dale M Baum, Audrey S Chan, Justin P Hardee, Wenlan Li, Andrew J Kueh, Marco J Herold, Kate T Murphy, Paul Gregorevic, Gordon S Lynch.
       AIMS: Cancer cachexia affects up to 80 % of patients with advanced cancer and accounts for >20 % of all cancer-related deaths. Sarcolemmal localization of dystrophin, a key protein within the dystrophin-glycoprotein complex (DGC), is perturbed in multiple muscle wasting conditions, including cancer cachexia, indicating a potential role for dystrophin in the maintenance of muscle mass. Strategies to preserve dystrophin expression at the sarcolemma might therefore combat muscle wasting. Phosphorylation of dystrophin serine 3059 (S3059) enhances the interaction between dystrophin and β-dystroglycan and attenuates atrophy of mouse muscle myotubes in vitro when cultured in the presence of colon-26 (C-26) cancer cells. Whether dystrophin S3059 phosphorylation can attenuate cachexia in tumor-bearing mice has not been determined.
    MATERIALS AND METHODS: Mice with systemic mutations of serine 3059 to alanine (DmdS3059A; phospho-null) or glutamate (DmdS3059E; phosphomimetic) were generated to investigate the impact of S3059 phosphorylation on survival and skeletal muscle health in the C-26 tumor-bearing mouse model of cancer cachexia using measures of skeletal muscle function in situ combined with biochemical and histological assessments.
    KEY FINDINGS: In a model of mild cachexia, loss of skeletal muscle mass and function was greater in DmdS3059A mice. Conversely, in a model of severe cachexia, overall survival was prolonged, and markers of protein degradation were decreased in skeletal muscles of DmdS3059E mice. Thus, manipulating dystrophin S3059 phosphorylation can alter the progression of cachexia in tumor-bearing mice.
    SIGNIFICANCE: Strategies to increase phosphorylation of this site, and/or increase dystrophin protein expression, have therapeutic potential for cancer cachexia.
    Keywords:  Cancer cachexia; Dystrophin; Dystrophin-glycoprotein complex; Mouse; Phosphorylation; S3059; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.lfs.2024.123343
  6. Nat Commun. 2025 Jan 02. 16(1): 345
    Pantothenate kinase 4 controls skeletal muscle substrate metabolism.
    Adriana Miranda-Cervantes, Andreas M Fritzen, Steffen H Raun, Ondřej Hodek, Lisbeth L V Møller, Kornelia Johann, Luisa Deisen, Paul Gregorevic, Anders Gudiksen, Anna Artati, Jerzy Adamski, Nicoline R Andersen, Casper M Sigvardsen, Christian S Carl, Christian T Voldstedlund, Rasmus Kjøbsted, Stefanie M Hauck, Peter Schjerling, Thomas E Jensen, Alberto Cebrian-Serrano, Markus Jähnert, Pascal Gottmann, Ingo Burtscher, Heiko Lickert, Henriette Pilegaard, Annette Schürmann, Matthias H Tschöp, Thomas Moritz, Timo D Müller, Lykke Sylow, Bente Kiens, Erik A Richter, Maximilian Kleinert.
      Metabolic flexibility in skeletal muscle is essential for maintaining healthy glucose and lipid metabolism, and its dysfunction is closely linked to metabolic diseases. Exercise enhances metabolic flexibility, making it an important tool for discovering mechanisms that promote metabolic health. Here we show that pantothenate kinase 4 (PanK4) is a new conserved exercise target with high abundance in muscle. Muscle-specific deletion of PanK4 impairs fatty acid oxidation which is related to higher intramuscular acetyl-CoA and malonyl-CoA levels. Elevated acetyl-CoA levels persist regardless of feeding state and are associated with whole-body glucose intolerance, reduced insulin-stimulated glucose uptake in glycolytic muscle, and impaired glucose uptake during exercise. Conversely, increasing PanK4 levels in glycolytic muscle lowers acetyl-CoA and enhances glucose uptake. Our findings highlight PanK4 as an important regulator of acetyl-CoA levels, playing a key role in both muscle lipid and glucose metabolism.
