bims-moremu Biomed News
on Molecular regulators of muscle mass
Issue of 2024‒02‒11
43 papers selected by
Anna Vainshtein, Craft Science Inc.
  1. Molecular and Structural Alterations of Skeletal Muscle Tissue Nuclei during Aging.
  2. The mechanosensitive gene Arrestin domain containing 2 regulates myotube diameter with direct implications for disuse atrophy with aging.
  3. Wnt7a is Required for Regeneration of Dystrophic Skeletal Muscle.
  4. Parkin is a critical player in the effects of caffeine over mitochondrial quality control pathways during skeletal muscle regeneration in mice.
  5. Ablation of skeletal muscle estrogen receptor alpha impairs contractility in male mice.
  6. Plasminogen deficiency exacerbates skeletal muscle loss during mechanical unloading in developing mice.
  7. Chronic hypoxia impairs skeletal muscle repair via HIF-2α stabilization.
  8. Calcium-binding protein 7 expressed in muscle negatively regulates age-related degeneration of neuromuscular junctions in mice.
  9. Satellite Cell-Derived Exosomes: A Novel Approach to Alleviate Skeletal Muscle Atrophy and Fibrosis.
  10. Quantification of local matrix deposition during muscle stem cell activation using engineered hydrogels.
  11. β2-Adrenoceptors activation regulates muscle trophic-related genes following acute resistance exercise in mice.
  12. Resistance training does not increase myocellular garbage dumps: A pilot study on lipofuscin in skeletal muscle fibers of resistance trained young men.
  13. AMPK phosphorylation of FNIP1 (S220) controls mitochondrial function and muscle fuel utilization during exercise.
  14. Asynchronous Pattern of MAPKs' Activity during Aging of Different Tissues and of Distinct Types of Skeletal Muscle.
  15. EXERCISE AND MICRORNA.
  16. NASA SPRINT exercise program efficacy for vastus lateralis and soleus skeletal muscle health during 70 days of simulated microgravity.
  17. AMPK and Beyond: The Signaling Network Controlling RabGAPs and Contraction-Mediated Glucose Uptake in Skeletal Muscle.
  18. Ketone flux through BDH1 supports metabolic remodeling of skeletal and cardiac muscles in response to intermittent time-restricted feeding.
  19. Cyclin D3 Colocalizes with Myogenin and p21 in Skeletal Muscle Satellite Cells during Early-Stage Functional Overload.
  20. Functional consequences of familial ALS-associated SOD1L84F in neuronal and muscle cells.
  21. Examining the implications of glutathione peroxidase 4 overexpression and its impact on sarcopenia phenotypes in mice.
  22. Signatures of cysteine oxidation on muscle structural and contractile proteins are associated with physical performance and muscle function in older adults: Study of Muscle, Mobility and Aging (SOMMA).
  23. Age-Associated Differences in Recovery from Exercise-Induced Muscle Damage.
  24. Fatigue as hallmark of Fabry disease: role of bioenergetic alterations.
  25. Current situation and publication trends of skeletal muscle related research: A bibliometric analysis.
  26. S100b Treatment Overcomes RAGE Signaling Deficits in Myoblasts on Advanced Glycation End-product Cross-linked Collagen and Promotes Myogenic Differentiation.
  27. Differential effects of the venoms of Russell's viper and Indian cobra on human myoblasts.
  28. Transcriptional programming of translation by BCL6 controls skeletal muscle proteostasis.
  29. Depletion of SMN protein in mesenchymal progenitors impairs the development of bone and neuromuscular junction in spinal muscular atrophy.
  30. The Impact of miR-155-5p on Myotube Differentiation: Elucidating Molecular Targets in Skeletal Muscle Disorders.
  31. NLRP3 Contributes to Sarcopenia Associated to Dependency Recapitulating Inflammatory-Associated Muscle Degeneration.
  32. Utilization of the Rat Tibial Nerve Transection Model to Evaluate Cellular and Molecular Mechanisms Underpinning Denervation-Mediated Muscle Injury.
  33. The role of GPR81-cAMP-PKA pathway in endurance training-induced intramuscular triglyceride accumulation and mitochondrial content changes in rats.
  34. HDL-C and Apolipoprotein A-I are Independently Associated with Skeletal Muscle Mitochondrial Function in Healthy Humans.
  35. A new bio imagery user-friendly tool for automatic morphometry measurement on muscle cell cultures and histological sections.
  36. MCC950 Ameliorates Diabetic Muscle Atrophy in Mice by Inhibition of Pyroptosis and Its Synergistic Effect with Aerobic Exercise.
  37. The genetic and dietary landscape of the muscle insulin signalling network.
  38. Correlation between skeletal muscle acetylcarnitine and phosphocreatine metabolism during submaximal exercise and recovery: interleaved 1H/31P MRS 7 T study.
  39. Dysfunction of Akt/FoxO3a/Atg7 regulatory loop magnifies obesity-regulated muscular mass decline.
  40. The Current Landscape of Pharmacotherapies for Sarcopenia.
  41. Tankyrase-1 regulates RBP-mediated mRNA turnover to promote muscle fiber formation.
  42. Recurring homozygous ACTN2 variant (p.Arg506Gly) causes a recessive myopathy.
  43. Molecular Mechanisms of Cachexia: A Review.
  1. Int J Mol Sci. 2024 Feb 02. pii: 1833. [Epub ahead of print]25(3):
    Molecular and Structural Alterations of Skeletal Muscle Tissue Nuclei during Aging.
    Barbara Cisterna, Manuela Malatesta.
      Aging is accompanied by a progressive loss of skeletal muscle mass and strength. The mechanisms underlying this phenomenon are certainly multifactorial and still remain to be fully elucidated. Changes in the cell nucleus structure and function have been considered among the possible contributing causes. This review offers an overview of the current knowledge on skeletal muscle nuclei in aging, focusing on the impairment of nuclear pathways potentially involved in age-related muscle decline. In skeletal muscle two types of cells are present: fiber cells, constituting the contractile muscle mass and containing hundreds of myonuclei, and the satellite cells, i.e., the myogenic mononuclear stem cells occurring at the periphery of the fibers and responsible for muscle growth and repair. Research conducted on different experimental models and with different methodological approaches demonstrated that both the myonuclei and satellite cell nuclei of aged skeletal muscles undergo several structural and molecular alterations, affecting chromatin organization, gene expression, and transcriptional and post-transcriptional activities. These alterations play a key role in the impairment of muscle fiber homeostasis and regeneration, thus contributing to the age-related decrease in skeletal muscle mass and function.
    Keywords:  RNA processing; cell nucleus; chromatin; gene expression; myofiber; ribonucleic acid (RNA) transcription; satellite cell; skeletal muscle atrophy
    DOI:  https://doi.org/10.3390/ijms25031833
  2. Am J Physiol Cell Physiol. 2024 Feb 05.
    The mechanosensitive gene Arrestin domain containing 2 regulates myotube diameter with direct implications for disuse atrophy with aging.
    Grant R Laskin, Ana Regina Cabrera, Nicholas P Greene, Robert J Tomko, Cynthia Vied, Bradley S Gordon.
      Arrestin Domain Containing 2 and 3 (Arrdc2/3) are genes whose mRNA contents are decreased in young skeletal muscle following mechanical overload. Arrdc3 is linked to the regulation of signaling pathways in non-muscle cells that could influence skeletal muscle size. Despite a similar amino acid sequence, Arrdc2 function remains undefined. The purpose of this study was to further explore the relationship of Arrdc2/Arrdc3 expression with changes in mechanical load in young and aged muscle and define the effect of Arrdc2/3 expression on C2C12 myotube diameter. In young and aged mice, mechanical load was decreased using hindlimb suspension while mechanical load was increased by reloading previously unloaded muscle or inducing high force contractions. Arrdc2 and Arrdc3 mRNAs were overexpressed in C2C12 myotubes using adenoviruses. Myotube diameter was determined 48 h post-transfection and RNA sequencing was performed on those samples. Arrdc2 and Arrdc3 mRNA content was higher in the unloaded muscle within 1 day of disuse and remained higher up through 10 days. The induction of Arrdc2 mRNA was more pronounced in aged muscle than young muscle in response to unloading. Reloading previously unloaded muscle of young and aged mice restored Arrdc2 and Arrdc3 levels to ambulatory levels. Increasing mechanical load beyond normal ambulatory levels lowered Arrdc2 mRNA, but not Arrdc3 mRNA, in young and aged muscle. Arrdc2 overexpression only was sufficient to lower myotube diameter in C2C12 cells in part by altering the transcriptome favoring muscle atrophy. These data are consistent with Arrdc2 contributing to disuse atrophy, particularly in aged muscle.
    Keywords:  Mechanical overload; RNA sequencing; aging; electromyostimulation; mechanical unloading
    DOI:  https://doi.org/10.1152/ajpcell.00444.2023
  3. bioRxiv. 2024 Jan 25. pii: 2024.01.24.577041. [Epub ahead of print]
    Wnt7a is Required for Regeneration of Dystrophic Skeletal Muscle.
    Uxia Gurriaran-Rodriguez, Kasun Kodippili, David Datzkiw, Ehsan Javandoost, Fan Xiao, Maria Teresa Rejas, Michael A Rudnicki.
      Intramuscular injection of Wnt7a has been shown to accelerate and augment skeletal muscle regeneration and to ameliorate dystrophic progression in mdx muscle, a model for Duchenne muscular dystrophy (DMD). However, loss-of-function studies to investigate the requirement for Wnt7a in muscle regeneration has not been evaluated. Here, we assessed muscle regeneration and function in wild type (WT) and mdx mice where Wnt7a was specifically deleted in muscle using a conditional Wnt7a floxed allele and a Myf5-Cre driver. We found that both WT and mdx mice with deletion of Wnt7a in muscle, exhibited marked deficiencies in muscle regeneration at 21 d following cardiotoxin (CTX) induced injury. Unlike WT, deletion of Wnt7a in mdx resulted in a marked decrease in specific force generation prior to CTX injury. However, both WT and mdx muscle lacking Wnt7a displayed decreased specific force generation following CTX injection. Notably the regeneration deficit observed in mdx mice lacking Wnt7a in muscle was rescued by a single tail vein injection of an extracellular vesicle preparation containing Wnt7a (Wnt7a-EVs). Therefore, we conclude that the regenerative capacity of muscle in mdx mice is due to the upregulation of endogenous Wnt7a following injury, and that systemic delivery of Wnt7a-EVs represents a therapeutic strategy for treating DMD.
    DOI:  https://doi.org/10.1101/2024.01.24.577041
  4. Acta Physiol (Oxf). 2024 Feb 05. e14111
    Parkin is a critical player in the effects of caffeine over mitochondrial quality control pathways during skeletal muscle regeneration in mice.
    M V Esteca, I A Divino, A L Vieira da Silva, M B Severino, R R Braga, E R Ropelle, F M Simabuco, I L Baptista.
