bims-moremu Biomed News
on Molecular regulators of muscle mass
Issue of 2023–01–15
37 papers selected by
Anna Vainshtein, Craft Science Inc.
  1. The myonuclear domain in adult skeletal muscle fibres: Past, present, and future.
  2. Loss of CRY2 promotes regenerative myogenesis by enhancing PAX7 expression and satellite cell proliferation.
  3. Molecular regulation of satellite cells via intercellular signaling.
  4. Regulating eEF2 and eEF2K in skeletal muscle by exercise.
  5. Muscle fiber type grouping does not change in response to prolonged resistance exercise training in healthy older men.
  6. The X-linked Becker muscular dystrophy (bmx) mouse models Becker muscular dystrophy via deletion of murine dystrophin exons 45-47.
  7. Aging is associated with impaired postprandial response of skeletal muscle protein synthesis to high-intensity muscle contraction in mice.
  8. Dysferlin Deficiency Results in Myofiber-Type Specific Differences in Abundances of Calcium-Handling and Glycogen Metabolism Proteins.
  9. Serum concentration impacts myosin heavy chain expression but not cellular respiration in human LHCN-M2 myoblasts undergoing differentiation.
  10. Multi-omics analysis of sarcospan overexpression in mdx skeletal muscle reveals compensatory remodeling of cytoskeleton-matrix interactions that promote mechanotransduction pathways.
  11. Modulation of protease expression by the transcription factor Ptx1/PITX regulates protein quality control during aging.
  12. Morroniside ameliorates inflammatory skeletal muscle atrophy via inhibiting canonical and non-canonical NF-κB and regulating protein synthesis/degradation.
  13. LncRNA-TBP mediates TATA-binding protein recruitment to regulate myogenesis and induce slow-twitch myofibers.
  14. Myostatin Mutation Enhances Bovine Myogenic Differentiation through PI3K/AKT/mTOR Signalling via Removing DNA Methylation of RACK1.
  15. Establishment of quantitative and consistent in vitro skeletal muscle pathological models of myotonic dystrophy type 1 using patient-derived iPSCs.
  16. The lactate receptor GPR81 is predominantly expressed in type II human skeletal muscle fibers: potential for lactate autocrine signaling.
  17. Store-operated calcium entry: From physiology to tubular aggregate myopathy.
  18. Phosphodiesterase 5a Signalling in Skeletal Muscle Pathophysiology.
  19. Molecular predictors of resistance training outcomes in young untrained female adults.
  20. Disruption of mitochondrial dynamics triggers muscle inflammation through interorganellar contacts and mitochondrial DNA mislocation.
  21. Reversine ameliorates hallmarks of cellular senescence in human skeletal myoblasts via reactivation of autophagy.
  22. L-Carnitine Functionalization to Increase Skeletal Muscle Tropism of PLGA Nanoparticles.
  23. Relationship between Mitochondrial Quality Control Markers, Lower Extremity Tissue Composition, and Physical Performance in Physically Inactive Older Adults.
  24. From phosphorylation to phenotype - Recent key findings on kinase regulation, downstream signaling and disease surrounding the receptor tyrosine kinase MuSK.
  25. FOXO3A-short is a novel regulator of non-oxidative glucose metabolism associated with human longevity.
  26. Machine learning-based classification of dual fluorescence signals reveals muscle stem cell fate transitions in response to regenerative niche factors.
  27. Inhibition of the endocannabinoid system reverses obese phenotype in aged mice and partly restores skeletal muscle function.
  28. The Link between Mitochondrial Dysfunction and Sarcopenia: An Update Focusing on the Role of Pyruvate Dehydrogenase Kinase 4.
  29. FAT/CD36 Participation in Human Skeletal Muscle Lipid Metabolism: A Systematic Review.
  30. α-1,6-Fucosyltransferase Is Essential for Myogenesis in Zebrafish.
  31. Defining the age-dependent and tissue-specific circadian transcriptome in male mice.
  32. TrkB signaling is correlated with muscular fatigue resistance and less vulnerability to neurodegeneration.
  33. PDIA4, a new endoplasmic reticulum stress protein, modulates insulin resistance and inflammation in skeletal muscle.
  34. The Importance of mTORC1-Autophagy Axis for Skeletal Muscle Diseases.
  35. Independent, but not co-supplementation with nitrate and resveratrol improves glucose tolerance and reduces markers of cellular stress in high-fat-fed male mice.
  36. Genes encoding agrin (AGRN) and neurotrypsin (PRSS12) are associated with muscle mass, strength and plasma C-terminal agrin fragment concentration.
  37. The critical role of gut microbiota dysbiosis in skeletal muscle wasting: a systematic review.
  1. J Physiol. 2023 Jan 11.
    The myonuclear domain in adult skeletal muscle fibres: Past, present, and future.
    James R Bagley, Lance T Denes, John J McCarthy, Eric T Wang, Kevin A Murach.
       KEY POINTS: Various mechanisms and conditions contribute to regulation of the "myonuclear domain", or theoretically finite area that an individual myoncleus provides gene products to within a multinuclear muscle fiibre mRNA from an individual myonucleus and the protein it produces are actively transported by molecular motors along microtubules in muscle fibres, as are myonuclei The distance that an mRNA or protein travels away from its myonucleus of origin is variable based on a variety of known and unknown factors Current evidence indicates that myonuclei are added during muscle hypertrophy fibre and lost during atrophy, perhaps to stabilize the myonuclear domain Myonuclei within a muscle fibre are transcriptionally and functionally diverse, which may have consequences for myonuclear domain maintenance and muscle fibre homeostasis ABSTRACT: Most cells in the body are mononuclear whereas skeletal muscle fibres are uniquely multinuclear. The nuclei of muscle fibres (myonuclei) are usually situated peripherally which complicates the equitable distribution of gene products. Myonuclear abundance can also change under conditions such as hypertrophy and atrophy. Specialized zones in muscle fibres have different functions and thus distinct synthetic demands from myonuclei. The complex structure and regulatory requirements of multinuclear muscle cells understandably led to the hypothesis that myonuclei govern defined "domains" to maintain homeostasis and facilitate adaptation. The purpose of this review is to provide historical context for the myonuclear domain and evaluate its veracity with respect to mRNA and protein distribution resulting from myonuclear transcription. We synthesize insights from past and current in vitro and in vivo genetically modified models for studying the myonuclear domain under dynamic conditions. We also cover the most contemporary knowledge on mRNA and protein transport in muscle cells. Insights from emerging technologies such as single myonuclear RNA-sequencing further inform our discussion of the myonuclear domain. We broadly conclude: 1) the myonuclear domain can be flexible during muscle fibre growth and atrophy, 2) the mechanisms and role of myonuclear loss and motility deserve further consideration, 3) mRNA in muscle is actively transported via microtubules and locally restricted, but proteins may travel far from a myonucleus of origin, and 4) myonuclear transcriptional specialization extends beyond the classic neuromuscular and myotendinous populations. A deeper understanding of the myonuclear domain in muscle may promote effective therapies for ageing and disease. Abstract figure legend The "myonuclear domain" is the theoretically finite area that an individual muscle fibre nucleus provides RNA for within the multinuclear cell. The myonuclear domain may only expand to a certain extent during muscle fibre growth (hypertrophy) before the addition of a new myonucleus from a muscle stem cell (satellite cell) is required. Conversely, the myonuclear domain may shrink during muscle atrophy and myonuclei may eventually be lost (top left panel). mRNAs, as well as the proteins that are made from them from a given myonucleus, are actively transported along microtubule "tracks" in adult muscle. Myonuclei can also move along tracks using molecular motors to facilitate specialized gene expression and protein synthesis where needed (top right panel). mRNAs and proteins from an individual myonucleus can travel different distances in the cell based on specific molecular characteristics as well as enviromental conditions (bottom left panel). Furthermore, myonuclear gene expression is specialized based on location in the cell (bottom right panel). Collectively, various mechanisms may influence the size of the myonuclear domain. Undertanding how the myonuclear domain is regulated and maintained has implications for muscle adaptation and the etiology of disease. This article is protected by copyright. All rights reserved.
    Keywords:  microtubules; muscle fibre; myonuclei; myotubes; satellite cell; single cell RNA-sequencing
    DOI:  https://doi.org/10.1113/JP283658
  2. MedComm (2020). 2023 Feb;4(1): e202
    Loss of CRY2 promotes regenerative myogenesis by enhancing PAX7 expression and satellite cell proliferation.
    Yingxue Hao, Ting Xue, Song-Bai Liu, Sha Geng, Xinghong Shi, Panting Qian, Wei He, Jiqing Zheng, Yanfang Li, Jing Lou, Tianze Shi, Ge Wang, Xiaoxiao Wang, Yanli Wang, Yangxin Li, Yao-Hua Song.
      The regenerative capacity of skeletal muscle is dependent on satellite cells. The circadian clock regulates the maintenance and function of satellite cells. Cryptochrome 2 (CRY2) is a critical component of the circadian clock, and its role in skeletal muscle regeneration remains controversial. Using the skeletal muscle lineage and satellite cell-specific CRY2 knockout mice (CRY2scko), we show that the deletion of CRY2 enhances muscle regeneration. Single myofiber analysis revealed that deletion of CRY2 stimulates the proliferation of myoblasts. The differentiation potential of myoblasts was enhanced by the loss of CRY2 evidenced by increased expression of myosin heavy chain (MyHC) and myotube formation in CRY2-/- cells versus CRY2+/+ cells. Immunostaining revealed that the number of mononucleated paired box protein 7 (PAX7+) cells associated with myotubes formed by CRY2-/- cells was increased compared with CRY2+/+ cells, suggesting that more reserve cells were produced in the absence of CRY2. Loss of CRY2 leads to the activation of the ERK1/2 signaling pathway and ETS1, which binds to the promoter of PAX7 to induce its transcription. CRY2 deficient myoblasts survived better in ischemic muscle. Therefore, CRY2 is essential in regulating skeletal muscle repair.