    DOI:  https://doi.org/10.1038/s41467-024-55036-w
  7. Neuromolecular Med. 2025 Jan 03. 27(1): 3
    IL-6 Promotes Muscle Atrophy by Increasing Ubiquitin-Proteasome Degradation of Muscle Regeneration Factors After Cerebral Infarction in Rats.
    Fangyu Chen, Juanjuan Fu, Hui Feng.
      Muscle atrophy in pathological or diseased muscles arises from an imbalance between protein synthesis and degradation. Elevated levels of interleukin-6 (IL-6) are a hallmark of ischemic stroke and have been associated with muscle atrophy in certain pathological contexts. However, the mechanisms by which IL-6 induces muscle atrophy in the context of stroke remain unclear. To investigate these effects, we used a rat model of middle cerebral artery occlusion (MCAO) and an in vitro model with the C2C12 cell line to uncover potential molecular mechanisms underlying IL-6-induced muscle atrophy. Our findings revealed elevated protein and serum levels of IL-6, along with increased markers of muscle atrophy, in MCAO rats compared to sham controls. We also observed overactivation of protein ubiquitination pathways and downregulation of muscle regeneration markers in MCAO rats. Further analysis indicated that IL-6 contributes to increased muscle protein ubiquitination. Inhibition of IL-6 signaling led to a significant reduction in infarct size and improved neurological deficit scores. Targeting the IL-6/IL-6R signaling pathway presents a promising therapeutic approach to mitigate muscle atrophy in individuals affected by ischemic stroke.
    Keywords:  IL-6; Ischemic stroke; MACO; Muscle atrophy
    DOI:  https://doi.org/10.1007/s12017-024-08825-x
  8. Nat Commun. 2024 Dec 30. 15(1): 10786
    Higher skeletal muscle mitochondrial oxidative capacity is associated with preserved brain structure up to over a decade.
    Qu Tian, Erin E Greig, Christos Davatzikos, Bennett A Landman, Susan M Resnick, Luigi Ferrucci.
      Impaired muscle mitochondrial oxidative capacity is associated with future cognitive impairment, and higher levels of PET and blood biomarkers of Alzheimer's disease and neurodegeneration. Here, we examine its associations with up to over a decade-long changes in brain atrophy and microstructure. Higher in vivo skeletal muscle oxidative capacity via MR spectroscopy (post-exercise recovery rate, kPCr) is associated with less ventricular enlargement and brain aging progression, and less atrophy in specific regions, notably primary sensorimotor cortex, temporal white and gray matter, thalamus, occipital areas, cingulate cortex, and cerebellum white matter. Higher kPCr is also associated with less microstructural integrity decline in white matter around cingulate, including superior longitudinal fasciculus, corpus callosum, and cingulum. Higher in vivo muscle oxidative capacity is associated with preserved brain structure up to over a decade, particularly in areas important for cognition, motor function, and sensorimotor integration.
    DOI:  https://doi.org/10.1038/s41467-024-55009-z
  9. Nat Metab. 2025 Jan 02.
    Cellular Feimin enhances exercise performance by suppressing muscle thermogenesis.
    Ying Peng, Liangjie Jia, Xiao Hu, Xiaoliu Shi, Xinlei Fang, Yifu Qiu, Zhenji Gan, Yiguo Wang.
      Exercise can rapidly increase core body temperature, and research has indicated that elevated internal body temperature can independently contribute to fatigue during physical activity. However, the precise mechanisms responsible for regulating thermogenesis in muscles during exercise have remained unclear. Here, we demonstrate that cellular Feimin (cFeimin) enhances exercise performance by inhibiting muscle thermogenesis during physical activity. Mechanistically, we found that AMP-activated protein kinase (AMPK) phosphorylates cFeimin and facilitates its translocation into the cell nucleus during exercise. Within the nucleus, cFeimin binds to the forkhead transcription factor FOXC2, leading to the suppressed expression of sarcolipin (Sln), which is a key regulator of muscle thermogenesis. In addition, our results further reveal that short-term AMPK agonist treatments can enhance exercise performance through the activation of the AMPK-cFeimin signalling pathway. In summary, these results underscore the crucial role of cFeimin in enhancing exercise performance by modulating SLN-mediated thermogenesis.
    DOI:  https://doi.org/10.1038/s42255-024-01176-8
  10. Nat Commun. 2025 Jan 02. 16(1): 122
    Effects of seven days' fasting on physical performance and metabolic adaptation during exercise in humans.