      AIM: This study aimed to investigate the effects of caffeine on pathways associated with mitochondrial quality control and mitochondrial capacity during skeletal muscle regeneration, focusing on the role of Parkin, a key protein involved in mitophagy.METHODS: We used in vitro C2C12 myoblast during differentiation with and without caffeine in the medium, and we evaluated several markers of mitochondrial quality control pathways and myotube growth. In vivo experiments, we used C57BL/6J (WT) and Parkintm 1Shn lineage (Parkin-/- ) mice and injured tibial anterior muscle. The mice regenerated TA muscle for 3, 10, and 21 days with or without caffeine ingestion. TA muscle was used to analyze the protein content of several markers of mitochondrial quality pathways, muscle satellite cell differentiation, and protein synthesis. Furthermore, it analyzed mtDNA, mitochondrial respiration, and myofiber growth.
    RESULTS: C2C12 differentiation experiments showed that caffeine decreased Parkin content, potentially leading to increased DRP1 and PGC-1α content and altered mitochondrial population, thereby enhancing growth capacity. Using Parkin-/- mice, we found that caffeine intake during the regenerative process induces an increase in AMPKα phosphorylation and PGC-1α and TFAM content, changes that were partly Parkin-dependent. In addition, the absence of Parkin potentiates the ergogenic effect of caffeine by increasing mitochondrial capacity and myotube growth. Those effects are related to increased ATF4 content and activation of protein synthesis pathways, such as increased 4E-BP1 phosphorylation.
    CONCLUSION: These findings demonstrate that caffeine ingestion changes mitochondrial quality control during skeletal muscle regeneration, and Parkin is a central player in those mechanisms.
    Keywords:  AMPK; caffeine; mitochondrial respiration; muscle recovery
    DOI:  https://doi.org/10.1111/apha.14111
  5. J Appl Physiol (1985). 2024 Feb 08.
    Ablation of skeletal muscle estrogen receptor alpha impairs contractility in male mice.
    Brian P Sullivan, Brittany C Collins, Shawna L McMillin, Elise Toussaint, Clara Z Stein, Espen E Spangenburg, Dawn A Lowe.
      Estradiol and estrogen receptor α (ERα) have been shown to be important for the maintenance of skeletal muscle strength in females, however little is known about the roles of estradiol and ERα in male muscle. The purpose of this study was to determine if skeletal muscle ERα is required for optimal contractility in male mice. We hypothesize that reduced ERα in skeletal muscle impairs contractility in male mice. Skeletal muscle specific knockout (skmERαKO) male mice exhibited reduced strength across multiple muscles and several contractile parameters related to force generation and kinetics compared to wildtype littermates (skmERαWT). Isolated EDL muscle specific isometric tetanic force, peak twitch force, peak concentric and peak eccentric forces, as well as the maximal rates of force development and relaxation were 11-21% lower in skmERαKO compared to skmERαWT mice. In contrast, isolated soleus muscles from skmERaKO mice were not affected. In vivo peak torque of the anterior crural muscles were 20% lower in skmERαKO compared to skmERαWT mice. Muscle masses, contractile protein contents, fiber types, phosphorylation of the myosin regulatory light chain, and caffeine-elicited force did not differ between muscles of skmERαKO and skmERαWT mice suggesting that strength deficits were not due to size, composition, or calcium release components of muscle contraction. These results indicate that in male mice reduced skeletal muscle ERα blunts contractility to a magnitude similar to that previously reported in females, however, the mechanism may be sexually dimorphic.
    Keywords:  Estradiol; Strength; knockout; physiology; sex differences
    DOI:  https://doi.org/10.1152/japplphysiol.00714.2023
  6. J Appl Physiol (1985). 2024 Feb 08.
    Plasminogen deficiency exacerbates skeletal muscle loss during mechanical unloading in developing mice.
    Takashi Ohira, Yoko Ino, Naoyuki Kawao, Yuya Mizukami, Kiyotaka Okada, Osamu Matsuo, Hisashi Hirano, Yayoi Kimura, Hiroshi Kaji.
      Mechanical-unloading-induced skeletal muscle atrophy results in physical frailty and disability. Elucidating its mechanism is required to establish effective countermeasures for this muscle adaptation. First, we analyzed the proteome profile in the gastrocnemius (Gast) and soleus muscles of space-flown mice raised under microgravity or artificial 1-g for 30 days, and found that the expression levels of fibrinolysis-related proteins were significantly elevated in the mechanical-unloaded muscles. Next, we investigated the roles of the fibrinolytic system in skeletal muscle atrophy induced by mechanical unloading on the ground. Eight-week-old male mice with plasminogen gene deficiency (Plg-/-) and their wild-type littermates were divided into control and hindlimb-suspended groups, and were raised for 21 days. Plasminogen deficiency significantly enhanced the decrease in muscle mass at the lower limbs of mice following hindlimb unloading, and the Gast muscle atrophy was more prominent in Plg-/- mice. Additionally, plasminogen deficiency significantly increased the expression of autophagy-related markers, beclin1 mRNA and LC3B protein, in the mechanical-unloaded Gast muscles, but did not affect the increase in the gene expression of ubiquitin ligases, atrogin-1 and MuRF1. Neither plasminogen deficiency nor hindlimb unloading affected the Akt/mechanistic target of rapamycin pathway in the Gast muscles. These results suggested that plasminogen deficiency might accelerate protein breakdown via the autophagy-lysosome, but not the ubiquitin-proteasome, system in the mechanical-unloaded Gast muscles. In conclusion, we first showed that plasminogen deficiency exacerbated the Gast muscle atrophy in hindlimb-unloaded mice. Plasminogen and the fibrinolysis system might play some protective roles against muscle atrophy induced by mechanical unloading in developing mice.
    Keywords:  Fibrinolysis; Mechanical unloading; Mouse; Protein breakdown; Skeletal muscle
    DOI:  https://doi.org/10.1152/japplphysiol.00300.2023
  7. J Cachexia Sarcopenia Muscle. 2024 Feb 09.
    Chronic hypoxia impairs skeletal muscle repair via HIF-2α stabilization.
    Amelia Yin, Wenyan Fu, Anthony Elengickal, Joonhee Kim, Yang Liu, Anne Bigot, Kamal Mamchaoui, Jarrod A Call, Hang Yin.
      BACKGROUND: Chronic hypoxia and skeletal muscle atrophy commonly coexist in patients with COPD and CHF, yet the underlying physio-pathological mechanisms remain elusive. Muscle regeneration, driven by muscle stem cells (MuSCs), holds therapeutic potential for mitigating muscle atrophy. This study endeavours to investigate the influence of chronic hypoxia on muscle regeneration, unravel key molecular mechanisms, and explore potential therapeutic interventions.METHODS: Experimental mice were exposed to prolonged normobaric hypoxic air (15% pO2 , 1 atm, 2 weeks) to establish a chronic hypoxia model. The impact of chronic hypoxia on body composition, muscle mass, muscle strength, and the expression levels of hypoxia-inducible factors HIF-1α and HIF-2α in MuSC was examined. The influence of chronic hypoxia on muscle regeneration, MuSC proliferation, and the recovery of muscle mass and strength following cardiotoxin-induced injury were assessed. The muscle regeneration capacities under chronic hypoxia were compared between wildtype mice, MuSC-specific HIF-2α knockout mice, and mice treated with HIF-2α inhibitor PT2385, and angiotensin converting enzyme (ACE) inhibitor lisinopril. Transcriptomic analysis was performed to identify hypoxia- and HIF-2α-dependent molecular mechanisms. Statistical significance was determined using analysis of variance (ANOVA) and Mann-Whitney U tests.
    RESULTS: Chronic hypoxia led to limb muscle atrophy (EDL: 17.7%, P < 0.001; Soleus: 11.5% reduction in weight, P < 0.001) and weakness (10.0% reduction in peak-isometric torque, P < 0.001), along with impaired muscle regeneration characterized by diminished myofibre cross-sectional areas, increased fibrosis (P < 0.001), and incomplete strength recovery (92.3% of pre-injury levels, P < 0.05). HIF-2α stabilization in MuSC under chronic hypoxia hindered MuSC proliferation (26.1% reduction of MuSC at 10 dpi, P < 0.01). HIF-2α ablation in MuSC mitigated the adverse effects of chronic hypoxia on muscle regeneration and MuSC proliferation (30.9% increase in MuSC numbers at 10 dpi, P < 0.01), while HIF-1α ablation did not have the same effect. HIF-2α stabilization under chronic hypoxia led to elevated local ACE, a novel direct target of HIF-2α. Notably, pharmacological interventions with PT2385 or lisinopril enhanced muscle regeneration under chronic hypoxia (PT2385: 81.3% increase, P < 0.001; lisinopril: 34.6% increase in MuSC numbers at 10 dpi, P < 0.05), suggesting their therapeutic potential for alleviating chronic hypoxia-associated muscle atrophy.
    CONCLUSIONS: Chronic hypoxia detrimentally affects skeletal muscle regeneration by stabilizing HIF-2α in MuSC and thereby diminishing MuSC proliferation. HIF-2α increases local ACE levels in skeletal muscle, contributing to hypoxia-induced regenerative deficits. Administration of HIF-2α or ACE inhibitors may prove beneficial to ameliorate chronic hypoxia-associated muscle atrophy and weakness by improving muscle regeneration under chronic hypoxia.
    Keywords:  Angiotensin converting enzyme; Hypoxia; Hypoxia-inducible factor 2A; Muscle atrophy; Muscle regeneration; Muscle stem cells
    DOI:  https://doi.org/10.1002/jcsm.13436
  8. iScience. 2024 Feb 16. 27(2): 108997
    Calcium-binding protein 7 expressed in muscle negatively regulates age-related degeneration of neuromuscular junctions in mice.
    Takahiro Eguchi, Tohru Tezuka, Yuji Watanabe, Akane Inoue-Yamauchi, Hiroshi Sagara, Manabu Ozawa, Yuji Yamanashi.
      The neuromuscular junction (NMJ) forms centrally in myotubes and, as the only synapse between motor neuron and myotube, are indispensable for motor activity. The midmuscle formation of NMJs, including midmuscle-restricted expression of NMJ-related genes, is governed by the muscle-specific kinase (MuSK). However, mechanisms underlying MuSK-mediated signaling are unclear. Here, we find that the Calcium-binding protein 7 (Cabp7) gene shows midmuscle-restricted expression, and muscle-specific depletion of Cabp7 in mice accelerated age-related NMJ degeneration, muscle weakness/atrophy, and motor dysfunction. Surprisingly, forced expression in muscle of CIP, an inhibitory peptide of the negative regulator of NMJ formation cyclin-dependent kinase 5 (Cdk5), restored NMJ integrity and muscle strength, and healed muscle atrophy in muscle-specific Cabp7-deficient mice, which showed increased muscle expression of the Cdk5 activator p25. These findings together demonstrate that MuSK-mediated signaling induces muscle expression of Cabp7, which suppresses age-related NMJ degeneration likely by attenuating p25 expression, providing insights into prophylactic/therapeutic intervention against age-related motor dysfunction.