    Keywords:  CRY2; muscle regeneration; satellite cells
    DOI:  https://doi.org/10.1002/mco2.202
  3. Gene. 2023 Jan 05. pii: S0378-1119(23)00013-6. [Epub ahead of print] 147172
    Molecular regulation of satellite cells via intercellular signaling.
    Chung-Ju Yeh, Kristina Marie Sattler, Christoph Lepper.
      Somatic stem cells are tissue-specific reserve cells tasked to sustain tissue homeostasis in adulthood and/or effect tissue regeneration after traumatic injury. The stem cells of skeletal muscle tissue are the satellite cells, which were originally described and named after their localization beneath the muscle fiber lamina and attached to the multi-nucleated muscle fibers. During adult homeostasis, satellite cells are maintained in quiescence, a state of reversible cell cycle arrest. Yet, upon injury, satellite cells are rapidly activated, becoming highly mitotically active to generate large numbers of myoblasts that differentiate and fuse to regenerate the injured muscle fibers. A subset self-renews to replenish the pool of muscle stem cells.Complex intrinsic gene regulatory networks maintain the quiescent state of satellite cells, or upon injury, direct their activation, proliferation, differentiation and self-renewal. Molecular cues from the satellite cells' environment provide the essential information as to when and where satellite cells are to stay quiescent or break quiescence and effect regenerative myogenesis. Predominantly, these cues are secreted, diffusible or membrane-bound ligands that bind to and activate their specific cognate receptors on the satellite cell to activate downstream signaling cascades and elicit context-specific cell behavior. This review aims to offer a concise overview of major intercellular signaling pathways regulating satellite cells during quiescence and in injury-induced skeletal muscle regeneration.
    Keywords:  Intercellular signaling; Muscle regeneration; Satellite cells
    DOI:  https://doi.org/10.1016/j.gene.2023.147172
  4. Arch Physiol Biochem. 2023 Jan 12. 1-12
    Regulating eEF2 and eEF2K in skeletal muscle by exercise.
    Kia Salimi, Masoomeh Alvandi, Mahdi Saberi Pirouz, Kamran Rakhshan, Glyn Howatson.
      Skeletal muscle is a flexible and adaptable tissue that strongly responds to exercise training. The skeletal muscle responds to exercise by increasing muscle protein synthesis (MPS) when energy is available. One of protein synthesis's major rate-limiting and critical regulatory steps is the translation elongation pathway. The process of translation elongation in skeletal muscle is highly regulated. It requires elongation factors that are intensely affected by various physiological stimuli such as exercise and the total available energy of cells. Studies have shown that exercise involves the elongation pathway by numerous signalling pathways. Since the elongation pathway, has been far less studied than the other translation steps, its comprehensive prospect and quantitative understanding remain in the dark. This study highlights the current understanding of the effect of exercise training on the translation elongation pathway focussing on the molecular factors affecting the pathway, including Ca2+, AMPK, PKA, mTORC1/P70S6K, MAPKs, and myostatin. We further discussed the mode and volume of exercise training intervention on the translation elongation pathway.What is the topic of this review? This review summarises the impacts of exercise training on the translation elongation pathway in skeletal muscle focussing on eEF2 and eEF2K.What advances does it highlight? This review highlights mechanisms and factors that profoundly influence the translation elongation pathway and argues that exercise might modulate the response. This review also combines the experimental observations focussing on the regulation of translation elongation during and after exercise. The findings widen our horizon to the notion of mechanisms involved in muscle protein synthesis (MPS) through translation elongation response to exercise training.
    Keywords:  Skeletal muscle; elongation pathway; exercise training
    DOI:  https://doi.org/10.1080/13813455.2023.2164898
  5. Exp Gerontol. 2023 Jan 05. pii: S0531-5565(23)00004-9. [Epub ahead of print] 112083
    Muscle fiber type grouping does not change in response to prolonged resistance exercise training in healthy older men.
    Dominika Kraková, Andrew M Holwerda, Milan W Betz, Kaleen M Lavin, Marcas M Bamman, Luc J C van Loon, Lex B Verdijk, Tim Snijders.
       BACKGROUND: Ageing of skeletal muscle is characterized in some by muscle fiber type grouping due to denervation-reinnervation cycles, but the severity of fiber type grouping varies widely across individuals of the same chronological age. It remains unknown whether fiber type grouping is associated with lower muscle mass and/or reduced physical function in elderly. Therefore, we assessed the relationship between fiber type grouping and indices of muscle mass and physical function in older adults. In addition, we assessed whether fiber type grouping is affected by prolonged resistance training in older adults.
    METHODS: Twenty young (21 ± 2 y) and twenty older (70 ± 4 y) healthy men participated in the present study. Body composition (DXA-scan), quadriceps cross-sectional area (CT-scan) and muscle strength (1RM) were assessed at baseline (young and old) and following 12 weeks of resistance training (old only). Percutaneous skeletal muscle biopsies from the vastus lateralis were collected at baseline (young and old) and following exercise training (old only). Immunohistochemical analyses were performed to evaluate type I and type II muscle fiber distribution, size, myonuclear content and grouping.
    RESULTS: At baseline, type II fibers were significantly (P < 0.05) smaller in older compared with young adults (5366 ± 1288 vs 6705 ± 1168 μm2). Whereas no differences were observed in type I, type II fiber grouping was significantly (P < 0.05) lower in older (18 ± 18 %) compared with young (32 ± 25 %) men. No significant correlations were observed between fiber type grouping and muscle mass or physical function. Prolonged resistance training in old men resulted in a significant increase (P < 0.05) in type II fiber size (from 5366 ± 1288 to 6165 ± 1484 μm2) with no significant changes in the proportion of type I muscle fibers found grouped.
    CONCLUSION: Muscle fiber type grouping is not associated with lower body strength or muscle mass in healthy, older men. In addition, twelve weeks of resistance exercise training results in type II muscle fiber specific hypertrophy but does not affect fiber type grouping.
    Keywords:  Hypertrophy; Morphology; Myosin heavy chain; Sarcopenia
    DOI:  https://doi.org/10.1016/j.exger.2023.112083
  6. J Cachexia Sarcopenia Muscle. 2023 Jan 11.
    The X-linked Becker muscular dystrophy (bmx) mouse models Becker muscular dystrophy via deletion of murine dystrophin exons 45-47.
    Christopher R Heier, Nikki M McCormack, Christopher B Tully, James S Novak, Breanne L Newell-Stamper, Alan J Russell, Alyson A Fiorillo.
       BACKGROUND: Becker muscular dystrophy (BMD) is a genetic neuromuscular disease of growing importance caused by in-frame, partial loss-of-function mutations in the dystrophin (DMD) gene. BMD presents with reduced severity compared with Duchenne muscular dystrophy (DMD), the allelic disorder of complete dystrophin deficiency. Significant therapeutic advancements have been made in DMD, including four FDA-approved drugs. BMD, however, is understudied and underserved-there are no drugs and few clinical trials. Discordance in therapeutic efforts is due in part to lack of a BMD mouse model which would enable greater understanding of disease and de-risk potential therapeutics before first-in-human trials. Importantly, a BMD mouse model is becoming increasingly critical as emerging DMD dystrophin restoration therapies aim to convert a DMD genotype into a BMD phenotype.
    METHODS: We use CRISPR/Cas9 technology to generate bmx (Becker muscular dystrophy, X-linked) mice, which express an in-frame ~40 000  bp deletion of exons 45-47 in the murine Dmd gene, reproducing the most common BMD patient mutation. Here, we characterize muscle pathogenesis using molecular and histological techniques and then test skeletal muscle and cardiac function using muscle function assays and echocardiography.
    RESULTS: Overall, bmx mice present with significant muscle weakness and heart dysfunction versus wild-type (WT) mice, despite a substantial improvement in pathology over dystrophin-null mdx52 mice. bmx mice show impaired motor function in grip strength (-39%, P < 0.0001), wire hang (P = 0.0025), and in vivo as well as ex vivo force assays. In aged bmx, echocardiography reveals decreased heart function through reduced fractional shortening (-25%, P = 0.0036). Additionally, muscle-specific serum CK is increased >60-fold (P < 0.0001), indicating increased muscle damage. Histologically, bmx muscles display increased myofibre size variability (minimal Feret's diameter: P = 0.0017) and centrally located nuclei indicating degeneration/regeneration (P < 0.0001). bmx muscles also display dystrophic pathology; however, levels of the following parameters are moderate in comparison with mdx52: inflammatory/necrotic foci (P < 0.0001), collagen deposition (+1.4-fold, P = 0.0217), and sarcolemmal damage measured by intracellular IgM (P = 0.0878). Like BMD patients, bmx muscles show reduced dystrophin protein levels (~20-50% of WT), whereas Dmd transcript levels are unchanged. At the molecular level, bmx muscles express increased levels of inflammatory genes, inflammatory miRNAs and fibrosis genes.
    CONCLUSIONS: The bmx mouse recapitulates BMD disease phenotypes with histological, molecular and functional deficits. Importantly, it can inform both BMD pathology and DMD dystrophin restoration therapies. This novel model will enable further characterization of BMD disease progression, identification of biomarkers, identification of therapeutic targets and new preclinical drug studies aimed at developing therapies for BMD patients.