    Kristoffer J Kolnes, Emelie T F Nilsen, Steffen Brufladt, Allison M Meadows, Per B Jeppesen, Øyvind Skattebo, Egil I Johansen, Jesper B Birk, Kurt Højlund, Janne Hingst, Bjørn S Skålhegg, Rasmus Kjøbsted, Julian L Griffin, Anders J Kolnes, Stephen O'Rahilly, Jørgen F P Wojtaszewski, Jørgen Jensen.
      Humans have, throughout history, faced periods of starvation necessitating increased physical effort to gather food. To explore adaptations in muscle function, 13 participants (7 males and 6 females) fasted for seven days. They lost 4.6 ± 0.3 kg lean and 1.4 ± 0.1 kg fat mass. Maximal isometric and isokinetic strength remained unchanged, while peak oxygen uptake decreased by 13%. Muscle glycogen was halved, while expression of electron transport chain proteins was unchanged. Pyruvate dehydrogenase kinase 4 (PDK4) expression increased 13-fold, accompanied by inhibitory pyruvate dehydrogenase phosphorylation, reduced carbohydrate oxidation and decreased exercise endurance capacity. Fasting had no impact on 5' AMP-activated protein kinase (AMPK) activity, challenging its proposed role in muscle protein degradation. The participants maintained muscle strength and oxidative enzymes in skeletal muscle during fasting but carbohydrate oxidation and high-intensity endurance capacity were reduced.
    DOI:  https://doi.org/10.1038/s41467-024-55418-0
  11. Eur Geriatr Med. 2025 Jan 02.
    The role of the circadian timing system in sarcopenia in old age: a scoping review.
    Francesco Palmese, Ylenia Druda, Rossella Del Toro, Giorgio Bedogni, Marco Domenicali, Alessandro Silvani.
       PURPOSE: Sarcopenia is a progressive and generalized skeletal muscle disorder, involving the accelerated loss of skeletal muscle mass and function, associated with an increased probability of adverse outcomes including falls. The circadian timing system may be involved in molecular pathways leading to sarcopenia in older adults. We aimed to provide an updated and systematic map of the available evidence on the role of the circadian timing system in sarcopenia, specifically related to the aging process.
    METHODS: We developed a scoping review protocol following the PRISMA-ScR guidelines. Searches were conducted on PubMed, Scopus, Web of Science, RESULTS: We identified 373 papers from three online databases, screened 97 for full-text analysis. and selected 37 papers for inclusion. These papers included 17 primary research studies on human persons, focusing on cortisol and melatonin secretion, rest-activity rhythms, chrono-exercise, and chrono-dietary regimens, 9 primary research studies on animal models (mice, rats, fruit flies) focusing on direct expression measurement or mutations of core clock genes, and 11 narrative reviews.
    CONCLUSION: While several reports supported the role of the circadian timing system in sarcopenia, specifically related to the aging process, the available evidence is fragmented and limited. The field is thus open to preclinical and clinical research that addresses the wide knowledge gaps in the available evidence, taking advantage of what has already been published to optimize and refine experimental and clinical protocols.
    Keywords:  Aging; Circadian; Physical performance; Skeletal muscle force; Skeletal muscle mass
    DOI:  https://doi.org/10.1007/s41999-024-01129-0
  12. Aging Dis. 2024 Dec 16.
    Exposure of Young Mice to Atmospherically Relevant PM2.5 Has Sex-Dependent Long-Lasting Impacts on the Skeletal Muscle System.
    Wenduo Liu, Zilin Wang, Min-Hye Kim, Yu Gu, Hyun-Jaung Sim, Jeong-Chae Lee, Sung-Ho Kook, Sang Hyun Kim.