    Keywords:  Molecular biology; Neuroscience; Physiology
    DOI:  https://doi.org/10.1016/j.isci.2024.108997
  9. Adv Biol (Weinh). 2024 Feb 08. e2300558
    Satellite Cell-Derived Exosomes: A Novel Approach to Alleviate Skeletal Muscle Atrophy and Fibrosis.
    Hongwen Liu, Shiguo Yuan, Gaofeng Liu, Junhua Li, Kai Zheng, Zhiwei Zhang, Sheng Zheng, Li Yin, Yikai Li.
      Skeletal muscle atrophy coincides with extensive fibrous tissue hyperplasia in muscle-atrophied patients, and fibrous tissue plays a vital role in skeletal muscle function and hinders muscle fiber regeneration. However, effective drugs to manage skeletal muscle atrophy and fibrosis remain elusive. This study isolated and characterized exosomes derived from skeletal muscle satellite cells (MuSC-Exo). The study investigated their effects on denervated skeletal muscle atrophy and fibrosis in Sprague Dawley (SD) rats via intramuscular injection. MuSC-Exo demonstrated the potential to alleviate skeletal muscle atrophy and fibrosis. The underlying mechanism using single-cell RNA sequencing data and functional analysis are analyzed. Mechanistic studies reveal close associations between fibroblasts and myoblasts, with the transforming growth factor β1 (TGF-β1)-Smad3-Pax7 axis governing fibroblast activation in atrophic skeletal muscle. MuSC-Exo intervention inhibited the TGF-β1/Smad3 pathway and improved muscle atrophy and fibrosis. In conclusion, MuSC-Exo-based therapy may represent a novel strategy to alleviate skeletal muscle atrophy and reduce excessive fibrotic tissue by targeting Pax7 through the TGF-β1/Smad3 pathway.
    Keywords:  exosomes; muscle atrophy; muscle fibrosis; satellite cells
    DOI:  https://doi.org/10.1002/adbi.202300558
  10. bioRxiv. 2024 Jan 23. pii: 2024.01.20.576326. [Epub ahead of print]
    Quantification of local matrix deposition during muscle stem cell activation using engineered hydrogels.
    Pamela Duran, Benjamin A Yang, Eleanor Plaster, Madeline Eiken, Claudia Loebel, Carlos A Aguilar.
      Adult stem cells occupy a niche that contributes to their function, but how stem cells remodel their microenvironment remains an open-ended question. Herein, biomaterials-based systems and metabolic labeling were utilized to evaluate how skeletal muscle stem cells deposit extracellular matrix. Muscle stem cells and committed myoblasts were observed to generate less nascent matrix than muscle resident fibro-adipogenic progenitors. When cultured on substrates that matched the stiffness of physiological uninjured and injured muscles, the increased nascent matrix deposition was associated with stem cell activation. Reducing the ability to deposit nascent matrix in muscle stem cells attenuated function and mimicked impairments observed from muscle stem cells isolated from old aged muscles, which could be rescued with therapeutic supplementation of insulin-like growth factors. These results highlight how nascent matrix production is critical for maintaining healthy stem cell function.
    DOI:  https://doi.org/10.1101/2024.01.20.576326
  11. Front Physiol. 2024 ;15 1268380
    β2-Adrenoceptors activation regulates muscle trophic-related genes following acute resistance exercise in mice.
    Ronaldo L Abdalla-Silva, Gustavo O Zanetti, Natalia Lautherbach, Aline Zanatta Schavinski, Lilian C Heck, Dawit A P Gonçalves, Isis C Kettelhut, Luiz C C Navegantes, Wilian A Silveira.
      Resistance exercise (RE) training and pharmacological stimulation of β2-Adrenoceptors (β2-ARs) alone can promote muscle hypertrophy and prevent muscle atrophy. Although the activation of the sympathetic nervous system (SNS) is a well-established response during RE, the physiological contribution of the endogenous catecholamines and β2-ARs to the RE-induced changes on skeletal muscle protein metabolism remains unclear. This study investigated the effects of the β2-ARs blockade on the acute molecular responses induced by a single bout of RE in rodent skeletal muscles. Male C57BL6/J mice were subjected to a single bout of progressive RE (until exhaustion) on a vertical ladder under β2-AR blockade with ICI 118,551 (ICI; 10 mg kg-1, i. p.), or vehicle (sterile saline; 0.9%, i. p.), and the gene expression was analyzed in gastrocnemius (GAS) muscles by qPCR. We demonstrated that a single bout of RE acutely increased the circulating levels of stress-associated hormones norepinephrine (NE) and corticosterone (CORT), as well as the muscle phosphorylation levels of AMPK, p38 MAPK and CREB, immediately after the session. The acute increase in the phosphorylation levels of CREB was followed by the upregulation of CREB-target genes Sik1, Ppargc1a and Nr4a3 (a central regulator of the acute RE response), 3 h after the RE session. Conversely, β2-AR blockade reduced significantly the Sik1 and Nr4a3 mRNA levels in muscles of exercised mice. Furthermore, a single bout of RE stimulated the mRNA levels of the atrophic genes Map1lc3b and Gabarapl1 (autophagy-related genes) and Mstn (a well-known negative regulator of muscle growth). Unexpectedly, the gene expression of Igf-1 or Il-6 were not affected by RE, while the atrophic genes Murf1/Trim63 and Atrogin-1/Mafbx32 (ubiquitin-ligases) were increased only in muscles of exercised mice under β2-AR blockade. Interestingly, performing a single bout of RE under β2-AR blockade increased the mRNA levels of Mstn in muscles of exercised mice. These data suggest that β2-ARs stimulation during acute RE stimulates the hypertrophic gene Nr4a3 and prevents the overexpression of atrophic genes such as Mstn, Murf1/Trim63, and Atrogin-1/Mafbx32 in the first hours of postexercise recovery, indicating that he SNS may be physiologically important to muscle adaptations in response to resistance training.
    Keywords:  NR4A3; myostatin; resistance exercise; skeletal muscle; β2-adrenoceptor
    DOI:  https://doi.org/10.3389/fphys.2024.1268380
  12. Physiol Rep. 2024 Feb;12(3): e15922
    Resistance training does not increase myocellular garbage dumps: A pilot study on lipofuscin in skeletal muscle fibers of resistance trained young men.
    Daniel Jacko, Lukas Masur, Kirill Schaaf, Jonas Zacher, Käthe Bersiner, Markus de Marées, Wilhelm Bloch, Sebastian Gehlert.
      Lipofuscin (LF) is an intracellular aggregate associated with proteostatic impairments, especially prevalent in nondividing skeletal muscle fibers. Reactive oxygen species (ROS) drive LF-formation. Resistance training (RT) improves muscle performance but also increases ROS production, potentially promoting LF-formation. Thus, we aimed to investigate if RT of a mesocycle duration increases LF-formation in type-I and II muscle fibers and whether RT increases the antioxidant capacity (AOC) in terms of SOD1 and SOD2 content. An intervention group (IG) performed 14 eccentrically accented RT-sessions within 7 weeks. Vastus lateralis muscle biopsies were collected before and after the intervention from IG as well as from a control group (CG) which refrained from RT for the same duration. LF was predominantly found near nuclei, followed by membrane-near and a minor amount in the fiber core, with corresponding spot sizes. Overall, LF-content was higher in type-I than type-II fibers (p < 0.05). There was no increase in LF-content in type-I or IIA fibers, neither for the IG following RT nor for the CG. The same is valid for SOD1/2. We conclude that, in healthy subjects, RT can be safely performed, without adverse effects on increased LF-formation.
    Keywords:  SOD; exercise; fiber types; human skeletal muscle; lipofuscin
    DOI:  https://doi.org/10.14814/phy2.15922
  13. Sci Adv. 2024 Feb 09. 10(6): eadj2752
    AMPK phosphorylation of FNIP1 (S220) controls mitochondrial function and muscle fuel utilization during exercise.
    Liwei Xiao, Yujing Yin, Zongchao Sun, Jing Liu, Yuhuan Jia, Likun Yang, Yan Mao, Shujun Peng, Zhifu Xie, Lei Fang, Jingya Li, Xiaoduo Xie, Zhenji Gan.
      Exercise-induced activation of adenosine monophosphate-activated protein kinase (AMPK) and substrate phosphorylation modulate the metabolic capacity of mitochondria in skeletal muscle. However, the key effector(s) of AMPK and the regulatory mechanisms remain unclear. Here, we showed that AMPK phosphorylation of the folliculin interacting protein 1 (FNIP1) serine-220 (S220) controls mitochondrial function and muscle fuel utilization during exercise. Loss of FNIP1 in skeletal muscle resulted in increased mitochondrial content and augmented metabolic capacity, leading to enhanced exercise endurance in mice. Using skeletal muscle-specific nonphosphorylatable FNIP1 (S220A) and phosphomimic (S220D) transgenic mouse models as well as biochemical analysis in primary skeletal muscle cells, we demonstrated that exercise-induced FNIP1 (S220) phosphorylation by AMPK in muscle regulates mitochondrial electron transfer chain complex assembly, fuel utilization, and exercise performance without affecting mechanistic target of rapamycin complex 1-transcription factor EB signaling. Therefore, FNIP1 is a multifunctional AMPK effector for mitochondrial adaptation to exercise, implicating a mechanism for exercise tolerance in health and disease.
    DOI:  https://doi.org/10.1126/sciadv.adj2752
  14. Int J Mol Sci. 2024 Jan 30. pii: 1713. [Epub ahead of print]25(3):
    Asynchronous Pattern of MAPKs' Activity during Aging of Different Tissues and of Distinct Types of Skeletal Muscle.
    Nechama Gilad, Manju Payini Mohanam, Ilona Darlyuk-Saadon, C K Matthew Heng, Inbar Plaschkes, Hadar Benyamini, Nikolay V Berezhnoy, David Engelberg.
      The MAPK p38α was proposed to be a prominent promoter of skeletal muscle aging. The skeletal muscle tissue is composed of various muscle types, and it is not known if p38α is associated with aging in all of them. It is also not known if p38α is associated with aging of other tissues. JNK and ERK were also proposed to be associated with aging of several tissues. Nevertheless, the pattern of p38α, JNK, and ERK activity during aging was not documented. Here, we documented the levels of phosphorylated/active p38α, Erk1/2, and JNKs in several organs as well as the soleus, tibialis anterior, quadriceps, gastrocnemius, and EDL muscles of 1-, 3-, 6-, 13-, 18-, and 24-month-old mice. We report that in most tissues and skeletal muscles, the MAPKs' activity does not change in the course of aging. In most tissues and muscles, p38α is in fact active at younger ages. The quadriceps and the lungs are exceptions, where p38α is significantly active only in mice 13 months old or older. Curiously, levels of active JNK and ERKs are also elevated in aged lungs and quadriceps. RNA-seq analysis of the quadriceps during aging revealed downregulation of proteins related to the extra-cellular matrix (ECM) and ERK signaling. A panel of mRNAs encoding cell cycle inhibitors and senescence-associated proteins, considered to be aging markers, was not found to be elevated. It seems that the pattern of MAPKs' activation in aging, as well as expression of known 'aging' components, are tissue- and muscle type-specific, supporting a notion that the process of aging is tissue- and even cell-specific.