    Keywords:  Becker muscular dystrophy; Duchenne muscular dystrophy; dystrophin; dystrophin-associated proteins; exon skipping; inflammation; microRNAs
    DOI:  https://doi.org/10.1002/jcsm.13171
  7. J Gerontol A Biol Sci Med Sci. 2023 Jan 12. pii: glad014. [Epub ahead of print]
    Aging is associated with impaired postprandial response of skeletal muscle protein synthesis to high-intensity muscle contraction in mice.
    Satoru Ato, Hiroshi Matsunami, Riki Ogasawara.
      The purpose of this study was to investigate whether aging alters the effect of nutritional status on contraction-induced muscle protein metabolism. In an overnight fasted or fed states, the right gastrocnemius muscle of young (3 months) and aged (24 months) male C57BL/6J mice was isometrically contracted via percutaneous electrical stimulation. The left gastrocnemius muscle served as a control. In the fasted state, there were no differences in basal or contraction-induced muscle protein synthesis between young and old mice. However, in the fed state, basal muscle protein synthesis was greater in young mice, and contraction increased muscle protein synthesis only in young mice. In the fed state, although phosphorylation of 4E-BP1 was similarly increased by contraction in both ages, the increase in phosphorylation of p70S6K was greater in young mice. Our results indicate that aging impairs the ability to integrate signals from muscle contraction and nutrition, leading to aging-induced anabolic resistance to muscle contraction in the postprandial state.
    Keywords:  chaperone; exercise; mTOR; protein metabolism; sarcopenia
    DOI:  https://doi.org/10.1093/gerona/glad014
  8. Int J Mol Sci. 2022 Dec 21. pii: 76. [Epub ahead of print]24(1):
    Dysferlin Deficiency Results in Myofiber-Type Specific Differences in Abundances of Calcium-Handling and Glycogen Metabolism Proteins.
    Erin M Lloyd, Gavin J Pinniger, Miranda D Grounds, Robyn M Murphy.
      Dysferlinopathies are a clinically heterogeneous group of muscular dystrophies caused by a genetic deficiency of the membrane-associated protein dysferlin, which usually manifest post-growth in young adults. The disease is characterized by progressive skeletal muscle wasting in the limb-girdle and limbs, inflammation, accumulation of lipid droplets in slow-twitch myofibers and, in later stages, replacement of muscles by adipose tissue. Previously we reported myofiber-type specific differences in muscle contractile function of 10-month-old dysferlin-deficient BLAJ mice that could not be fully accounted for by altered myofiber-type composition. In order to further investigate these findings, we examined the impact of dysferlin deficiency on the abundance of calcium (Ca2+) handling and glucose/glycogen metabolism-related proteins in predominantly slow-twitch, oxidative soleus and fast-twitch, glycolytic extensor digitorum longus (EDL) muscles of 10-month-old wild-type (WT) C57BL/6J and dysferlin-deficient BLAJ male mice. Additionally, we compared the Ca2+ activation properties of isolated slow- and fast-twitch myofibers from 3-month-old WT and BLAJ male mice. Differences were observed for some Ca2+ handling and glucose/glycogen metabolism-related protein levels between BLAJ soleus and EDL muscles (compared with WT) that may contribute to the previously reported differences in function in these BLAJ muscles. Dysferlin deficiency did not impact glycogen content of whole muscles nor Ca2+ activation of the myofilaments, although soleus muscle from 10-month-old BLAJ mice had more glycogen than EDL muscles. These results demonstrate a further impact of dysferlin deficiency on proteins associated with excitation-contraction coupling and glycogen metabolism in skeletal muscles, potentially contributing to altered contractile function in dysferlinopathy.
    Keywords:  BLAJ mouse; calcium-handling proteins; dysferlinopathy; glucose/glycogen metabolism proteins; myofiber-types; skeletal muscle contraction
    DOI:  https://doi.org/10.3390/ijms24010076
  9. Exp Physiol. 2023 Jan 09.
    Serum concentration impacts myosin heavy chain expression but not cellular respiration in human LHCN-M2 myoblasts undergoing differentiation.
    Mark C Turner, Ryan Brett, Amarjit Saini, Claire E Stewart, Derek Renshaw.
       NEW FINDINGS: What is the central question of this study? Does the concentration of human serum affect skeletal muscle differentiation and cellular respiration of LHCN-M2 myoblasts? What is the main finding and its importance? The concentration of serum used to differentiate LHCN-M2 skeletal muscle cells impacts the coverage of myosin heavy chain, a marker of terminally differentiated myotubes. Normalisation of mitochondrial function data to total protein negates the differences observed in absolute values, which differ as a result of increased protein content when differentiation occurs with increasing concentration of serum.
    ABSTRACT: The human LHCN-M2 myoblast cell line has the potential to be used to investigate skeletal muscle development and metabolism. Experiments were performed to determine how different concentrations of human serum affect myogenic differentiation and mitochondrial function of LHCN-M2 cells. LHCN-M2 myoblasts were differentiated in serum-free medium, 0.5% or 2% human serum for 5 and 10 days. Myotube formation was assessed by immunofluorescence staining of myosin heavy chain (MHC) and molecularly by mRNA expression of Myogenic differentiation 1 (MYOD1) and Myoregulatory factor 5 (MYF5). Following differentiation, mitochondrial function was assessed to establish the impact of serum concentration on mitochondrial function. Time in differentiation increased mRNA expression of MYOD1 (day 5, 6.58 ± 1.33-fold; and day 10, 4.28 ± 1.71-fold) (P = 0.012), while suppressing the expression of MYF5 (day 5, 0.21 ± 0.11-fold; and day 10, 0.06 ± 0.03-fold) (P = 0.001), regardless of the serum concentration. Higher serum concentrations increased MHC area (serum free, 11.92 ± 0.85%; 0.5%, 23.10 ± 5.82%; 2%, 43.94 ± 8.92%) (P = 0.001). Absolute basal respiration approached significance (P = 0.06) with significant differences in baseline oxygen consumption rate (P = 0.025) and proton leak (P = 0.006) when differentiated in 2% human serum, but these were not different between conditions when normalised to total protein. Our findings show that increasing concentrations of serum of LHCN-M2 skeletal muscle cells into multinucleated myotubes, but this does not affect relative mitochondrial function.
    Keywords:  cell culture; cell respiration; ex vivo; human serum; myogenesis
    DOI:  https://doi.org/10.1113/EP090564
  10. Skelet Muscle. 2023 Jan 06. 13(1): 1
    Multi-omics analysis of sarcospan overexpression in mdx skeletal muscle reveals compensatory remodeling of cytoskeleton-matrix interactions that promote mechanotransduction pathways.
    Jackie L McCourt, Kristen M Stearns-Reider, Hafsa Mamsa, Pranav Kannan, Mohammad Hossein Afsharinia, Cynthia Shu, Elizabeth M Gibbs, Kara M Shin, Yerbol Z Kurmangaliyev, Lauren R Schmitt, Kirk C Hansen, Rachelle H Crosbie.
       BACKGROUND: The dystrophin-glycoprotein complex (DGC) is a critical adhesion complex of the muscle cell membrane, providing a mechanical link between the extracellular matrix (ECM) and the cortical cytoskeleton that stabilizes the sarcolemma during repeated muscle contractions. One integral component of the DGC is the transmembrane protein, sarcospan (SSPN). Overexpression of SSPN in the skeletal muscle of mdx mice (murine model of DMD) restores muscle fiber attachment to the ECM in part through an associated increase in utrophin and integrin adhesion complexes at the cell membrane, protecting the muscle from contraction-induced injury. In this study, we utilized transcriptomic and ECM protein-optimized proteomics data sets from wild-type, mdx, and mdx transgenic (mdxTG) skeletal muscle tissues to identify pathways and proteins driving the compensatory action of SSPN overexpression.
    METHODS: The tibialis anterior and quadriceps muscles were isolated from wild-type, mdx, and mdxTG mice and subjected to bulk RNA-Seq and global proteomics analysis using methods to enhance capture of ECM proteins. Data sets were further analyzed through the ingenuity pathway analysis (QIAGEN) and integrative gene set enrichment to identify candidate networks, signaling pathways, and upstream regulators.
    RESULTS: Through our multi-omics approach, we identified 3 classes of differentially expressed genes and proteins in mdxTG muscle, including those that were (1) unrestored (significantly different from wild type, but not from mdx), (2) restored (significantly different from mdx, but not from wild type), and (3) compensatory (significantly different from both wild type and mdx). We identified signaling pathways that may contribute to the rescue phenotype, most notably cytoskeleton and ECM organization pathways. ECM-optimized proteomics revealed an increased abundance of collagens II, V, and XI, along with β-spectrin in mdxTG samples. Using ingenuity pathway analysis, we identified upstream regulators that are computationally predicted to drive compensatory changes, revealing a possible mechanism of SSPN rescue through a rewiring of cell-ECM bidirectional communication. We found that SSPN overexpression results in upregulation of key signaling molecules associated with regulation of cytoskeleton organization and mechanotransduction, including Yap1, Sox9, Rho, RAC, and Wnt.
    CONCLUSIONS: Our findings indicate that SSPN overexpression rescues dystrophin deficiency partially through mechanotransduction signaling cascades mediated through components of the ECM and the cortical cytoskeleton.
    Keywords:  Duchenne muscular dystrophy; Dystroglycan; Dystrophin; Extracellular matrix; Sarcospan
    DOI:  https://doi.org/10.1186/s13395-022-00311-x
  11. Cell Rep. 2023 Jan 10. pii: S2211-1247(22)01874-5. [Epub ahead of print]42(1): 111970
    Modulation of protease expression by the transcription factor Ptx1/PITX regulates protein quality control during aging.
    Jianqin Jiao, Michelle Curley, Flavia A Graca, Maricela Robles-Murguia, Abbas Shirinifard, David Finkelstein, Beisi Xu, Yiping Fan, Fabio Demontis.