      The negative effects of particulate matter up to 2.5 μm in diameter (PM2.5) and their mediating mechanisms have been studied in various tissues. However, little is known about the mechanism and long-term tracking underlying the sex-dependent effects of PM2.5 on skeletal muscle system modulation. During youth, skeletal muscle grows rapidly and develops at its highest rate. Here we explore how exposure to atmospherically relevant levels of artificial PM2.5 affects the skeletal muscle system in 4-week-old C57BL6 mice according to sex and track the effects for 15 months post-exposure. We found that PM2.5 retarded muscle fiber growth and caused mitochondrial damage by modulating factors related to mitochondrial kinetics. However, the effects of PM2.5 on the modulation of the skeletal muscle system differed by sex and post-exposure time. The negative impacts of PM2.5 on skeletal muscle continued until they were overwhelmed by aging-related oxidative stress and inflammation, which were more severe in older PM2.5-exposed female mice compared with male mice. Older PM2.5-exposed female mice, but not older PM2.5-exposed male mice, exhibited obesity-related phenotypes in the form of increased weight and fat mass. Overall, initial exposure to PM2.5 affected the skeletal muscle system with long-lasting impacts that differed according to sex.
    DOI:  https://doi.org/10.14336/AD.2024.1047
  13. J Proteomics. 2024 Dec 26. pii: S1874-3919(24)00303-8. [Epub ahead of print]312 105371
    Cardio-metabolic and cytoskeletal proteomic signatures differentiate stress hypersensitivity in dystrophin-deficient mdx mice.
    Gretel S Major, Craig W Herbold, Flora Cheng, Albert Lee, Shuzhao Zhuang, Aaron P Russell, Angus Lindsay.
      Extreme heterogeneity exists in the hypersensitive stress response exhibited by the dystrophin-deficient mdx mouse model of Duchenne muscular dystrophy. Because stress hypersensitivity can impact dystrophic phenotypes, this research aimed to understand the peripheral pathways driving this inter-individual variability. Male and female mdx mice were phenotypically stratified into "stress-resistant" or "stress-sensitive" groups based on their response to two laboratory stressors. Quantitative proteomics of striated muscle revealed that stress-resistant females were most dissimilar from all other groups, with over 250 proteins differentially regulated with stress hypersensitivity. Males showed less proteomic variation with stress hypersensitivity; however, these changes were associated with pathway enrichment. In the heart, stress-sensitive males had significant enrichment of pathways related to mitochondrial ATP synthesis, suggesting that increased cardio-metabolic capacity is associated with stress hypersensitivity in male mdx mice. In both sexes, stress hypersensitivity was associated with greater expression of beta-actin-like protein 2, indicative of altered cytoskeletal organisation. Despite identifying proteomic signatures associated with stress hypersensitivity, these did not correlate with differences in the serum metabolome acutely after a stressor. These data suggest that the heterogeneity in stress hypersensitivity in mdx mice is partially driven by cytoskeletal organisation, but that sex-specific cardio-metabolic reprogramming may also underpin this phenotype. SIGNIFICANCE: Duchenne muscular dystrophy (DMD) is a fatal muscle wasting disease which is associated with a premature loss of ambulation and neurocognitive dysfunction. The hypersensitive stress response in DMD is a heterogeneous phenotype which is poorly understood. This study provided the first investigation of the peripheral mechanisms regulating the hypersensitive stress response by undertaking multi-omics analysis of phenotypically stratified mdx mice. Variations in behaviour and the striated muscle proteomic profiles suggest that cardio-metabolic remodelling and cytoskeletal organisation may contribute to this phenotype. This research offers significant insights into understanding how peripheral dystrophin deficiency relates to the cognitive abnormalities seen in patients with DMD.
    Keywords:  Cytoskeletal organisation; Duchenne muscular dystrophy; Fear; Mitochondrial function; Proteomics; Stress
    DOI:  https://doi.org/10.1016/j.jprot.2024.105371
  14. Proc Natl Acad Sci U S A. 2025 Jan 07. 122(1): e2409596121
    Molecular basis of Spns1-mediated lysophospholipid transport from the lysosome.
    Hongwen Chen, Hoa T T Ha, Nadia Elghobashi-Meinhardt, Nhung A Le, Philip Schmiege, Long N Nguyen, Xiaochun Li.