    Keywords:  ERK; JNK; MAPKs; p38
    DOI:  https://doi.org/10.3390/ijms25031713
  15. Georgian Med News. 2023 Dec; 146-153
    EXERCISE AND MICRORNA.
    M Pala.
      Physical activity stimulates numerous structural, metabolic, and morphological adaptations. These adaptations are vital for maintaining human health throughout life. Developments in molecular biology, biochemistry, and bioinformatics, along with exercise physiology have identified many signaling pathways, and transcriptional and translational processes responsible for exercise-related adaptations. The molecular mechanisms underlying the beneficial effects of exercise are not fully understood. Recently, the focus has been on microRNAs (miRNAs). They are small noncoding RNA molecules that negatively modulate gene expression and are involved in fundamental biological processes. This review describes miRNAs whose activities change in the heart, skeletal muscle, and circulation due to exercise. In addition, miRNAs with altered activity may be parameters adaptation to exercise, preventing injuries, and monitoring health status.
  16. J Appl Physiol (1985). 2024 Feb 08.
    NASA SPRINT exercise program efficacy for vastus lateralis and soleus skeletal muscle health during 70 days of simulated microgravity.
    Todd A Trappe, Kiril Minchev, Ryan K Perkins, Kaleen M Lavin, Bozena Jemiolo, Stephen M Ratchford, Alex Claiborne, Gary A Lee, W Holmes Finch, Jeffrey W Ryder, Lori Ploutz-Snyder, Scott W Trappe.
      The efficacy of the NASA SPRINT exercise countermeasures program for quadriceps (vastus lateralis) and triceps surae (soleus) skeletal muscle health was investigated during 70 days of simulated microgravity. Individuals completed 6° head-down-tilt bedrest (BR, n=9), bedrest with resistance and aerobic exercise (BRE, n=9), or bedrest with resistance and aerobic exercise and low-dose testosterone (BRE+T, n=8). All groups were periodically tested for muscle (n=9 times) and aerobic (n=4 times) power during bedrest. In BR, surprisingly, the typical bedrest-induced decrements in vastus lateralis myofiber size and power were either blunted (MHC I) or eliminated (MHC IIa), along with no change (P>0.05) in %MHC distribution and blunted quadriceps atrophy. In BRE, MHC I (vastus lateralis and soleus) and IIa (vastus lateralis) contractile performance was maintained (P>0.05) or increased (P<0.05). Vastus lateralis hybrid fiber percentage was reduced (P<0.05) and energy metabolism enzymes and capillarization were generally maintained (P>0.05), while not all of these positive responses were observed in the soleus. Exercise offset 100% of quadriceps and ~ ⅔ of soleus whole muscle mass loss. Testosterone (BRE+T) did not provide any benefit over exercise alone for either muscle, and for some myocellular parameters appeared detrimental. In summary, the periodic testing likely provided a partial exercise countermeasure for the quadriceps in the bedrest group, which is a novel finding given the extremely low exercise dose. The SPRINT exercise program appears to be viable for the quadriceps; however, refinement is needed to completely protect triceps surae myocellular and whole muscle health for astronauts on long-duration spaceflights.
    Keywords:  exercise; microgravity; skeletal muscle; weightlessness
    DOI:  https://doi.org/10.1152/japplphysiol.00489.2023
  17. Int J Mol Sci. 2024 Feb 05. pii: 1910. [Epub ahead of print]25(3):
    AMPK and Beyond: The Signaling Network Controlling RabGAPs and Contraction-Mediated Glucose Uptake in Skeletal Muscle.
    Leon Peifer-Weiß, Hadi Al-Hasani, Alexandra Chadt.
      Impaired skeletal muscle glucose uptake is a key feature in the development of insulin resistance and type 2 diabetes. Skeletal muscle glucose uptake can be enhanced by a variety of different stimuli, including insulin and contraction as the most prominent. In contrast to the clearance of glucose from the bloodstream in response to insulin stimulation, exercise-induced glucose uptake into skeletal muscle is unaffected during the progression of insulin resistance, placing physical activity at the center of prevention and treatment of metabolic diseases. The two Rab GTPase-activating proteins (RabGAPs), TBC1D1 and TBC1D4, represent critical nodes at the convergence of insulin- and exercise-stimulated signaling pathways, as phosphorylation of the two closely related signaling factors leads to enhanced translocation of glucose transporter 4 (GLUT4) to the plasma membrane, resulting in increased cellular glucose uptake. However, the full network of intracellular signaling pathways that control exercise-induced glucose uptake and that overlap with the insulin-stimulated pathway upstream of the RabGAPs is not fully understood. In this review, we discuss the current state of knowledge on exercise- and insulin-regulated kinases, hypoxia, nitric oxide (NO) and bioactive lipids that may be involved in the regulation of skeletal muscle glucose uptake.
    Keywords:  AMPK; RabGAPs; contraction; glucose uptake; skeletal muscle
    DOI:  https://doi.org/10.3390/ijms25031910
  18. Cell Metab. 2024 Feb 06. pii: S1550-4131(24)00007-X. [Epub ahead of print]36(2): 422-437.e8
    Ketone flux through BDH1 supports metabolic remodeling of skeletal and cardiac muscles in response to intermittent time-restricted feeding.
    Ashley S Williams, Scott B Crown, Scott P Lyons, Timothy R Koves, Rebecca J Wilson, Jordan M Johnson, Dorothy H Slentz, Daniel P Kelly, Paul A Grimsrud, Guo-Fang Zhang, Deborah M Muoio.
      Time-restricted feeding (TRF) has gained attention as a dietary regimen that promotes metabolic health. This study questioned if the health benefits of an intermittent TRF (iTRF) schedule require ketone flux specifically in skeletal and cardiac muscles. Notably, we found that the ketolytic enzyme beta-hydroxybutyrate dehydrogenase 1 (BDH1) is uniquely enriched in isolated mitochondria derived from heart and red/oxidative skeletal muscles, which also have high capacity for fatty acid oxidation (FAO). Using mice with BDH1 deficiency in striated muscles, we discover that this enzyme optimizes FAO efficiency and exercise tolerance during acute fasting. Additionally, iTRF leads to robust molecular remodeling of muscle tissues, and muscle BDH1 flux does indeed play an essential role in conferring the full adaptive benefits of this regimen, including increased lean mass, mitochondrial hormesis, and metabolic rerouting of pyruvate. In sum, ketone flux enhances mitochondrial bioenergetics and supports iTRF-induced remodeling of skeletal muscle and heart.
    Keywords:  acylcarnitines; beta-oxidation; fiber type; intermittent fasting; ketones; metabolic flux; mitochondria; proteomics; striated muscles; time-restricted feeding
    DOI:  https://doi.org/10.1016/j.cmet.2024.01.007
  19. Acta Histochem Cytochem. 2023 Dec 28. 56(6): 111-119
    Cyclin D3 Colocalizes with Myogenin and p21 in Skeletal Muscle Satellite Cells during Early-Stage Functional Overload.
    Minenori Ishido.
      Myogenic cell differentiation is modulated by multiple regulatory factors, such as myogenin, p21, and cyclin D3 during myogenesis in vitro. It is also recognized that myogenin and p21 play important roles in regulating muscle satellite cell (SC) differentiation during overload-induced muscle hypertrophy in vivo. However, the expression patterns and functional role of cyclin D3 in the progress of muscle hypertrophy remain unclear. Thus, the present study investigated cyclin D3 expression in skeletal muscles during early-stage functional overload. Plantaris muscles were exposed to functional overload due to ablation of the gastrocnemius and soleus muscles. As a result, cyclin D3 expression was detected in the nuclei of SCs but not in myonuclei on day 1 after surgery. Cyclin D3 expression, after functional overload, gradually increased, reaching a maximum on day 7 along with myogenin expression. Moreover, in response to the functional overload, cyclin D3 was expressed simultaneously with myogenin and p21 in SC nuclei. Therefore, the present study suggests that cyclin D3 with myogenin and p21 may interactively regulate SC differentiation during early-stage functional overload.
    Keywords:  cyclin D3; muscle hypertrophy; satellite cell; skeletal muscle
    DOI:  https://doi.org/10.1267/ahc.23-00041
  20. FASEB J. 2024 Feb 15. 38(3): e23461
    Functional consequences of familial ALS-associated SOD1L84F in neuronal and muscle cells.
    Sagar Verma, Abhishek Vats, Vanshika Ahuja, Kavita Vats, Shiffali Khurana, Yuvraj Vats, Mandaville Gourie-Devi, Saima Wajid, Nirmal Kumar Ganguly, Pradip Chakraborti, Vibha Taneja.
      Amyotrophic lateral sclerosis is a fatal neurodegenerative disorder characterized by progressive skeletal muscle denervation and loss of motor neurons that results in muscle atrophy and eventual death due to respiratory failure. Previously, we identified a novel SOD1L84F variation in a familial ALS case. In this study, we examined the functional consequences of SOD1L84F overexpression in the mouse motor neuron cell line (NSC-34). The cells expressing SOD1L84F showed increased oxidative stress and increased cell death. Interestingly, SOD1L84F destabilized the native dimer and formed high molecular weight SDS-resistant protein aggregates. Furthermore, SOD1L84F also decreased the percentage of differentiated cells and significantly reduced neurite length. A plethora of evidence suggested active involvement of skeletal muscle in disease initiation and progression. We observed differential processing of the mutant SOD1 and perturbations of cellular machinery in NSC-34 and muscle cell line C2C12. Unlike neuronal cells, mutant protein failed to accumulate in muscle cells probably due to the activated autophagy, as evidenced by increased LC3-II and reduced p62. Further, SOD1L84F altered mitochondrial dynamics only in NSC-34. In addition, microarray analysis also revealed huge variations in differentially expressed genes between NSC-34 and C2C12. Interestingly, SOD1L84F hampered the endogenous FUS autoregulatory mechanism in NSC-34 by downregulating retention of introns 6 and 7 resulting in a two-fold upregulation of FUS. No such changes were observed in C2C12. Our findings strongly suggest the differential processing and response towards the mutant SOD1 in neuronal and muscle cell lines.
    Keywords:  FUS; SOD1; microarray; mitochondrial dysfunction; mutant SOD1 aggregates; neurite outgrowth; protein degradation machinery
    DOI:  https://doi.org/10.1096/fj.202301979R
  21. J Physiol. 2024 Feb 03.
    Examining the implications of glutathione peroxidase 4 overexpression and its impact on sarcopenia phenotypes in mice.
    Scylas José de Andrade Junior, Matheus Biscaro Rocha, Carlos Kiyoshi Katashima.
      
    Keywords:  aging; glutathione Peroxidase 4; muscle; sarcopenia
    DOI:  https://doi.org/10.1113/JP285881
  22. Aging Cell. 2024 Feb 08. e14094
    Signatures of cysteine oxidation on muscle structural and contractile proteins are associated with physical performance and muscle function in older adults: Study of Muscle, Mobility and Aging (SOMMA).