      Protein quality control is important for healthy aging and is dysregulated in age-related diseases. The autophagy-lysosome and ubiquitin-proteasome are key for proteostasis, but it remains largely unknown whether other proteolytic systems also contribute to maintain proteostasis during aging. Here, we find that expression of proteolytic enzymes (proteases/peptidases) distinct from the autophagy-lysosome and ubiquitin-proteasome systems declines during skeletal muscle aging in Drosophila. Age-dependent protease downregulation undermines proteostasis, as demonstrated by the increase in detergent-insoluble poly-ubiquitinated proteins and pathogenic huntingtin-polyQ levels in response to protease knockdown. Computational analyses identify the transcription factor Ptx1 (homologous to human PITX1/2/3) as a regulator of protease expression. Consistent with this model, Ptx1 protein levels increase with aging, and Ptx1 RNAi counteracts the age-associated downregulation of protease expression. Moreover, Ptx1 RNAi improves muscle protein quality control in a protease-dependent manner and extends lifespan. These findings indicate that proteases and their transcriptional modulator Ptx1 ensure proteostasis during aging.
    Keywords:  CP: Cell biology; CP: Molecular biology; PITX; Ptx1; aging; betaTry; huntingtin; peptidase; protease; protein quality control; proteostasis; skeletal muscle
    DOI:  https://doi.org/10.1016/j.celrep.2022.111970
  12. Front Pharmacol. 2022 ;13 1056460
    Morroniside ameliorates inflammatory skeletal muscle atrophy via inhibiting canonical and non-canonical NF-κB and regulating protein synthesis/degradation.
    Xiangjiao Yi, Jianguo Tao, Yu Qian, Feng Feng, Xueqin Hu, Taotao Xu, Hongting Jin, Hongfeng Ruan, Hou-Feng Zheng, Peijian Tong.
      No drug options exist for skeletal muscle atrophy in clinical, which poses a huge socio-economic burden, making development on drug interventions a general wellbeing need. Patients with a variety of pathologic conditions associated with skeletal muscle atrophy have systemically elevated inflammatory factors. Morroniside, derived from medicinal herb Cornus officinalis, possesses anti-inflammatory effect. However, whether and how morroniside combat muscle atrophy remain unknown. Here, we identified crucial genetic associations between TNFα/NF-κB pathway and grip strength based on population using 377,807 European participants from the United Kingdom Biobank dataset. Denervation increased TNFα in atrophying skeletal muscles, which inhibited myotube formation in vitro. Notably, morroniside treatment rescued TNFα-induced myotube atrophy in vitro and impeded skeletal muscle atrophy in vivo, resulting in increased body/muscles weights, No. of satellite cells, size of type IIA, IIX and IIB myofibers, and percentage of type IIA myofibers in denervated mice. Mechanistically, in vitro and/or in vivo studies demonstrated that morroniside could not only inhibit canonical and non-canonical NF-κB, inflammatory mediators (IL6, IL-1b, CRP, NIRP3, PTGS2, TNFα), but also down-regulate protein degradation signals (Follistatin, Myostatin, ALK4/5/7, Smad7/3), ubiquitin-proteasome molecules (FoxO3, Atrogin-1, MuRF1), autophagy-lysosomal molecules (Bnip3, LC3A, and LC3B), while promoting protein synthesis signals (IGF-1/IGF-1R/IRS-1/PI3K/Akt, and BMP14/BMPR2/ALK2/3/Smad5/9). Moreover, morroniside had no obvious liver and kidney toxicity. This human genetic, cells and mice pathological evidence indicates that morroniside is an efficacious and safe inflammatory muscle atrophy treatment and suggests its translational potential on muscle wasting.
    Keywords:  autophagylysosomal pathway; denervation; genetic association study; inflammation; morroniside; muscle atrophy; protein synthesis and degradation; ubiquitin-proteasome system
    DOI:  https://doi.org/10.3389/fphar.2022.1056460
  13. Cell Commun Signal. 2023 Jan 12. 21(1): 7
    LncRNA-TBP mediates TATA-binding protein recruitment to regulate myogenesis and induce slow-twitch myofibers.
    Manting Ma, Bolin Cai, Zhen Zhou, Shaofen Kong, Jing Zhang, Haiping Xu, Xiquan Zhang, Qinghua Nie.
       BACKGROUND: Skeletal muscle is comprised of heterogeneous myofibers that differ in their physiological and metabolic parameters. Of these, slow-twitch (type I; oxidative) myofibers have more myoglobin, more mitochondria, and higher activity of oxidative metabolic enzymes compared to fast-twitch (type II; glycolytic) myofibers.
    METHODS: In our previous study, we found a novel LncRNA-TBP (for "LncRNA directly binds TBP transcription factor") is specifically enriched in the soleus (which has a higher proportion of slow myofibers). The primary myoblast cells and animal model were used to assess the biological function of the LncRNA-TBP in vitro or in vivo. Meanwhile, we performed a RNA immunoprecipitation (RIP) and pull-down analysis to validate this interaction between LncRNA-TBP and TBP.
    RESULTS: Functional studies demonstrated that LncRNA-TBP inhibits myoblast proliferation but promotes myogenic differentiation in vitro. In vivo, LncRNA-TBP reduces fat deposition, activating slow-twitch muscle phenotype and inducing muscle hypertrophy. Mechanistically, LncRNA-TBP acts as a regulatory RNA that directly interacts with TBP protein to regulate the transcriptional activity of TBP-target genes (such as KLF4, GPI, TNNI2, and CDKN1A).
    CONCLUSION: Our findings present a novel model about the regulation of LncRNA-TBP, which can regulate the transcriptional activity of TBP-target genes by recruiting TBP protein, thus modulating myogenesis progression and inducing slow-twitch fibers. Video Abstract.
    Keywords:  LncRNA-TBP; Muscle phenotype transformation; Myogenesis; RNA binding proteins (RBPs); TBP
    DOI:  https://doi.org/10.1186/s12964-022-01001-3
  14. Cells. 2022 Dec 23. pii: 59. [Epub ahead of print]12(1):
    Myostatin Mutation Enhances Bovine Myogenic Differentiation through PI3K/AKT/mTOR Signalling via Removing DNA Methylation of RACK1.
    Yiping Zhao, Xiaoxia Xia, Qiaomeng Wang, Debao Hu, Linlin Zhang, Xin Li, Xiangbin Ding, Hong Guo, Yiwen Guo.
      Myostatin (MSTN) is a negative regulator of skeletal muscle development and plays an important role in muscle development. Fluctuations in gene expression influenced by DNA methylation are critical for homeostatic responses in muscle. However, little is known about the mechanisms underlying this fluctuation regulation and myogenic differentiation of skeletal muscle. Here we report a genome-wide analysis of DNA methylation dynamics in bovine skeletal muscle myogenesis after myostatin editing. We show that, after myostatin editing, an increase in TETs (DNA demethylases) and a concomitant increase in the receptor for activated C kinase 1 (RACK1) control the myogenic development of skeletal muscle. Interestingly, enhancement of PI3K/AKT/mTOR signaling by RACK1 appears to be an essential driver of myogenic differentiation, as it was associated with an increase in myogenic differentiation marker factors (MyHC and MyoG) during muscle differentiation. Overall, our results suggest that loss of myostatin promotes the myogenic differentiation response in skeletal muscle by decreasing DNA methylation of RACK1.
    Keywords:  DNA methylation; PI3K/AKT/mTOR signaling; RACK1; myogenic differentiation; myostatin
    DOI:  https://doi.org/10.3390/cells12010059
  15. Sci Rep. 2023 Jan 11. 13(1): 94
    Establishment of quantitative and consistent in vitro skeletal muscle pathological models of myotonic dystrophy type 1 using patient-derived iPSCs.
    Ryu Kawada, Tatsuya Jonouchi, Akihiro Kagita, Masae Sato, Akitsu Hotta, Hidetoshi Sakurai.
      Myotonic dystrophy type 1 (DM1) is caused by expanded CTG repeats (CTGexp) in the dystrophia myotonica protein kinase (DMPK) gene, and the transcription products, expanded CUG repeats, sequester muscleblind like splicing regulator 1 (MBNL1), resulting in the nuclear MBNL1 aggregation in the DM1 cells. Loss of MBNL1 function is the pivotal mechanism underlying the pathogenesis of DM1. To develop therapeutics for DM1, proper human in vitro models based on the pathologic mechanism of DM1 are required. In this study, we established robust in vitro skeletal muscle cell models of DM1 with patient-derived induced pluripotent stem cells (iPSCs) using the MyoD1-induced system and iPSCs-derived muscle stem cell (iMuSC) differentiation system. Our newly established DM1 models enable simple quantitative evaluation of nuclear MBNL1 aggregation and the downstream splicing defects. Quantitative analyses using the MyoD1-induced myotubes showed that CTGexp-deleted DM1 skeletal myotubes exhibited a reversal of MBNL1-related pathologies, and antisense oligonucleotide treatment recovered these disease phenotypes in the DM1-iPSCs-derived myotubes. Furthermore, iMuSC-derived myotubes exhibited higher maturity than the MyoD1-induced myotubes, which enabled us to recapitulate the SERCA1 splicing defect in the DM1-iMuSC-derived myotubes. Our quantitative and reproducible in vitro models for DM1 established using human iPSCs are promising for drug discovery against DM1.
    DOI:  https://doi.org/10.1038/s41598-022-26614-z
  16. Am J Physiol Cell Physiol. 2023 Jan 09.
    The lactate receptor GPR81 is predominantly expressed in type II human skeletal muscle fibers: potential for lactate autocrine signaling.