      Spns1 mediates the rate-limiting efflux of lysophospholipids from the lysosome to the cytosol. Deficiency of Spns1 is associated with embryonic senescence, as well as liver and skeletal muscle atrophy in animal models. However, the mechanisms by which Spns1 transports lysophospholipid and proton sensing remain unclear. Here, we present a cryogenic electron microscopy structure of human Spns1 in lysophosphatidylcholine (LPC)-bound lumen-facing conformation. Notably, LPC snugly binds within the luminal-open cavity, where the molecular dynamics simulations reveal that LPC presents a propensity to enter between transmembrane-helices (TM) 5 and 8. Structural comparisons and cell-based transport assays uncover several pivotal residues at TM 5/8 that orchestrate the transport cycle, which are unique to Spns1. Furthermore, we identify a five-residue network that is crucial for proton-sensing by Spns1. Transference of these network residues to Spns2, a sphingosine-1-phosphate uniporter, causes the chimeric Spns2 to be low pH dependent. Our results reveal molecular insights into lysosomal LPC transport and the proton-sensing mechanism by Spns1.
    Keywords:  cryo-EM; lysophospholipids; proton-sensing; transporter
    DOI:  https://doi.org/10.1073/pnas.2409596121
  15. J Physiol. 2025 Jan 03.
    Metabolite mysteries: Decoding age-related muscle fatigue mechanisms at the myofibrillar level.
    Andrew J Richards, Rohin Malekzadeh, Quinn Steele, Azin Akbarimoheb, Nathaniel J Andrews.
      
    Keywords:  ageing; force–velocity; isometric; metabolites; power; sex differences; skinned fibre
    DOI:  https://doi.org/10.1113/JP288185
  16. Nat Commun. 2025 Jan 02. 16(1): 120
    Gene-editing in patient and humanized-mice primary muscle stem cells rescues dysferlin expression in dysferlin-deficient muscular dystrophy.
    Helena Escobar, Silvia Di Francescantonio, Julia Smirnova, Robin Graf, Stefanie Müthel, Andreas Marg, Alexej Zhogov, Supriya Krishna, Eric Metzler, Mina Petkova, Oliver Daumke, Ralf Kühn, Simone Spuler.
      Dystrophy-associated fer-1-like protein (dysferlin) conducts plasma membrane repair. Mutations in the DYSF gene cause a panoply of genetic muscular dystrophies. We targeted a frequent loss-of-function, DYSF exon 44, founder frameshift mutation with mRNA-mediated delivery of SpCas9 in combination with a mutation-specific sgRNA to primary muscle stem cells from two homozygous patients. We observed a consistent >60% exon 44 re-framing, rescuing a full-length and functional dysferlin protein. A new mouse model harboring a humanized Dysf exon 44 with the founder mutation, hEx44mut, recapitulates the patients' phenotype and an identical re-framing outcome in primary muscle stem cells. Finally, gene-edited murine primary muscle stem-cells are able to regenerate muscle and rescue dysferlin when transplanted back into hEx44mut hosts. These findings are the first to show that a CRISPR-mediated therapy can ameliorate dysferlin deficiency. We suggest that gene-edited primary muscle stem cells could exhibit utility, not only in treating dysferlin deficiency syndromes, but also perhaps other forms of muscular dystrophy.
    DOI:  https://doi.org/10.1038/s41467-024-55086-0
  17. Aging Dis. 2024 Dec 21.
    Mitochondrial Quality Control: A New Perspective in Skeletal Muscle Dysfunction of Chronic Obstructive Pulmonary Disease.
    Yanxia Song, Xiaoyu Han, Yingqi Wang, Kangxia Li, Huanping Li, Yizhu Tian, Xiaoqing Ma, Weibing Wu, Jihong Wang.
      Skeletal muscle dysfunction (SMD), one of the extrapulmonary complications in patients with chronic obstructive pulmonary disease (COPD), considerably influences patient prognosis. Mitochondria regulates their dynamic networks through a mitochondria quality control (MQC) mechanism, involving mitochondrial biogenesis, mitochondrial dynamics, and mitophagy. The MQC is crucial for mitochondrial homeostasis and health, and disruption of it can lead to mitochondrial damage, which is a key factor in the structural and functional impairment of skeletal muscle in COPD. The mitochondria in the skeletal muscles of these patients undergo changes, mainly including decrease in mitochondrial density and biogenesis levels, imbalanced mitochondrial fission and fusion, and altered mitophagy status. However, the potential mechanisms linking MQC to the damaged structure and function of skeletal muscles in COPD have not been fully clarified. Therefore, this review highlights the effects and potential pathways of the MQC system on the dysfunction of skeletal muscle (muscle atrophy, impaired myogenesis and regeneration, and aerobic endurance) in patients with COPD, and summarizes potential interventions targeted MQC, intending to provide a theoretical basis for further research on COPD, improve SMD, and enhance the quality of life.