    Nicholas J Day, Shane S Kelly, Li-Yung Lui, Tyler A Mansfield, Matthew J Gaffrey, Jesse B Trejo, Tyler J Sagendorf, Isaac K Attah, Ronald J Moore, Collin M Douglas, Anne B Newman, Stephen B Kritchevsky, Philip A Kramer, David J Marcinek, Paul M Coen, Bret H Goodpaster, Russell T Hepple, Peggy M Cawthon, Vladislav A Petyuk, Karyn A Esser, Wei-Jun Qian, Steven R Cummings.
      Oxidative stress is considered a contributor to declining muscle function and mobility during aging; however, the underlying molecular mechanisms remain poorly described. We hypothesized that greater levels of cysteine (Cys) oxidation on muscle proteins are associated with decreased measures of mobility. Herein, we applied a novel redox proteomics approach to measure reversible protein Cys oxidation in vastus lateralis muscle biopsies collected from 56 subjects in the Study of Muscle, Mobility and Aging (SOMMA), a community-based cohort study of individuals aged 70 years and older. We tested whether levels of Cys oxidation on key muscle proteins involved in muscle structure and contraction were associated with muscle function (leg power and strength), walking speed, and fitness (VO2 peak on cardiopulmonary exercise testing) using linear regression models adjusted for age, sex, and body weight. Higher oxidation levels of select nebulin Cys sites were associated with lower VO2 peak, while greater oxidation of myomesin-1, myomesin-2, and nebulin Cys sites was associated with slower walking speed. Higher oxidation of Cys sites in key proteins such as myomesin-2, alpha-actinin-2, and skeletal muscle alpha-actin were associated with lower leg power and strength. We also observed an unexpected correlation (R = 0.48) between a higher oxidation level of eight Cys sites in alpha-actinin-3 and stronger leg power. Despite this observation, the results generally support the hypothesis that Cys oxidation of muscle proteins impairs muscle power and strength, walking speed, and cardiopulmonary fitness with aging.
    Keywords:  cysteine oxidation; fitness; muscle; posttranslational modifications; power; redox
    DOI:  https://doi.org/10.1111/acel.14094
  23. Cells. 2024 Jan 30. pii: 255. [Epub ahead of print]13(3):
    Age-Associated Differences in Recovery from Exercise-Induced Muscle Damage.
    Donna Ching Wah Li, Stefan Rudloff, Henning Tim Langer, Kristina Norman, Catrin Herpich.
      Understanding the intricate mechanisms governing the cellular response to resistance exercise is paramount for promoting healthy aging. This narrative review explored the age-related alterations in recovery from resistance exercise, focusing on the nuanced aspects of exercise-induced muscle damage in older adults. Due to the limited number of studies in older adults that attempt to delineate age differences in muscle discovery, we delve into the multifaceted cellular influences of chronic low-grade inflammation, modifications in the extracellular matrix, and the role of lipid mediators in shaping the recovery landscape in aging skeletal muscle. From our literature search, it is evident that aged muscle displays delayed, prolonged, and inefficient recovery. These changes can be attributed to anabolic resistance, the stiffening of the extracellular matrix, mitochondrial dysfunction, and unresolved inflammation as well as alterations in satellite cell function. Collectively, these age-related impairments may impact subsequent adaptations to resistance exercise. Insights gleaned from this exploration may inform targeted interventions aimed at enhancing the efficacy of resistance training programs tailored to the specific needs of older adults, ultimately fostering healthy aging and preserving functional independence.
    Keywords:  EIMD; aging; exercise; recovery
    DOI:  https://doi.org/10.3390/cells13030255
  24. Front Cardiovasc Med. 2024 ;11 1341590
    Fatigue as hallmark of Fabry disease: role of bioenergetic alterations.
    Jessica Gambardella, Eleonora Riccio, Antonio Bianco, Antonella Fiordelisi, Federica Andrea Cerasuolo, Antonietta Buonaiuto, Teodolinda Di Risi, Alessandro Viti, Roberta Avvisato, Antonio Pisani, Daniela Sorriento, Guido Iaccarino.
      Fabry disease (FD) is a lysosomal storage disorder due to the impaired activity of the α-galactosidase A (GLA) enzyme which induces Gb3 deposition and multiorgan dysfunction. Exercise intolerance and fatigue are frequent and early findings in FD patients, representing a self-standing clinical phenotype with a significant impact on the patient's quality of life. Several determinants can trigger fatigability in Fabry patients, including psychological factors, cardiopulmonary dysfunctions, and primary alterations of skeletal muscle. The "metabolic hypothesis" to explain skeletal muscle symptoms and fatigability in Fabry patients is growing acknowledged. In this report, we will focus on the primary alterations of the motor system emphasizing the role of skeletal muscle metabolic disarrangement in determining the altered exercise tolerance in Fabry patients. We will discuss the most recent findings about the metabolic profile associated with Fabry disease offering new insights for diagnosis, management, and therapy.
    Keywords:  Fabry; exercise intolerance; fatigue; metabolism; skeletal muscle
    DOI:  https://doi.org/10.3389/fcvm.2024.1341590
  25. Heliyon. 2024 Feb 15. 10(3): e24942
    Current situation and publication trends of skeletal muscle related research: A bibliometric analysis.
    Syed Sayeed Ahmad, Inho Choi.
      Skeletal muscle (SM) is a highly plastic and dynamic tissue of the body and is largely responsible for body maintenance. SM is primarily responsible for body balance, movement, postural support, thermogenesis, and blood glucose homeostasis. SM regeneration depends on the activation of muscle satellite (stem) cells (MSCs) under the regulation of several muscle regulatory factors that regulate myogenesis. Bibliometric analysis involves the quantitative and qualitative assessments of research and scientific progress that provides researchers access to recent publications, research directions, and thus generates ideas that can be implemented to guide future research. In this analysis, the Web of Science database was searched for articles using the search term "skeletal muscle AND myogenesis AND muscle satellite cell", and 1777 articles (original research/review articles) published from the year 1997 to June 2023 were retrieved. After applying several other exclusion and inclusion criteria, 129 articles were considered for analysis. Types of research, keywords, journals, authors, years, institutions, funding agencies, and average annual citations were analyzed. Muscle regeneration, satellite cell, and myogenesis were often used keywords and exhibited increasing trends in research articles over the decades. Some journals were found to strongly support research publications with high impact factors and citation scores. This study aimed to examine research ideas and growth in the skeletal muscle related field for atrophy and aging improvement.
    Keywords:  Aging; Bibliometric analysis; Muscle satellite cell; Myogenesis; Skeletal muscle; Web of science
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e24942
  26. Am J Physiol Cell Physiol. 2024 Feb 05.
    S100b Treatment Overcomes RAGE Signaling Deficits in Myoblasts on Advanced Glycation End-product Cross-linked Collagen and Promotes Myogenic Differentiation.
    Lucas C Olson, Tri Nguyen, Eleanor L Sabalewski, Jennifer L Puetzer, Zvi Schwartz, Michael J McClure.
      Advanced glycation end products (AGEs) stochastically accrue in skeletal muscle and on collagen over an individual's lifespan, stiffening the muscle and modifying the stem cell (MuSC) microenvironment while promoting proinflammatory, anti-regenerative signaling via the receptor for advanced glycation end products (RAGE). In the present study, a novel in vitro model was developed of this phenomenon by cross-linking a 3D collagen scaffold with AGEs and investigating how myoblasts responded to such an environment. Briefly, collagen scaffolds were incubated with D-ribose (0, 25, 40, 100, or 250 mM) for 5 days at 37° C. C2C12 immortalized mouse myoblasts were grown on the scaffolds for 6 days in growth conditions for proliferation, and 12 days for differentiation and fusion. Human primary myoblasts were also used to confirm the C2C12 data. AGEs aberrantly extended the DNA production stage of C2C12s (but not in human primary myoblasts) which is known to delay differentiation in myogenesis, and this effect was prevented by RAGE inhibition. Further, the differentiation and fusion of myoblasts were disrupted by AGEs, which were associated with reductions in integrins and suppression of RAGE. The addition of S100b (RAGE agonist) recovered the differentiation and fusion of myoblasts, and the addition of RAGE inhibitors (FPS-ZM1 and Azeliragon) inhibited the differentiation and fusion of myoblasts. Our results provide novel insights into the role of the AGE-RAGE axis in skeletal muscle aging, and future work is warranted on the potential application of S100b as a pro-regenerative factor in aged skeletal muscle.
    Keywords:  advanced glycation end products; collagen; cross-linking; myogenesis; skeletal muscle aging
    DOI:  https://doi.org/10.1152/ajpcell.00502.2023
  27. Sci Rep. 2024 02 07. 14(1): 3184
    Differential effects of the venoms of Russell's viper and Indian cobra on human myoblasts.
    Husain Bin Haidar, José R Almeida, Jarred Williams, Bokai Guo, Anne Bigot, Subramanian Senthilkumaran, Sakthivel Vaiyapuri, Ketan Patel.
      Local tissue damage following snakebite envenoming remains a poorly researched area. To develop better strategies to treat snakebites, it is critical to understand the mechanisms through which venom toxins induce envenomation effects including local tissue damage. Here, we demonstrate how the venoms of two medically important Indian snakes (Russell's viper and cobra) affect human skeletal muscle using a cultured human myoblast cell line. The data suggest that both venoms affect the viability of myoblasts. Russell's viper venom reduced the total number of cells, their migration, and the area of focal adhesions. It also suppressed myogenic differentiation and induced muscle atrophy. While cobra venom decreased the viability, it did not largely affect cell migration and focal adhesions. Cobra venom affected the formation of myotubes and induced atrophy. Cobra venom-induced atrophy could not be reversed by small molecule inhibitors such as varespladib (a phospholipase A2 inhibitor) and prinomastat (a metalloprotease inhibitor), and soluble activin type IIb receptor (a molecule used to promote regeneration of skeletal muscle), although the antivenom (raised against the Indian 'Big Four' snakes) has attenuated the effects. However, all these molecules rescued the myotubes from Russell's viper venom-induced atrophy. This study demonstrates key steps in the muscle regeneration process that are affected by both Indian Russell's viper and cobra venoms and offers insights into the potential causes of clinical features displayed in envenomed victims. Further research is required to investigate the molecular mechanisms of venom-induced myotoxicity under in vivo settings and develop better therapies for snakebite-induced muscle damage.
    DOI:  https://doi.org/10.1038/s41598-024-53366-9
  28. Nat Metab. 2024 Feb 09.
    Transcriptional programming of translation by BCL6 controls skeletal muscle proteostasis.
    Krithika Ramachandran, Christopher R Futtner, Meredith A Sommars, Mattia Quattrocelli, Yasuhiro Omura, Ellen Fruzyna, Janice C Wang, Nathan J Waldeck, Madhavi D Senagolage, Carmen G Telles, Alexis R Demonbreun, Erin Prendergast, Nicola Lai, Daniel Arango, Ilya R Bederman, Elizabeth M McNally, Grant D Barish.