    Fabian Nordström, Rasmus Liegnell, William Apró, Sarah J Blackwood, Abram Katz, Marcus Moberg.
      GPR81 was first identified in adipocytes as a receptor for L-lactate, which upon binding inhibits cAMP-PKA-CREB signaling. Moreover, incubation of myotubes with lactate augments expression of GPR81 and genes and proteins involved in lactate- and energy metabolism. However, characterization of GPR81 expression and investigation of related signaling in human skeletal muscle under conditions of elevated circulating lactate levels are lacking. Muscle biopsies were obtained from healthy men and women at rest, after leg extension exercise, with or without venous infusion of sodium lactate, and 90 and 180 min after exercise (8 men and 8 women). Analyses included protein and mRNA levels of GPR81, as well as GPR81-dependent signaling molecules. GPR81 expression was 2.5-fold higher in type II glycolytic compared with type I oxidative muscle fibers, and the expression was inversely related to the percentage of type I muscle fibers. Muscle from women expressed about 25% more GPR81 protein than from men. Global PKA-activity increased by 5-8% after exercise, with no differences between trials. CREBS133 phosphorylation was reduced by 30% after exercise and remained repressed during the entire trials, with no influence of the lactate infusion. The mRNA expression of VEGF and PGC-1α were increased by 2.5 - 6-fold during recovery, and that of LDH reduced by 15% with no differences between trials for any gene at any time point. The high expression of GPR81-protein in type II fibers suggests that lactate functions as an autocrine signaling molecule in muscle; however, lactate does not appear to regulate CREB signaling during exercise.
    Keywords:  CREB; HCAR1; PGC-1alpha; PKA; Resistance exercise
    DOI:  https://doi.org/10.1152/ajpcell.00443.2022
  17. Curr Opin Pharmacol. 2023 Jan 04. pii: S1471-4892(22)00174-6. [Epub ahead of print]68 102347
    Store-operated calcium entry: From physiology to tubular aggregate myopathy.
    Feliciano Protasi, Barbara Girolami, Sara Roccabianca, Daniela Rossi.
      Store-Operated Ca2+ entry (SOCE) is recognized as a key mechanism in muscle physiology necessary to refill intracellular Ca2+ stores during sustained muscle activity. For many years the cell structures expected to mediate SOCE in skeletal muscle fibres remained unknown. Recently, the identification of Ca2+ Entry Units (CEUs) in exercised muscle fibres opened new insights into the role of extracellular Ca2+ in muscle contraction and, more generally, in intracellular Ca2+ homeostasis. Accordingly, intracellular Ca2+ unbalance due to alterations in SOCE strictly correlates with muscle disfunction and disease. Mutations in proteins involved in SOCE (STIM1, ORAI1, and CASQ1) have been linked to tubular aggregate myopathy (TAM), a disease that causes muscle weakness and myalgia and is characterized by a typical accumulation of highly ordered and packed membrane tubules originated from the sarcoplasmic reticulum (SR). Achieving a full understanding of the molecular pathways activated by alterations in Ca2+ entry mechanisms is a necessary step to design effective therapies for human SOCE-related disorders.
    DOI:  https://doi.org/10.1016/j.coph.2022.102347
  18. Int J Mol Sci. 2022 Dec 31. pii: 703. [Epub ahead of print]24(1):
    Phosphodiesterase 5a Signalling in Skeletal Muscle Pathophysiology.
    Valeria De Arcangelis, Luciana De Angelis, Federica Barbagallo, Federica Campolo, Ana Gabriela de Oliveira do Rego, Manuela Pellegrini, Fabio Naro, Mauro Giorgi, Lucia Monaco.
      Phosphodiesterase 5A (PDE5A) is involved in cGMP hydrolysis, regulating many physiological processes. Increased activity of PDE5A has been found in several pathological conditions, and the pharmacological inhibition of PDE5 has been demonstrated to have several therapeutic applications. We have identified the presence of three different Pde5a isoforms in cardiomyocytes, and we have found that the expression of specific Pde5a isoforms may have a causal role in the onset of pathological responses in these cells. In our previous study, we demonstrated that PDE5A inhibition could ameliorate muscular dystrophy by acting at different levels, as assessed by the altered genomic response of muscular cells following treatment with the PDE5A inhibitor tadalafil. Thus, considering the importance of PDE5A in various pathophysiological conditions, we further investigated the regulation of this enzyme. Here, we analysed the expression of Pde5a isoforms in the pathophysiology of skeletal muscle. We found that skeletal muscle tissues and myogenic cells express Pde5a1 and Pde5a2 isoforms, and we observed an increased expression of Pde5a1 in damaged skeletal muscles, while Pde5a2 levels remained unchanged. We also cloned and characterized the promoters that control the transcription of Pde5a isoforms, investigating which of the transcription factors predicted by bioinformatics analysis could be involved in their modulation. In conclusion, we found an overexpression of Pde5a1 in compromised muscle and identified an involvement of MyoD and Runx1 in Pde5a1 transcriptional activity.
    Keywords:  Pde5a isoforms; atrophy; muscular disorders; phosphodiesterases
    DOI:  https://doi.org/10.3390/ijms24010703
  19. J Appl Physiol (1985). 2023 Jan 12.
    Molecular predictors of resistance training outcomes in young untrained female adults.
    Morgan A Smith, Casey L Sexton, Kristen A Smith, Shelby C Osburn, Joshua S Godwin, Jonathan P Beausejour, Bradley A Ruple, Michael D Goodlett, Joseph L Edison, Andrew D Fruge, Austin T Robinson, L Bruce Gladden, Kaelin C Young, Michael D Roberts.
      We sought to determine if the myofibrillar protein synthetic (MyoPS) response to a naïve resistance exercise (RE) bout, or chronic changes in satellite cell number and muscle ribosome content, were associated with hypertrophic outcomes in females or differed in those who classified as higher (HR) or lower (LR) responders to resistance training (RT). Thirty-four untrained college-aged females (23.4±3.4 kg/m2) completed a 10-week RT protocol (twice weekly). Body composition and leg imaging assessments, a right leg vastus lateralis biopsy, and strength testing occurred before and following the intervention. A composite score, which included changes in whole-body lean tissue mass (LSTM), vastus lateralis (VL) muscle cross-sectional area (mCSA), mid-thigh mCSA, and deadlift strength, was used to delineate upper and lower HR (n=8) and LR (n=8) quartiles. In all participants, training significantly (p<0.05) increased LSTM, VL mCSA, mid-thigh mCSA, deadlift strength, mean muscle fiber cross-sectional area, satellite cell abundance, and myonuclear number. Increases in LSTM (p<0.001), VL mCSA (p<0.001), mid-thigh mCSA (p<0.001), and deadlift strength (p=0.001) were greater in HR versus LR. The first-bout 24-hour MyoPS response was similar between HR and LR (p=0.367). While a no significant responder*time interaction existed for muscle total RNA concentrations (i.e., ribosome content) (p=0.888), satellite cell abundance increased in HR (p=0.026) but not LR (p=0.628). Pre-training LSTM (p=0.010) VL mCSA (p=0.028), and mid-thigh mCSA (p<0.001) were also greater in HR versus LR. Female participants with an enhanced satellite cell response to RT, and more muscle mass prior to RT, exhibited favorable resistance training adaptations.
    Keywords:  myofibrillar protein synthesis; physiology; resistance training; ribosomes; satellite cells
    DOI:  https://doi.org/10.1152/japplphysiol.00605.2022
  20. Nat Commun. 2023 Jan 06. 14(1): 108
    Disruption of mitochondrial dynamics triggers muscle inflammation through interorganellar contacts and mitochondrial DNA mislocation.
    Andrea Irazoki, Isabel Gordaliza-Alaguero, Emma Frank, Nikolaos Nikiforos Giakoumakis, Jordi Seco, Manuel Palacín, Anna Gumà, Lykke Sylow, David Sebastián, Antonio Zorzano.
      Some forms of mitochondrial dysfunction induce sterile inflammation through mitochondrial DNA recognition by intracellular DNA sensors. However, the involvement of mitochondrial dynamics in mitigating such processes and their impact on muscle fitness remain unaddressed. Here we report that opposite mitochondrial morphologies induce distinct inflammatory signatures, caused by differential activation of DNA sensors TLR9 or cGAS. In the context of mitochondrial fragmentation, we demonstrate that mitochondria-endosome contacts mediated by the endosomal protein Rab5C are required in TLR9 activation in cells. Skeletal muscle mitochondrial fragmentation promotes TLR9-dependent inflammation, muscle atrophy, reduced physical performance and enhanced IL6 response to exercise, which improved upon chronic anti-inflammatory treatment. Taken together, our data demonstrate that mitochondrial dynamics is key in preventing sterile inflammatory responses, which precede the development of muscle atrophy and impaired physical performance. Thus, we propose the targeting of mitochondrial dynamics as an approach to treating disorders characterized by chronic inflammation and mitochondrial dysfunction.
    DOI:  https://doi.org/10.1038/s41467-022-35732-1
  21. Aging Cell. 2023 Jan 10. e13764
    Reversine ameliorates hallmarks of cellular senescence in human skeletal myoblasts via reactivation of autophagy.
    Nika Rajabian, Debanik Choudhury, Izuagie Ikhapoh, Shilpashree Saha, Aishwarya S Kalyankar, Pihu Mehrotra, Aref Shahini, Kendall Breed, Stelios T Andreadis.