    DOI:  https://doi.org/10.14336/AD.2024.1129
  18. Sci Adv. 2025 Jan 03. 11(1): eadk9373
    Histone mark age of human tissues and cell types.
    Lucas Paulo de Lima Camillo, Muhammad Haider Asif, Steve Horvath, Erica Larschan, Ritambhara Singh.
      Aging is a complex and multifaceted process involving many epigenetic alterations. One key area of interest in aging research is the role of histone modifications, which can dynamically regulate gene expression. Here, we conducted a pan-tissue analysis of the dynamics of seven key histone modifications during human aging. Our histone-specific age prediction models showed surprisingly accurate performance, proving resilient to experimental and artificial noise. Simulation experiments for comparison with DNA methylation age predictors revealed competitive performance. Moreover, gene set enrichment analysis uncovered several critical developmental pathways for age prediction. Different from DNA methylation age predictors, genes known to be involved in aging biology are among the most important ones for the models. Last, we developed a pan-tissue pan-histone age predictor, suggesting that age-related epigenetic information is degenerated across the epigenome. This research highlights the power of histone marks as input for creating robust age predictors and opens avenues for understanding the role of epigenetic changes during aging.
    DOI:  https://doi.org/10.1126/sciadv.adk9373
  19. Trends Endocrinol Metab. 2024 Dec 31. pii: S1043-2760(24)00326-6. [Epub ahead of print]
    Sex- and endurance training-mediated cardiovascular protection through lipids during exercise.
    Julia An, Ariel S Thorson, David H Wasserman, John M Stafford, Lin Zhu.
      Premenopausal women and endurance-trained individuals of either sex have reduced cardiovascular disease (CVD) risk. Endurance training shifts fuel selection towards fats to spare carbohydrates; interestingly, women prioritize fats as an energy resource more than men do during exercise. Relying on fats during exercise drives whole-body lipolysis and promotes lipid uptake and oxidation capacity in skeletal muscles. These metabolic adaptations during exercise result in protection against diet-induced obesity, a healthy body fat distribution, and reduced plasma triacylglycerol (TG) concentrations. Here, we analyze how sex differences and endurance training mediate changes in skeletal muscles, including exercise-induced lipolysis, lipid uptake and β-oxidation, intramuscular TG storage, and postexercise lipid metabolism, and discuss how regulating this processes affects CVD risk.
    Keywords:  CVD risk; endurance training; intramyocellular triacylglycerol (IMTG); muscle fiber types; post-exercise recovery; sex differences in fuel selection
    DOI:  https://doi.org/10.1016/j.tem.2024.12.004
  20. FEBS J. 2024 Dec 30.
    Hypoxia-induced increase in sphingomyelin synthase 2 aggravates ischemic skeletal muscle inflammation.
    Hinano Mizugaki, Masaki Nagane, Hideo Sato-Akaba, Maciej Kmiec, Periannan Kuppusamy, Hironobu Yasui, Osamu Inanami, Hironobu Murakami, Naoyuki Aihara, Junichi Kamiie, Wataru Mizunoya, Ibuki Yasuda, Tomoki Fukuyama, Yuko Naya, Tadashi Yamashita.
      Critical limb ischemia (CLI) is the most advanced stage of peripheral arterial disease, posing a high risk of mortality. Sphingomyelin, a sphingolipid synthesized by sphingomyelin synthases (SMSs) 1 and 2, plays an essential role in signal transduction as a component of lipid rafts. However, the role of sphingomyelin in the inflammation of ischemic skeletal muscles remains unclear. In this study, we analyzed the roles of sphingomyelin and SMSs in CLI-induced myopathy using a mouse hindlimb ischemia model. We observed that hypoxia after CLI triggered an increase in SMS2 levels, thereby elevating sphingomyelin concentrations in ischemic skeletal muscles. The expression of SMS2 and sphingomyelin was induced by hypoxia in C2C12 myotubes and regulated by the prolyl hydroxylase domain enzyme. Additionally, SMS2 deficiency suppressed skeletal muscle inflammation after CLI, attenuated the phosphorylation of inhibitor of κBα (IκBα), and reduced the nuclear translocation of nuclear factor κB (NFκB) p65. Meanwhile, the administration of sphingomyelin hampered skeletal muscle inflammation by inhibiting IκBα phosphorylation and NFκB p65 nuclear translocation and extending inflammation post-CLI. Our results suggest that hypoxia-induced enhancement in SMS2 levels and the consequent increase in sphingomyelin expression levels promote inflammation in ischemic muscle tissues via the NFκB pathway and propose sphingomyelin as a potential therapeutic target in patients with CLI and other hypoxia-related inflammatory diseases.