      Skeletal muscle is dynamically controlled by the balance of protein synthesis and degradation. Here we discover an unexpected function for the transcriptional repressor B cell lymphoma 6 (BCL6) in muscle proteostasis and strength in mice. Skeletal muscle-specific Bcl6 ablation in utero or in adult mice results in over 30% decreased muscle mass and force production due to reduced protein synthesis and increased autophagy, while it promotes a shift to a slower myosin heavy chain fibre profile. Ribosome profiling reveals reduced overall translation efficiency in Bcl6-ablated muscles. Mechanistically, tandem chromatin immunoprecipitation, transcriptomic and translational analyses identify direct BCL6 repression of eukaryotic translation initiation factor 4E-binding protein 1 (Eif4ebp1) and activation of insulin-like growth factor 1 (Igf1) and androgen receptor (Ar). Together, these results uncover a bifunctional role for BCL6 in the transcriptional and translational control of muscle proteostasis.
    DOI:  https://doi.org/10.1038/s42255-024-00983-3
  29. Elife. 2024 Feb 06. pii: RP92731. [Epub ahead of print]12
    Depletion of SMN protein in mesenchymal progenitors impairs the development of bone and neuromuscular junction in spinal muscular atrophy.
    Sang-Hyeon Hann, Seon-Yong Kim, Ye Lynne Kim, Young-Woo Jo, Jong-Seol Kang, Hyerim Park, Se-Young Choi, Young-Yun Kong.
      Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by the deficiency of the survival motor neuron (SMN) protein, which leads to motor neuron dysfunction and muscle atrophy. In addition to the requirement for SMN in motor neurons, recent studies suggest that SMN deficiency in peripheral tissues plays a key role in the pathogenesis of SMA. Using limb mesenchymal progenitor cell (MPC)-specific SMN-depleted mouse models, we reveal that SMN reduction in limb MPCs causes defects in the development of bone and neuromuscular junction (NMJ). Specifically, these mice exhibited impaired growth plate homeostasis and reduced insulin-like growth factor (IGF) signaling from chondrocytes, rather than from the liver. Furthermore, the reduction of SMN in fibro-adipogenic progenitors (FAPs) resulted in abnormal NMJ maturation, altered release of neurotransmitters, and NMJ morphological defects. Transplantation of healthy FAPs rescued the morphological deterioration. Our findings highlight the significance of mesenchymal SMN in neuromusculoskeletal pathogenesis of SMA and provide insights into potential therapeutic strategies targeting mesenchymal cells for the treatment of SMA.
    Keywords:  IGF signaling; chondrocyte; fibro-adipogenic progenitor; growth plate; medicine; mouse; neuromuscular junction; neuroscience; spinal muscular atrophy
    DOI:  https://doi.org/10.7554/eLife.92731
  30. Int J Mol Sci. 2024 Feb 01. pii: 1777. [Epub ahead of print]25(3):
    The Impact of miR-155-5p on Myotube Differentiation: Elucidating Molecular Targets in Skeletal Muscle Disorders.
    Letícia Oliveira Lopes, Sarah Santiloni Cury, Diogo de Moraes, Jakeline Santos Oliveira, Grasieli de Oliveira, Otavio Cabral-Marques, Geysson Javier Fernandez, Mario Hiroyuki Hirata, Da-Zhi Wang, Maeli Dal-Pai-Silva, Robson Francisco Carvalho, Paula Paccielli Freire.
      MicroRNAs are small regulatory molecules that control gene expression. An emerging property of muscle miRNAs is the cooperative regulation of transcriptional and epitranscriptional events controlling muscle phenotype. miR-155 has been related to muscular dystrophy and muscle cell atrophy. However, the function of miR-155 and its molecular targets in muscular dystrophies remain poorly understood. Through in silico and in vitro approaches, we identify distinct transcriptional profiles induced by miR-155-5p in muscle cells. The treated myotubes changed the expression of 359 genes (166 upregulated and 193 downregulated). We reanalyzed muscle transcriptomic data from dystrophin-deficient patients and detected overlap with gene expression patterns in miR-155-treated myotubes. Our analysis indicated that miR-155 regulates a set of transcripts, including Aldh1l, Nek2, Bub1b, Ramp3, Slc16a4, Plce1, Dync1i1, and Nr1h3. Enrichment analysis demonstrates 20 targets involved in metabolism, cell cycle regulation, muscle cell maintenance, and the immune system. Moreover, digital cytometry confirmed a significant increase in M2 macrophages, indicating miR-155's effects on immune response in dystrophic muscles. We highlight a critical miR-155 associated with disease-related pathways in skeletal muscle disorders.
    Keywords:  DMD; RNA sequencing; miR-155; microRNA; muscular dystrophies; non-coding RNAs
    DOI:  https://doi.org/10.3390/ijms25031777
  31. Int J Mol Sci. 2024 Jan 24. pii: 1439. [Epub ahead of print]25(3):
    NLRP3 Contributes to Sarcopenia Associated to Dependency Recapitulating Inflammatory-Associated Muscle Degeneration.
    Eduardo Antuña, Yaiza Potes, Francisco Javier Baena-Huerta, Cristina Cachán-Vega, Nerea Menéndez-Coto, Eva Álvarez Darriba, Marta Fernández-Fernández, Natalie Burgos Bencosme, Manuel Bermúdez, Eva María López Álvarez, José Gutiérrez-Rodríguez, José Antonio Boga, Beatriz Caballero, Ignacio Vega-Naredo, Ana Coto-Montes, Claudia Garcia-Gonzalez.
      Sarcopenia, a complex and debilitating condition characterized by progressive deterioration of skeletal muscle, is the primary cause of age-associated disability and significantly impacts healthspan in elderly patients. Despite its prevalence among the aging population, the underlying molecular mechanisms are still under investigation. The NLRP3 inflammasome is crucial in the innate immune response and has a significant impact on diseases related to inflammation and aging. Here, we investigated the expression of the NLRP3 inflammasome pathway and pro-inflammatory cytokines in skeletal muscle and peripheral blood of dependent and independent patients who underwent hip surgery. Patients were categorized into independent and dependent individuals based on their Barthel Index. The expression of NLRP3 inflammasome components was significantly upregulated in sarcopenic muscle from dependent patients, accompanied by higher levels of Caspase-1, IL-1β and IL-6. Among older dependent individuals with sarcopenia, there was a significant increase in the MYH3/MYH2 ratio, indicating a transcriptional shift in expression from mature to developmental myosin isoforms. Creatine kinase levels and senescence markers were also higher in dependent patients, altogether resembling dystrophic diseases and indicating muscle degeneration. In summary, we present evidence for the involvement of the NLRP3/ASC/NEK7/Caspase-1 inflammasome pathway with activation of pro-inflammatory SASP in the outcome of sarcopenia in the elderly.
    Keywords:  ASC; Caspase-1; MYH3; NLRP3 inflammasome; SASP; dependency; inflammaging; sarcopenia
    DOI:  https://doi.org/10.3390/ijms25031439
  32. Int J Mol Sci. 2024 Feb 03. pii: 1847. [Epub ahead of print]25(3):
    Utilization of the Rat Tibial Nerve Transection Model to Evaluate Cellular and Molecular Mechanisms Underpinning Denervation-Mediated Muscle Injury.
    Christina Doherty, Monika Lodyga, Judy Correa, Caterina Di Ciano-Oliveira, Pamela J Plant, James R Bain, Jane Batt.
      Peripheral nerve injury denervates muscle, resulting in muscle paralysis and atrophy. This is reversible if timely muscle reinnervation occurs. With delayed reinnervation, the muscle's reparative ability declines, and muscle-resident fibro-adipogenic progenitor cells (FAPs) proliferate and differentiate, inducing fibro-fatty muscle degradation and thereby physical disability. The mechanisms by which the peripheral nerve regulates FAPs expansion and differentiation are incompletely understood. Using the rat tibial neve transection model, we demonstrated an increased FAPs content and a changing FAPs phenotype, with an increased capacity for adipocyte and fibroblast differentiation, in gastrocnemius muscle post-denervation. The FAPs response was inhibited by immediate tibial nerve repair with muscle reinnervation via neuromuscular junctions (NMJs) and sensory organs (e.g., muscle spindles) or the sensory protection of muscle (where a pure sensory nerve is sutured to the distal tibial nerve stump) with reinnervation by muscle spindles alone. We found that both procedures reduced denervation-mediated increases in glial-cell-line-derived neurotrophic factor (GDNF) in muscle and that GDNF promoted FAPs adipogenic and fibrogenic differentiation in vitro. These results suggest that the peripheral nerve controls FAPs recruitment and differentiation via the modulation of muscle GDNF expression through NMJs and muscle spindles. GDNF can serve as a therapeutic target in the management of denervation-induced muscle injury.
    Keywords:  adipogenesis; denervation; fibro-adipogenic progenitors (FAPs); flow cytometry/FACS; gastrocnemius; glial-cell-line-derived neurotrophic factor (GDNF); primary cell culture; sensory protection; sural nerve
    DOI:  https://doi.org/10.3390/ijms25031847
  33. J Physiol Sci. 2024 Feb 08. 74(1): 8
    The role of GPR81-cAMP-PKA pathway in endurance training-induced intramuscular triglyceride accumulation and mitochondrial content changes in rats.
    Lin Li, Xiangdeng Lai, Yihan Ni, Siyu Chen, Yaqian Qu, Zhiqiang Hu, Jingquan Sun.
      The athlete's paradox phenomenon involves the accumulation of intramuscular triglycerides (IMTG) in both insulin-resistant and insulin-sensitive endurance athletes. Nevertheless, a complete understanding of this phenomenon is yet to be achieved. Recent research indicates that lactate, a common byproduct of physical activity, may increase the accumulation of IMTG in skeletal muscle. This is achieved through the activation of G protein-coupled receptor 81 (GPR81) leads to the suppression of the cyclic adenosine monophosphate-protein kinase A (cAMP-PKA) pathway. The mechanism accountable for the increase in mitochondrial content in skeletal muscle triggered by lactate remains incomprehensible. Based on current research, our objective is to explore the role of the GPR81-inhibited cAMP-PKA pathway in the aggregation of IMTG and the increase in mitochondrial content as a result of prolonged exercise. The GPR81-cAMP-PKA-signaling pathway regulates the buildup of IMTG caused by extended periods of endurance training (ET). This is likely due to a decrease in proteins related to fat breakdown and an increase in proteins responsible for fat production. It is possible that the GPR81-cAMP-PKA pathway does not contribute to the long-term increase in mitochondrial biogenesis and content, which is induced by chronic ET. Additional investigation is required to explore the possible hindrance of the mitochondrial biogenesis and content process during physical activity by the GPR81-cAMP-PKA signal.
    Keywords:  Endurance training; Intramuscular triglyceride; Lactate; Mitochondrial content; Skeletal muscle; cAMP
    DOI:  https://doi.org/10.1186/s12576-024-00902-x
  34. Am J Physiol Heart Circ Physiol. 2024 Feb 09.
    HDL-C and Apolipoprotein A-I are Independently Associated with Skeletal Muscle Mitochondrial Function in Healthy Humans.