      Cellular senescence leads to the depletion of myogenic progenitors and decreased regenerative capacity. We show that the small molecule 2,6-disubstituted purine, reversine, can improve some well-known hallmarks of cellular aging in senescent myoblast cells. Reversine reactivated autophagy and insulin signaling pathway via upregulation of Adenosine Monophosphate-activated protein kinase (AMPK) and Akt2, restoring insulin sensitivity and glucose uptake in senescent cells. Reversine also restored the loss of connectivity of glycolysis to the TCA cycle, thus restoring dysfunctional mitochondria and the impaired myogenic differentiation potential of senescent myoblasts. Altogether, our data suggest that cellular senescence can be reversed by treatment with a single small molecule without employing genetic reprogramming technologies.
    Keywords:  aging; cellular senescence; metabolism; methionine pathway; skeletal muscle
    DOI:  https://doi.org/10.1111/acel.13764
  22. Int J Mol Sci. 2022 Dec 24. pii: 294. [Epub ahead of print]24(1):
    L-Carnitine Functionalization to Increase Skeletal Muscle Tropism of PLGA Nanoparticles.
    Ilaria Andreana, Manuela Malatesta, Maria Assunta Lacavalla, Federico Boschi, Paola Milla, Valeria Bincoletto, Carlo Pellicciari, Silvia Arpicco, Barbara Stella.
      Muscular dystrophies are a group of rare genetic pathologies, encompassing a variety of clinical phenotypes and mechanisms of disease. Several compounds have been proposed to treat compromised muscles, but it is known that pharmacokinetics and pharmacodynamics problems could occur. To solve these issues, it has been suggested that nanocarriers could be used to allow controlled and targeted drug release. Therefore, the aim of this study was to prepare actively targeted poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs) for the treatment of muscular pathologies. By taking advantage of the high affinity for carnitine of skeletal muscle cells due to the expression of Na+-coupled carnitine transporter (OCTN), NPs have been actively targeted via association to an amphiphilic derivative of L-carnitine. Furthermore, pentamidine, an old drug repurposed for its positive effects on myotonic dystrophy type I, was incorporated into NPs. We obtained monodispersed targeted NPs, with a mean diameter of about 100 nm and a negative zeta potential. To assess the targeting ability of the NPs, cell uptake studies were performed on C2C12 myoblasts and myotubes using confocal and transmission electron microscopy. The results showed an increased uptake of carnitine-functionalized NPs compared to nontargeted carriers in myotubes, which was probably due to the interaction with OCTN receptors occurring in large amounts in these differentiated muscle cells.
    Keywords:  L-carnitine; PLGA; active targeting; fluorescence microscopy; nanoparticles; skeletal muscle cells; transmission electron microscopy
    DOI:  https://doi.org/10.3390/ijms24010294
  23. Cells. 2023 Jan 02. pii: 183. [Epub ahead of print]12(1):
    Relationship between Mitochondrial Quality Control Markers, Lower Extremity Tissue Composition, and Physical Performance in Physically Inactive Older Adults.
    Anna Picca, Matthew Triolo, Stephanie E Wohlgemuth, Matthew S Martenson, Robert T Mankowski, Stephen D Anton, Emanuele Marzetti, Christiaan Leeuwenburgh, David A Hood.
      Altered mitochondrial quality and function in muscle may be involved in age-related physical function decline. The role played by the autophagy-lysosome system, a major component of mitochondrial quality control (MQC), is incompletely understood. This study was undertaken to obtain initial indications on the relationship between autophagy, mitophagy, and lysosomal markers in muscle and measures of physical performance and lower extremity tissue composition in young and older adults. Twenty-three participants were enrolled, nine young (mean age: 24.3 ± 4.3 years) and 14 older adults (mean age: 77.9 ± 6.3 years). Lower extremity tissue composition was quantified volumetrically by magnetic resonance imaging and a tissue composition index was calculated as the ratio between muscle and intermuscular adipose tissue volume. Physical performance in older participants was assessed via the Short Physical Performance Battery (SPPB). Protein levels of the autophagy marker p62, the mitophagy mediator BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3), the lysosomal markers transcription factor EB, vacuolar-type ATPase, and lysosomal-associated membrane protein 1 were measured by Western immunoblotting in vastus lateralis muscle biopsies. Older adults had smaller muscle volume and lower tissue composition index than young participants. The protein content of p62 and BNIP3 was higher in older adults. A negative correlation was detected between p62 and BNIP3 and the tissue composition index. p62 and BNIP3 were also related to the performance on the 5-time sit-to-stand test of the SPPB. Our results suggest that an altered expression of markers of the autophagy/mitophagy-lysosomal system is related to deterioration of lower extremity tissue composition and muscle dysfunction. Additional studies are needed to clarify the role of defective MQC in human muscle aging and identify novel biological targets for drug development.
    Keywords:  Short Physical Performance Battery (SPPB); aging; functional decline; intermuscular adipose tissue (IMAT); lysosomes; mitochondrial dysfunction; mitochondrion; muscle aging; physical performance; sarcopenia
    DOI:  https://doi.org/10.3390/cells12010183
  24. Cell Signal. 2023 Jan 03. pii: S0898-6568(22)00346-1. [Epub ahead of print]104 110584
    From phosphorylation to phenotype - Recent key findings on kinase regulation, downstream signaling and disease surrounding the receptor tyrosine kinase MuSK.
    Jakob Prömer, Cinzia Barresi, Ruth Herbst.
      Muscle-specific kinase (MuSK) is the key regulator of neuromuscular junction development. MuSK acts via several distinct pathways and is responsible for pre- and postsynaptic differentiation. MuSK is unique among receptor tyrosine kinases as activation and signaling are particularly tightly regulated. Initiation of kinase activity requires Agrin, a heparan sulphate proteoglycan derived from motor neurons, the low-density lipoprotein receptor-related protein-4 (Lrp4) and the intracellular adaptor protein Dok-7. There is a great knowledge gap between MuSK activation and downstream signaling. Recent studies using omics techniques have addressed this knowledge gap, thereby greatly contributing to a better understanding of MuSK signaling. Impaired MuSK signaling causes severe muscle weakness as described in congenital myasthenic syndromes or myasthenia gravis but the underlying pathophysiology is often unclear. This review focuses on recent advances in deciphering MuSK activation and downstream signaling. We further highlight latest break-throughs in understanding and treatment of MuSK-related disorders and discuss the role of MuSK in non-muscle tissue.
    Keywords:  Agrin; MuSK; Neuromuscular disorders; Neuromuscular junction; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.cellsig.2022.110584
  25. Aging Cell. 2023 Jan 08. e13763
    FOXO3A-short is a novel regulator of non-oxidative glucose metabolism associated with human longevity.
    Evan E Santo, Rasmus Ribel-Madsen, Peter J Stroeken, Vincent C J de Boer, Ninna S Hansen, Maaike Commandeur, Allan A Vaag, Rogier Versteeg, Jihye Paik, Ellen M Westerhout.
      Intronic single-nucleotide polymorphisms (SNPs) in FOXO3A are associated with human longevity. Currently, it is unclear how these SNPs alter FOXO3A functionality and human physiology, thereby influencing lifespan. Here, we identify a primate-specific FOXO3A transcriptional isoform, FOXO3A-Short (FOXO3A-S), encoding a major longevity-associated SNP, rs9400239 (C or T), within its 5' untranslated region. The FOXO3A-S mRNA is highly expressed in the skeletal muscle and has very limited expression in other tissues. We find that the rs9400239 variant influences the stability and functionality of the primarily nuclear protein(s) encoded by the FOXO3A-S mRNA. Assessment of the relationship between the FOXO3A-S polymorphism and peripheral glucose clearance during insulin infusion (Rd clamp) in a cohort of Danish twins revealed that longevity T-allele carriers have markedly faster peripheral glucose clearance rates than normal lifespan C-allele carriers. In vitro experiments in human myotube cultures utilizing overexpression of each allele showed that the C-allele represses glycolysis independently of PI3K signaling, while overexpression of the T-allele represses glycolysis only in a PI3K-inactive background. Supporting this finding inducible knockdown of the FOXO3A-S C-allele in cultured myotubes increases the glycolytic rate. We conclude that the rs9400239 polymorphism acts as a molecular switch which changes the identity of the FOXO3A-S-derived protein(s), which in turn alters the relationship between FOXO3A-S and insulin/PI3K signaling and glycolytic flux in the skeletal muscle. This critical difference endows carriers of the FOXO3A-S T-allele with consistently higher insulin-stimulated peripheral glucose clearance rates, which may contribute to their longer and healthier lifespans.
    Keywords:  FOXO; FOXO3A; PI3K; SNP; aging; glycolysis; insulin; skeletal muscle
    DOI:  https://doi.org/10.1111/acel.13763
  26. NPJ Regen Med. 2023 Jan 14. 8(1): 4
    Machine learning-based classification of dual fluorescence signals reveals muscle stem cell fate transitions in response to regenerative niche factors.
    Matteo Togninalli, Andrew T V Ho, Christopher M Madl, Colin A Holbrook, Yu Xin Wang, Klas E G Magnusson, Anna Kirillova, Andrew Chang, Helen M Blau.
      The proper regulation of muscle stem cell (MuSC) fate by cues from the niche is essential for regeneration of skeletal muscle. How pro-regenerative niche factors control the dynamics of MuSC fate decisions remains unknown due to limitations of population-level endpoint assays. To address this knowledge gap, we developed a dual fluorescence imaging time lapse (Dual-FLIT) microscopy approach that leverages machine learning classification strategies to track single cell fate decisions with high temporal resolution. Using two fluorescent reporters that read out maintenance of stemness and myogenic commitment, we constructed detailed lineage trees for individual MuSCs and their progeny, classifying each division event as symmetric self-renewing, asymmetric, or symmetric committed. Our analysis reveals that treatment with the lipid metabolite, prostaglandin E2 (PGE2), accelerates the rate of MuSC proliferation over time, while biasing division events toward symmetric self-renewal. In contrast, the IL6 family member, Oncostatin M (OSM), decreases the proliferation rate after the first generation, while blocking myogenic commitment. These insights into the dynamics of MuSC regulation by niche cues were uniquely enabled by our Dual-FLIT approach. We anticipate that similar binary live cell readouts derived from Dual-FLIT will markedly expand our understanding of how niche factors control tissue regeneration in real time.