    Keywords:  NFκB; critical limb ischemia; hypoxia; sphingomyelin; sphingomyelin synthase 2
    DOI:  https://doi.org/10.1111/febs.17379
  21. Sci Rep. 2024 Dec 30. 14(1): 31998
    Investigating skeletal muscle micro-trauma with time-dependent diffusion and the random permeable barrier model.
    Susanne S Rauh, Donnie Cameron, Oliver J Gurney-Champion, Frank Smithuis, Mario Maas, Martijn Froeling, Hermien E Kan, Aart J Nederveen, Gustav J Strijkers, Melissa T Hooijmans.
      Repeated muscle micro-trauma may cause severe muscle damage. Diffusion tensor imaging (DTI) exhibits sensitivity to microstructural changes in skeletal muscle. We hypothesize that longer diffusion times enhance sensitivity to micro-trauma and that membrane permeability increases with micro-trauma. We obtained DTI scans of the thighs in ten male runners 1 week before (TP-0), 24-48 h after (TP-1), and 2 weeks after (TP-2) they completed a marathon. Diffusion times were 28.1, 116.7, and 316.7 ms. The random permeable barrier model (RPBM) was fitted to the radial diffusivities to obtain estimates for fiber diameter and membrane permeability. Hamstring and quadriceps muscles were manually segmented. A linear mixed model assessed variations across time points and diffusion times within the DTI and RPBM parameters and assessed sensitivity to micro-trauma by comparing %-changes in DTI parameters at TP-1 and TP-2 to TP-0. All DTI parameters except FA significantly changed between TP-0 and TP-1, and between TP-1 and TP-2. The %-change did not differ between diffusion times. The permeability increased at TP-1 and TP-2 compared to TP-0. In conclusion, longer diffusion times did not improve sensitivity to micro-trauma. The increased permeability post-marathon underscores the potential of RPBM-derived parameters as a biomarker for micro-trauma and muscle injuries.
    DOI:  https://doi.org/10.1038/s41598-024-83644-5
  22. Bio Protoc. 2024 Dec 20. 14(24): e5137
    Muscle Biopsy Sample Preparation and Proteomics Analysis Based on UHPLC-MS/MS.
    Jiawei Du, Jinghua Hou, Hezhang Yun, Yafeng Song.
      Proteomics analysis is crucial for understanding the molecular mechanisms underlying muscle adaptations to different types of exercise, such as concentric and eccentric training. Traditional methods like two-dimensional gel electrophoresis and standard mass spectrometry have been used to analyze muscle protein content and modifications. This protocol details the preparation of muscle samples for proteomics analysis using ultra-high-performance liquid chromatography (UHPLC). It includes steps for muscle biopsy collection, protein extraction, digestion, and UHPLC-based analysis. The UHPLC method offers high-resolution separation of complex protein mixtures, providing more detailed and accurate proteomic profiles compared to conventional techniques. This protocol significantly enhances sensitivity, reproducibility, and efficiency, making it ideal for comprehensive muscle proteomics studies. Key features • Developed for analyzing muscle adaptations in response to concentric and eccentric training, applicable to various physiology exercise studies. • Utilizes UHPLC-MS/MS for high-resolution separation and detailed proteomic profiling. • Requires access to advanced UHPLC-MS/MS equipment and muscle biopsy collection tools. • The protocol can be completed within one week, including sample preparation and analysis.
    Keywords:  Concentric exercise; Eccentric exercise; Muscle biopsy; Muscle proteomics; UHPLC-MS/MS
    DOI:  https://doi.org/10.21769/BioProtoc.5137
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