    John M Giacona, Ursa B Bezan Petric, Weerapat Kositanurit, Jijia Wang, Suzanne Saldanha, Benjamin E Young, Ghazi Khan, Margery A Connelly, Scott A Smith, Anand Rohatgi, Wanpen Vongpatanasin.
      Prior animal and cell studies have demonstrated a direct role of high-density lipoprotein (HDL) and Apolipoprotein A-I (Apo A-I) in enhancing skeletal muscle mitochondrial function and exercise capacity. However, the relevance of these animal and cell investigations in humans remains unknown. Therefore, a cross-sectional study was conducted in 48 adults (67% female, 8% Black participants, age 39 ± 15.4 years) to characterize the associations between HDL measures, Apo A-I, and muscle mitochondrial function. Forearm muscle oxygen recovery time (tau) from post-exercise recovery kinetics was used to assess skeletal muscle mitochondrial function. Lipoprotein measures were assessed by nuclear magnetic resonance. HDL efflux capacity was assessed using J774 macrophages, radiolabeled cholesterol, and Apolipoprotein B-depleted plasma both with and without added cyclic adenosine monophosphate. In univariate analyses, faster skeletal muscle oxygen recovery time (lower tau) was significantly associated with higher levels of HDL cholesterol (HDL-C), ApoA-I, and larger mean HDL size, but not HDL cholesterol efflux capacity. Slower recovery time (higher tau) was positively associated with body mass index (BMI) and fasting plasma glucose (FPG). In multivariable linear regression analyses, higher levels of HDL-C and Apo A-I, as well as larger HDL size, were independently associated with faster skeletal muscle oxygen recovery times that persisted after adjusting for BMI and FPG (all p <0.05). In conclusion, higher levels of HDL-C, Apo A-I, and larger mean HDL size were independently associated with enhanced skeletal muscle mitochondrial function in healthy humans.
    Keywords:  Apolipoprotein A-I; High-density lipoprotein; Mitochondrial Function; Skeletal Muscle
    DOI:  https://doi.org/10.1152/ajpheart.00017.2024
  35. Sci Rep. 2024 02 07. 14(1): 3108
    A new bio imagery user-friendly tool for automatic morphometry measurement on muscle cell cultures and histological sections.
    Aurélien Brun, Guillaume Mougeot, Philippe Denis, Marie Laure Collin, Pierre Pouchin, Christophe Montaurier, Stéphane Walrand, Frédéric Capel, Marine Gueugneau.
      TRUEFAD (TRUE Fiber Atrophy Distinction) is a bioimagery user-friendly tool developed to allow consistent and automatic measurement of myotube diameter in vitro, muscle fiber size and type using rodents and human muscle biopsies. This TRUEFAD package was set up to standardize and dynamize muscle research via easy-to-obtain images run on an open-source plugin for FIJI. We showed here both the robustness and the performance of our pipelines to correctly segment muscle cells and fibers. We evaluated our pipeline on real experiment image sets and showed consistent reliability across images and conditions. TRUEFAD development makes possible systematical and rapid screening of substances impacting muscle morphology for helping scientists focus on their hypothesis rather than image analysis.
    DOI:  https://doi.org/10.1038/s41598-024-53658-0
  36. Molecules. 2024 Feb 04. pii: 712. [Epub ahead of print]29(3):
    MCC950 Ameliorates Diabetic Muscle Atrophy in Mice by Inhibition of Pyroptosis and Its Synergistic Effect with Aerobic Exercise.
    Xiaoyu Yan, Pengyu Fu, Yimin Zhang, Dongmei Ling, Lewis Reynolds, Weicheng Hua, Zhiyuan Wang, Fangyuan Ma, Boxuan Li, Jingjing Yu, Yujia Liu, Lijing Gong, Enming Zhang.
      Diabetic muscle atrophy is an inflammation-related complication of type-2 diabetes mellitus (T2DM). Even though regular exercise prevents further deterioration of atrophic status, there is no effective mediator available for treatment and the underlying cellular mechanisms are less explored. In this study, we investigated the therapeutic potential of MCC950, a specific, small-molecule inhibitor of NLRP3, to treat pyroptosis and diabetic muscle atrophy in mice. Furthermore, we used MCC950 to intervene in the protective effects of aerobic exercise against muscle atrophy in diabetic mice. Blood and gastrocnemius muscle (GAS) samples were collected after 12 weeks of intervention and the atrophic state was assessed. We initially corroborated a diabetic muscle atrophy phenotype in db/db mice (D) by comparison with control m/m mice (W) by examining parameters such as fasting blood glucose (D vs. W: 24.47 ± 0.45 mmol L-1 vs. 4.26 ± 0.6 mmol L-1, p < 0.05), grip strength (D vs. W: 166.87 ± 15.19 g vs. 191.76 ± 14.13 g, p < 0.05), exercise time (D vs. W: 1082.38 ± 104.67 s vs. 1716 ± 168.55 s, p < 0.05) and exercise speed to exhaustion (D vs. W: 24.25 ± 2.12 m min-1 vs. 34.75 ± 2.66 m min-1, p < 0.05), GAS wet weight (D vs. W: 0.07 ± 0.01 g vs. 0.13 ± 0.01 g, p < 0.05), the ratio of GAS wet weight to body weight (D vs. W: 0.18 ± 0.01% vs. 0.54 ± 0.02%, p < 0.05), and muscle fiber cross-sectional area (FCSA) (D vs. W: 1875 ± 368.19 µm2 vs. 2747.83 ± 406.44 µm2, p < 0.05). We found that both MCC950 (10 mg kg-1) treatment and exercise improved the atrophic parameters that had deteriorated in the db/db mice, inhibited serum inflammatory markers and significantly attenuated pyroptosis in atrophic GAS. In addition, a combined MCC950 treatment with exercise (DEI) exhibited a further improvement in glucose uptake capacity and muscle performance. This combined treatment also improved the FCSA of GAS muscle indicated by Laminin immunofluorescence compared to the group with the inhibitor treatment alone (DI) (DEI vs. DI: 2597 ± 310.97 vs. 1974.67 ± 326.15 µm2, p < 0.05) or exercise only (DE) (DEI vs. DE: 2597 ± 310.97 vs. 2006.33 ± 263.468 µm2, p < 0.05). Intriguingly, the combination of MCC950 treatment and exercise significantly reduced NLRP3-mediated inflammatory factors such as cleaved-Caspase-1, GSDMD-N and prevented apoptosis and pyroptosis in atrophic GAS. These findings for the first time demonstrate that targeting NLRP3-mediated pyroptosis with MCC950 improves diabetic muscle homeostasis and muscle function. We also report that inhibiting pyroptosis by MCC950 can enhance the beneficial effects of aerobic exercise on diabetic muscle atrophy. Since T2DM and muscle atrophy are age-related diseases, the young mice used in the current study do not seem to fully reflect the characteristics of diabetic muscle atrophy. Considering the fragile nature of db/db mice and for the complete implementation of the exercise intervention, we used relatively young db/db mice and the atrophic state in the mice was thoroughly confirmed. Taken together, the current study comprehensively investigated the therapeutic effect of NLRP3-mediated pyroptosis inhibited by MCC950 on diabetic muscle mass, strength and exercise performance, as well as the synergistic effects of MCC950 and exercise intervention, therefore providing a novel strategy for the treatment of the disease.
    Keywords:  MCC950; NLRP3; aerobic exercise; diabetes; muscle atrophy; pyroptosis
    DOI:  https://doi.org/10.3390/molecules29030712
  37. Elife. 2024 Feb 08. pii: RP89212. [Epub ahead of print]12
    The genetic and dietary landscape of the muscle insulin signalling network.
    Julian van Gerwen, Stewart W C Masson, Harry B Cutler, Alexis Diaz Vegas, Meg Potter, Jacqueline Stöckli, Søren Madsen, Marin E Nelson, Sean J Humphrey, David E James.
      Metabolic disease is caused by a combination of genetic and environmental factors, yet few studies have examined how these factors influence signal transduction, a key mediator of metabolism. Using mass spectrometry-based phosphoproteomics, we quantified 23,126 phosphosites in skeletal muscle of five genetically distinct mouse strains in two dietary environments, with and without acute in vivo insulin stimulation. Almost half of the insulin-regulated phosphoproteome was modified by genetic background on an ordinary diet, and high-fat high-sugar feeding affected insulin signalling in a strain-dependent manner. Our data revealed coregulated subnetworks within the insulin signalling pathway, expanding our understanding of the pathway's organisation. Furthermore, associating diverse signalling responses with insulin-stimulated glucose uptake uncovered regulators of muscle insulin responsiveness, including the regulatory phosphosite S469 on Pfkfb2, a key activator of glycolysis. Finally, we confirmed the role of glycolysis in modulating insulin action in insulin resistance. Our results underscore the significance of genetics in shaping global signalling responses and their adaptability to environmental changes, emphasising the utility of studying biological diversity with phosphoproteomics to discover key regulatory mechanisms of complex traits.
    Keywords:  computational biology; genetics; insulin resistance; mass spectrometry; metabolism; mouse; phosphoproteomics; rat; signalling; systems biology
    DOI:  https://doi.org/10.7554/eLife.89212
  38. Sci Rep. 2024 02 08. 14(1): 3254
    Correlation between skeletal muscle acetylcarnitine and phosphocreatine metabolism during submaximal exercise and recovery: interleaved 1H/31P MRS 7 T study.
    Radka Klepochová, Fabian Niess, Martin Meyerspeer, Dorota Slukova, Ivica Just, Siegfried Trattnig, Jozef Ukropec, Barbara Ukropcová, Alexandra Kautzky-Willer, Michael Leutner, Martin Krššák.
      Acetylcarnitine is an essential metabolite for maintaining metabolic flexibility and glucose homeostasis. The in vivo behavior of muscle acetylcarnitine content during exercise has not been shown with magnetic resonance spectroscopy. Therefore, this study aimed to explore the behavior of skeletal muscle acetylcarnitine during rest, plantar flexion exercise, and recovery in the human gastrocnemius muscle under aerobic conditions. Ten lean volunteers and nine overweight volunteers participated in the study. A 7 T whole-body MR system with a double-tuned surface coil was used to acquire spectra from the gastrocnemius medialis. An MR-compatible ergometer was used for the plantar flexion exercise. Semi-LASER-localized 1H MR spectra and slab-localized 31P MR spectra were acquired simultaneously in one interleaved exercise/recovery session. The time-resolved interleaved 1H/31P MRS acquisition yielded excellent data quality. A between-group difference in acetylcarnitine metabolism over time was detected. Significantly slower τPCr recovery, τPCr on-kinetics, and lower Qmax in the overweight group, compared to the lean group was found. Linear relations between τPCr on-kinetics, τPCr recovery, VO2max and acetylcarnitine content were identified. In conclusion, we are the first to show in vivo changes of skeletal muscle acetylcarnitine during acute exercise and immediate exercise recovery with a submaximal aerobic workload using interleaved 1H/31P MRS at 7 T.
    DOI:  https://doi.org/10.1038/s41598-024-53221-x
  39. Mol Metab. 2024 Feb 06. pii: S2212-8778(24)00023-1. [Epub ahead of print] 101892
    Dysfunction of Akt/FoxO3a/Atg7 regulatory loop magnifies obesity-regulated muscular mass decline.