    DOI:  https://doi.org/10.1038/s41536-023-00277-4
  27. Am J Physiol Endocrinol Metab. 2023 Jan 11.
    Inhibition of the endocannabinoid system reverses obese phenotype in aged mice and partly restores skeletal muscle function.
    Lucas Fajardo, Phelipe Sanchez, Jérôme Salles, Jean Paul Rigaudière, Véronique Patrac, Sylvie Caspar-Bauguil, Camille Bergoglgio, Cédric Moro, Stéphane Walrand, Olivier Le Bacquer.
      Sarcopenia, the age-related loss of skeletal muscle mass is associated with lipid accumulation and anabolic resistance; phenomena also observed in obesity and worsen when obesity and aging combined. The endocannabinoid system (ECS) is overactivated in obesity, but its role in aging obesity-related muscle dysfunction is unknown. The aims of this study were to evaluate the effect of an inhibition of the ECS by rimonabant (RIM) on the metabolic alterations induced by a high-fat high-sucrose diet, and on skeletal muscle mass/function in aged mice. 18-month old male mice were subjected to a control (CTL) or a high fat high sucrose (HFHS) diet for 24 weeks. Mice were administered with saline or RIM (10 mg/kg/d) for the last 4 weeks of the diet. Skeletal muscle function was evaluated by openfield, rotarod and grip strength tests. Metabolic alterations in liver, adipose tissue and skeletal muscle were investigated by RT-qPCR. Body mass was higher in HFHS mice compared to CTL mice (48.0 ± 1.5 vs. 33.5 ± 0.7 g, p<0.01), as a result of fat accumulation (34.8 ± 1.0 vs. 16.7 ± 0.8 %, p<0.01). RIM reduced body fat mass in both CTL (-16%, p<0.05) and HFHS condition (-40%, p<0.01), without affecting hindlimb skeletal muscle mass. In HFHS mice, grip strength evolution was improved (-0.29 ± 0.06 vs. -0.49 ± 0.06, p<0.05) and rotarod activity was increased by ≈60% in response to RIM (45.9 ± 6.3 vs 28.5 ± 4.6, p<0.05). Lipolysis and b-oxidation genes were up-regulated in the liver as well as genes involved in adipose tissue browning. These results demonstrate that inhibition of the ECS induces metabolic changes in liver and adipose tissue associated with a reversion of the obese phenotype, and that RIM is able to improve motor coordination and muscle strength in aged mice, without affecting skeletal muscle mass.
    Keywords:  muscle function; obesity; rimonabant; sarcopenia; skeletal muscle
    DOI:  https://doi.org/10.1152/ajpendo.00258.2022
  28. Diabetes Metab J. 2023 Jan 12.
    The Link between Mitochondrial Dysfunction and Sarcopenia: An Update Focusing on the Role of Pyruvate Dehydrogenase Kinase 4.
    Min-Ji Kim, Ibotombi Singh Sinam, Zerwa Siddique, Jae-Han Jeon, In-Kyu Lee.
      Sarcopenia, defined as a progressive loss of muscle mass and function, is typified by mitochondrial dysfunction and loss of mitochondrial resilience. Sarcopenia is associated not only with aging, but also with various metabolic diseases characterized by mitochondrial dyshomeostasis. Pyruvate dehydrogenase kinases (PDKs) are mitochondrial enzymes that inhibit the pyruvate dehydrogenase complex, which controls pyruvate entry into the tricarboxylic acid cycle and the subsequent adenosine triphosphate production required for normal cellular activities. PDK4 is upregulated in mitochondrial dysfunction-related metabolic diseases, especially pathologic muscle conditions associated with enhanced muscle proteolysis and aberrant myogenesis. Increases in PDK4 are associated with perturbation of mitochondria-associated membranes and mitochondrial quality control, which are emerging as a central mechanism in the pathogenesis of metabolic disease-associated muscle atrophy. Here, we review how mitochondrial dysfunction affects sarcopenia, focusing on the role of PDK4 in mitochondrial homeostasis. We discuss the molecular mechanisms underlying the effects of PDK4 on mitochondrial dysfunction in sarcopenia and show that targeting mitochondria could be a therapeutic target for treating sarcopenia.
    Keywords:  Metabolic diseases; Mitochondria; Muscular atrophy; Pyruvate dehydrogenase acetyl-transferring kinase; Pyruvate dehydrogenase complex; Sarcopenia
    DOI:  https://doi.org/10.4093/dmj.2022.0305
  29. J Clin Med. 2022 Dec 31. pii: 318. [Epub ahead of print]12(1):
    FAT/CD36 Participation in Human Skeletal Muscle Lipid Metabolism: A Systematic Review.
    Arnulfo Ramos-Jiménez, Ruth A Zavala-Lira, Verónica Moreno-Brito, Everardo González-Rodríguez.
      Fatty acid translocase/cluster of differentiation 36 (FAT/CD36) is a multifunctional membrane protein activated by a high-fat diet, physical exercise, fatty acids (FAs), leptin, and insulin. The principal function of FAT/CD36 is to facilitate the transport of long-chain fatty acids through cell membranes such as myocytes, adipocytes, heart, and liver. Under high-energy expenditure, the different isoforms of FAT/CD36 in the plasma membrane and mitochondria bind to the mobilization and oxidation of FAs. Furthermore, FAT/CD36 is released in its soluble form and becomes a marker of metabolic dysfunction. Studies with healthy animals and humans show that physical exercise and a high-lipid diet increase FAT/CD36 expression and caloric expenditure. However, several aspects such as obesity, diabetes, Single Nucleotide polymorphisms (SNPs), and oxidative stress affect the normal FAs metabolism and function of FAT/CD36, inducing metabolic disease. Through a comprehensive systematic review of primary studies, this work aimed to document molecular mechanisms related to FAT/CD36 in FAs oxidation and trafficking in skeletal muscle under basal conditions, physical exercise, and diet in healthy individuals.
    Keywords:  adenosine monophosphate activating protein; fat oxidation; fatty acid-binding protein; mitochondria; muscle contraction; nutrients; sarcolemmal; scavenger receptor type B2
    DOI:  https://doi.org/10.3390/jcm12010318
  30. Cells. 2022 Dec 29. pii: 144. [Epub ahead of print]12(1):
    α-1,6-Fucosyltransferase Is Essential for Myogenesis in Zebrafish.
    Nozomi Hayashiji, Genri Kawahara, Xing Xu, Tomohiko Fukuda, Aurelien Kerever, Jianguo Gu, Yukiko K Hayashi, Eri Arikawa-Hirasawa.
      Glycosylation is an important mechanism regulating various biological processes, including intercellular signaling and adhesion. α-1,6-fucosyltransferase (Fut8) belongs to a family of enzymes that determine the terminal structure of glycans. Fut8 is widely conserved from Caenorhabditis elegans to humans, and its mutants have been reported in humans, mice, and zebrafish. Although mutants show various symptoms, such as spinal deformity and growth retardation, its effects on skeletal muscles are unknown. We aimed to elucidate the function of Fut8 in skeletal muscle using zebrafish and C2C12 cells for evaluation. We observed that most fut8a morphants died at 2 days post-fertilization (dpf) or in earlier developmental stages even at low concentrations of morpholino oligonucleotides (MOs). Mutant juveniles also had small body sizes, and abnormal myocepta and sarcomere structures, suggesting that Fut8a plays important roles in myogenesis. Moreover, treatment of C2C12 cells with 2-fluorofucose (2FF), a fucosylation inhibitor, during cell differentiation dramatically reduced the expression of myogenic genes, such as Myomaker and other myogenic fusion genes, and inhibited myotube formation. These results indicate that Fut8 is an important factor in myogenesis, and myofusion in particular.
    Keywords:  muscle development; zebrafish; α-1,6-fucosyltransferase
    DOI:  https://doi.org/10.3390/cells12010144
  31. Cell Rep. 2023 Jan 09. pii: S2211-1247(22)01886-1. [Epub ahead of print]42(1): 111982
    Defining the age-dependent and tissue-specific circadian transcriptome in male mice.
    Christopher A Wolff, Miguel A Gutierrez-Monreal, Lingsong Meng, Xiping Zhang, Lauren G Douma, Hannah M Costello, Collin M Douglas, Elnaz Ebrahimi, Ann Pham, Aline C Oliveira, Chunhua Fu, Amy Nguyen, Bryan R Alava, Stuart J Hesketh, Andrew R Morris, Mehari M Endale, G Ryan Crislip, Kit-Yan Cheng, Elizabeth A Schroder, Brian P Delisle, Andrew J Bryant, Michelle L Gumz, Zhiguang Huo, Andrew C Liu, Karyn A Esser.
      Cellular circadian clocks direct a daily transcriptional program that supports homeostasis and resilience. Emerging evidence has demonstrated age-associated changes in circadian functions. To define age-dependent changes at the systems level, we profile the circadian transcriptome in the hypothalamus, lung, heart, kidney, skeletal muscle, and adrenal gland in three age groups. We find age-dependent and tissue-specific clock output changes. Aging reduces the number of rhythmically expressed genes (REGs), indicative of weakened circadian control. REGs are enriched for the hallmarks of aging, adding another dimension to our understanding of aging. Analyzing differential gene expression within a tissue at four different times of day identifies distinct clusters of differentially expressed genes (DEGs). Increased variability of gene expression across the day is a common feature of aged tissues. This analysis extends the landscape for understanding aging and highlights the impact of aging on circadian clock function and temporal changes in gene expression.