    Yang Yu, Jing Yang, Lixia Zheng, Han Su, Sunrun Cao, Xuehan Jiang, Xiyan Liu, Weiwei Liu, Zhuo Wang, Fang Meng, Hongde Xu, Deliang Wen, Chen Sun, Xiaoyu Song, Antonio Vidal-Puig, Liu Cao.
      BACKGROUND: Myoprotein degradation accelerates in obese individuals, resulting in a decline in muscular mass. Atg7 plays a crucial role in regulating protein stability and function through both autophagy-dependent and independent pathways. As obesity progresses, the expression of Atg7 gradually rises in muscle tissue. Nonetheless, the precise impact and mechanism of Atg7 in promoting muscle mass decline in obesity remain uncertain. The study aimed to elucidate the role and underly mechanism of Atg7 action in the context of obesity-induced muscle mass decline.METHODS: In this study, we established a murine model of high-fat diet-induced obesity (DIO) and introduced adeno-associated virus delivery of short hairpin RNA to knock down Atg7 (shAtg7) into the gastrocnemius muscle. We then examined the expressions of Atg7 and myoprotein degradation markers in the gastrocnemius tissues of obese patients and mice using immunofluorescence and western blotting techniques. To further investigate the effects of Atg7, we assessed skeletal muscle cell diameter and the myoprotein degradation pathway in C2C12 and HSkMC cells in the presence or absence of Atg7. Immunofluorescence staining for MyHC and western blotting were utilized for this purpose. To understand the transcriptional regulation of Atg7 in response to myoprotein degradation, we conducted luciferase reporter assays and chromatin immunoprecipitation experiments to examine whether FoxO3a enhances the transcription of Atg7. Moreover, we explored the role of Akt in Atg7-mediated regulation and its relevance to obesity-induced muscle mass decline. This was accomplished by Akt knockdown, treatment with MK2206, and GST pulldown assays to assess the interaction between Atg7 and Akt.
    RESULTS: After 20 weeks of being on a high-fat diet, obesity was induced, leading to a significant decrease in the gastrocnemius muscle area and a decline in muscle performance. This was accompanied by a notable increase in Atg7 protein expression (p < 0.01). Similarly, in gastrocnemius tissues of obese patients when compared to nonobese individuals, there was a significant increase in both Atg7 (p < 0.01) and TRIM63 (p < 0.01) levels. When palmitic acid was administered to C2C12 cells, it resulted in increased Atg7 (p < 0.01), LC3Ⅱ/Ⅰ (p < 0.01), and p62 levels (p < 0.01). Additionally, it promoted FoxO3a-mediated transcription of Atg7. The knockdown of Atg7 in the gastrocnemius partially reversed DIO-induced muscle mass decline. Furthermore, when Atg7 was knocked down in C2C12 and HSkMC cells, it mitigated palmitic acid-induced insulin resistance, increased the p-Akt/Akt ratio (p < 0.01), and reduced TRIM63 (p < 0.01). Muscular atrophy mediated by Atg7 was reversed by genetic knockdown of Akt and treatment with the p-Akt inhibitor MK2206. Palmitic acid administration increased the binding between Atg7 and Akt (p < 0.01) while weakening the binding of PDK1 (p < 0.01) and PDK2 (p < 0.01) to Akt. GST pulldown assays demonstrated that Atg7 directly interacted with the C-terminal domain of Akt.
    CONCLUSION: The consumption of a high-fat diet, along with lipid-induced effects, led to the inhibition of Akt signaling, which, in turn, promoted FoxO3a-mediated transcription, increasing Atg7 levels in muscle cells. The excess Atg7 inhibited the phosphorylation of Akt, leading to a cyclic activation of FoxO3a and exacerbating the decline in muscle mass regulated by obesity. Consequently, Atg7 serves as a regulatory point in determining the decline in muscle mass induced by obesity.
    Keywords:  Akt; Atg7; FoxO3a; insulin resistance; muscular mass decline; obesity
    DOI:  https://doi.org/10.1016/j.molmet.2024.101892
  40. Drugs Aging. 2024 Feb 05.
    The Current Landscape of Pharmacotherapies for Sarcopenia.
    Gulistan Bahat, Serdar Ozkok.
      Sarcopenia is a skeletal muscle disorder characterized by progressive and generalized decline in muscle mass and function. Although it is mostly known as an age-related disorder, it can also occur secondary to systemic diseases such as malignancy or organ failure. It has demonstrated a significant relationship with adverse outcomes, e.g., falls, disabilities, and even mortality. Several breakthroughs have been made to find a pharmaceutical therapy for sarcopenia over the years, and some have come up with promising findings. Yet still no drug has been approved for its treatment. The key factor that makes finding an effective pharmacotherapy so challenging is the general paradigm of standalone/single diseases, traditionally adopted in medicine. Today, it is well known that sarcopenia is a complex disorder caused by multiple factors, e.g., imbalance in protein turnover, satellite cell and mitochondrial dysfunction, hormonal changes, low-grade inflammation, senescence, anorexia of aging, and behavioral factors such as low physical activity. Therefore, pharmaceuticals, either alone or combined, that exhibit multiple actions on these factors simultaneously will likely be the drug of choice to manage sarcopenia. Among various drug options explored throughout the years, testosterone still has the most cumulated evidence regarding its effects on muscle health and its safety. A mas receptor agonist, BIO101, stands out as a recent promising pharmaceutical. In addition to the conventional strategies (i.e., nutritional support and physical exercise), therapeutics with multiple targets of action or combination of multiple therapeutics with different targets/modes of action appear to promise greater benefit for the prevention and treatment of sarcopenia.
    DOI:  https://doi.org/10.1007/s40266-023-01093-7
  41. Nucleic Acids Res. 2024 Feb 07. pii: gkae059. [Epub ahead of print]
    Tankyrase-1 regulates RBP-mediated mRNA turnover to promote muscle fiber formation.
    Souad Mubaid, Brenda Janice Sanchez, Rinad A Algehani, Viktoriia Skopenkova, Pauline Adjibade, Derek T Hall, Sandrine Busque, Xian Jin Lian, Kholoud Ashour, Anne-Marie K Tremblay, Graeme Carlile, Jean-Philippe Gagné, Andrea Diaz-Gaxiola, Shahryar Khattak, Sergio Di Marco, David Y Thomas, Guy G Poirier, Imed-Eddine Gallouzi.
      Poly(ADP-ribosylation) (PARylation) is a post-translational modification mediated by a subset of ADP-ribosyl transferases (ARTs). Although PARylation-inhibition based therapies are considered as an avenue to combat debilitating diseases such as cancer and myopathies, the role of this modification in physiological processes such as cell differentiation remains unclear. Here, we show that Tankyrase1 (TNKS1), a PARylating ART, plays a major role in myogenesis, a vital process known to drive muscle fiber formation and regeneration. Although all bona fide PARPs are expressed in muscle cells, experiments using siRNA-mediated knockdown or pharmacological inhibition show that TNKS1 is the enzyme responsible of catalyzing PARylation during myogenesis. Via this activity, TNKS1 controls the turnover of mRNAs encoding myogenic regulatory factors such as nucleophosmin (NPM) and myogenin. TNKS1 mediates these effects by targeting RNA-binding proteins such as Human Antigen R (HuR). HuR harbors a conserved TNKS-binding motif (TBM), the mutation of which not only prevents the association of HuR with TNKS1 and its PARylation, but also precludes HuR from regulating the turnover of NPM and myogenin mRNAs as well as from promoting myogenesis. Therefore, our data uncover a new role for TNKS1 as a key modulator of RBP-mediated post-transcriptional events required for vital processes such as myogenesis.
    DOI:  https://doi.org/10.1093/nar/gkae059
  42. Ann Clin Transl Neurol. 2024 Feb 04.
    Recurring homozygous ACTN2 variant (p.Arg506Gly) causes a recessive myopathy.
    Undiagnosed Diseases Network
      OBJECTIVE: ACTN2, encoding alpha-actinin-2, is essential for cardiac and skeletal muscle sarcomeric function. ACTN2 variants are a known cause of cardiomyopathy without skeletal muscle involvement. Recently, specific dominant monoallelic variants were reported as a rare cause of core myopathy of variable clinical onset, although the pathomechanism remains to be elucidated. The possibility of a recessively inherited ACTN2-myopathy has also been proposed in a single series.METHODS: We provide clinical, imaging, and histological characterization of a series of patients with a novel biallelic ACTN2 variant.
    RESULTS: We report seven patients from five families with a recurring biallelic variant in ACTN2: c.1516A>G (p.Arg506Gly), all manifesting with a consistent phenotype of asymmetric, progressive, proximal, and distal lower extremity predominant muscle weakness. None of the patients have cardiomyopathy or respiratory insufficiency. Notably, all patients report Palestinian ethnicity, suggesting a possible founder ACTN2 variant, which was confirmed through haplotype analysis in two families. Muscle biopsies reveal an underlying myopathic process with disruption of the intermyofibrillar architecture, Type I fiber predominance and atrophy. MRI of the lower extremities demonstrate a distinct pattern of asymmetric muscle involvement with selective involvement of the hamstrings and adductors in the thigh, and anterior tibial group and soleus in the lower leg. Using an in vitro splicing assay, we show that c.1516A>G ACTN2 does not impair normal splicing.
    INTERPRETATION: This series further establishes ACTN2 as a muscle disease gene, now also including variants with a recessive inheritance mode, and expands the clinical spectrum of actinopathies to adult-onset progressive muscle disease.
    DOI:  https://doi.org/10.1002/acn3.51983
  43. Cells. 2024 Jan 29. pii: 252. [Epub ahead of print]13(3):
    Molecular Mechanisms of Cachexia: A Review.
    Mahdi Neshan, Diamantis I Tsilimigras, Xu Han, Hua Zhu, Timothy M Pawlik.
      Cachexia is a condition characterized by substantial loss of body weight resulting from the depletion of skeletal muscle and adipose tissue. A considerable fraction of patients with advanced cancer, particularly those who have been diagnosed with pancreatic or gastric cancer, lung cancer, prostate cancer, colon cancer, breast cancer, or leukemias, are impacted by this condition. This syndrome manifests at all stages of cancer and is associated with an unfavorable prognosis. It heightens the susceptibility to surgical complications, chemotherapy toxicity, functional impairments, breathing difficulties, and fatigue. The early detection of patients with cancer cachexia has the potential to enhance both their quality of life and overall survival rates. Regarding this matter, blood biomarkers, although helpful, possess certain limitations and do not exhibit universal application. Additionally, the available treatment options for cachexia are currently limited, and there is a lack of comprehensive understanding of the underlying molecular pathways associated with this condition. Thus, this review aims to provide an overview of molecular mechanisms associated with cachexia and potential therapeutic targets for the development of effective treatments for this devastating condition.
    Keywords:  atrophy; cancer cachexia; cancer-related syndrome; muscular wasting; skeletal muscle; weight loss
    DOI:  https://doi.org/10.3390/cells13030252
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