    Keywords:  CP: Developmental biology; CP: Molecular biology; RNA-seq; adrenal gland; aging; circadian clock; heart; hypothalamus; kidney; lung; skeletal muscle
    DOI:  https://doi.org/10.1016/j.celrep.2022.111982
  32. Front Mol Neurosci. 2022 ;15 1069940
    TrkB signaling is correlated with muscular fatigue resistance and less vulnerability to neurodegeneration.
    Laia Just-Borràs, Víctor Cilleros-Mañé, Aleksandra Polishchuk, Marta Balanyà-Segura, Marta Tomàs, Neus Garcia, Josep Tomàs, Maria A Lanuza.
      At the neuromuscular junction (NMJ), motor neurons and myocytes maintain a bidirectional communication that guarantees adequate functionality. Thus, motor neurons' firing pattern, which is influenced by retrograde muscle-derived neurotrophic factors, modulates myocyte contractibility. Myocytes can be fast-twitch fibers and become easily fatigued or slow-twitch fibers and resistant to fatigue. Extraocular muscles (EOM) show mixed properties that guarantee fast contraction speed and resistance to fatigue and the degeneration caused by Amyotrophic lateral sclerosis (ALS) disease. The TrkB signaling is an activity-dependent pathway implicated in the NMJ well-functioning. Therefore, it could mediate the differences between fast and slow myocytes' resistance to fatigue. The present study elucidates a specific protein expression profile concerning the TrkB signaling that correlates with higher resistance to fatigue and better neuroprotective capacity through time. The results unveil that Extra-ocular muscles (EOM) express lower levels of NT-4 that extend TrkB signaling, differential PKC expression, and a higher abundance of phosphorylated synaptic proteins that correlate with continuous neurotransmission requirements. Furthermore, common molecular features between EOM and slow soleus muscles including higher neurotrophic consumption and classic and novel PKC isoforms balance correlate with better preservation of these two muscles in ALS. Altogether, higher resistance of Soleus and EOM to fatigue and ALS seems to be associated with specific protein levels concerning the TrkB neurotrophic signaling.
    Keywords:  EOM; PKA; PKC; TrkB-BDNF; fatigue-resistant; neuromuscular junction; skeletal muscle
    DOI:  https://doi.org/10.3389/fnmol.2022.1069940
  33. Front Endocrinol (Lausanne). 2022 ;13 1053882
    PDIA4, a new endoplasmic reticulum stress protein, modulates insulin resistance and inflammation in skeletal muscle.
    Chien-Hsing Lee, Chi-Fu Chiang, Fu-Huang Lin, Feng-Chih Kuo, Sheng-Chiang Su, Chia-Luen Huang, Peng-Fei Li, Jhih-Syuan Liu, Chieh-Hua Lu, Chang-Hsun Hsieh, Yi-Jen Hung, Yi-Shing Shieh.
       Introduction: Endoplasmic reticulum (ER) stress has emerged as a key player in insulin resistance (IR) progression in skeletal muscle. Recent reports revealed that ER stress-induced the expression of protein disulfide isomerase family a member 4 (PDIA4), which may be involved in IR-related diseases. A previous study showed that metformin modulated ER stress-induced IR. However, it remained unclear whether metformin alleviated IR by regulating PDIA4 expression in skeletal muscle.
    Methods: Herein, we used palmitate-induced IR in C2C12 cells and a high-fat diet-induced IR mouse model to document the relations between metformin, IR, and PDIA4.
    Results: In C2C12 cells, palmitate-induced IR increased inflammatory cytokines and PDIA4 expression. Besides, knocking down PDIA4 decreased palmitate-induced IR and inflammation in C2C12 cells. Furthermore, metformin modulated PDIA4 expression and alleviated IR both in vitro and in vivo. In addition, serum PDIA4 concentrations are associated with IR and inflammatory cytokines levels in human subjects.
    Discussion: Thus, this study is the first to demonstrate that PDIA4 participates in the metformin-induced effects on skeletal muscle IR and indicates that PDIA4 is a potential novel therapeutic target for directly alleviating IR.
    Keywords:  Endoplasmic reticulum; PDIA4; insulin resistance; metformin; skeletal muscle
    DOI:  https://doi.org/10.3389/fendo.2022.1053882
  34. Int J Mol Sci. 2022 Dec 24. pii: 297. [Epub ahead of print]24(1):
    The Importance of mTORC1-Autophagy Axis for Skeletal Muscle Diseases.
    Xujun Han, Kah Yong Goh, Wen Xing Lee, Sze Mun Choy, Hong-Wen Tang.
      The mechanistic target of rapamycin (mTOR) complex 1, mTORC1, integrates nutrient and growth factor signals with cellular responses and plays critical roles in regulating cell growth, proliferation, and lifespan. mTORC1 signaling has been reported as a central regulator of autophagy by modulating almost all aspects of the autophagic process, including initiation, expansion, and termination. An increasing number of studies suggest that mTORC1 and autophagy are critical for the physiological function of skeletal muscle and are involved in diverse muscle diseases. Here, we review recent insights into the essential roles of mTORC1 and autophagy in skeletal muscles and their implications in human muscle diseases. Multiple inhibitors targeting mTORC1 or autophagy have already been clinically approved, while others are under development. These chemical modulators that target the mTORC1/autophagy pathways represent promising potentials to cure muscle diseases.
    Keywords:  autophagy; mTORC1; muscle diseases
    DOI:  https://doi.org/10.3390/ijms24010297
  35. Am J Physiol Regul Integr Comp Physiol. 2023 Jan 09.
    Independent, but not co-supplementation with nitrate and resveratrol improves glucose tolerance and reduces markers of cellular stress in high-fat-fed male mice.
    Rachel M Handy, Geneviève J DesOrmeaux, Pierre-Andre Barbeau, Sara M Frangos, Graham P Holloway.
      Independent supplementation with nitrate (NIT) and resveratrol (RSV) enrich various aspects of mitochondrial biology in key metabolic tissues. While RSV is known to activate Sirt1 and initiate mitochondrial biogenesis, the metabolic benefits elicited by dietary nitrate appear to be dependent on AMPK-mediated signalling events, a process also linked to the activation of Sirt1. While the benefits of individual supplementation with these compounds has been characterized, it is unknown if co-supplementation may produce superior metabolic adaptations. Thus, we aimed to determine if treatment with combined +NIT and +RSV (+RN) could additively alter metabolic adaptations in the presence of a high-fat diet (HFD). Both +RSV and +NIT improved glucose tolerance compared to HFD (p<0.05), however, this response was attenuated following combined +RN supplementation. Within skeletal muscle, all supplements increased mitochondrial ADP-sensitivity compared to HFD (p<0.05), without altering mitochondrial content. While +RSV and +NIT decreased hepatic lipid deposition compared to HFD (p<0.05), this effect was abolished with +RN, which aligned with significant reductions in Sirt1 protein content (p<0.05) following combined treatment, in the absence of changes to mitochondrial content or function. Within eWAT, all supplements reduced crown-like structure accumulation compared to HFD (p<0.0001) and mitochondrial ROS emission (p<0.05), alongside reduced adipocyte CSA (p<0.05), with the greatest effect observed following +RN treatment (p=0.0001). While the present data suggests additive changes in adipose tissue metabolism following +RN treatment, concomitant impairments in hepatic lipid homeostasis appear to prevent improvements in whole-body glucose homeostasis observed with independent treatment, which may be Sirt1-dependent.
    Keywords:  Glucose homeostasis; Mitochondria; Nutrition; Resveratrol; Sodium nitrate
    DOI:  https://doi.org/10.1152/ajpregu.00196.2022
  36. Geroscience. 2023 Jan 07.
    Genes encoding agrin (AGRN) and neurotrypsin (PRSS12) are associated with muscle mass, strength and plasma C-terminal agrin fragment concentration.
    Jedd Pratt, Laura Whitton, Anthony Ryan, Thorhildur Juliusdottir, Jackie Dolan, Judith Conroy, Marco Narici, Giuseppe De Vito, Colin Boreham.
      Although physiological data suggest that neuromuscular junction (NMJ) dysfunction is a principal mechanism underpinning sarcopenia, genetic studies have implicated few genes involved in NMJ function. Accordingly, we explored whether genes encoding agrin (AGRN) and neurotrypsin (PRSS12) were associated with sarcopenia phenotypes: muscle mass, strength and plasma C-terminal agrin fragment (CAF). PhenoScanner was used to determine if AGRN and/or PRSS12 variants had previously been implicated with sarcopenia phenotypes. For replication, we combined genotype from whole genome sequencing with phenotypic data from 6715 GenoFit participants aged 18-83 years. Dual energy X-ray absorptiometry assessed whole body lean mass (WBLM) and appendicular lean mass (ALM), hand dynamometry determined grip strength and ELISA measured plasma CAF in a subgroup (n = 260). Follow-up analyses included eQTL analyses, carrier analyses, single-variant and gene-burden tests. rs2710873 (AGRN) and rs71608359 (PRSS12) associate with muscle mass and strength phenotypes, respectively, in the UKBB (p = 8.9 × 10-6 and p = 8.4 × 10-6) and GenoFit cohort (p = 0.019 and p = 0.014). rs2710873 and rs71608359 are eQTLs for AGRN and PRSS12, respectively, in ≥ three tissues. Compared to non-carriers, carriers of rs2710873 had 4.0% higher WBLM and ALM (both p < 0.001), and 9.5% lower CAF concentrations (p < 0.001), while carriers of rs71608359 had 2.3% lower grip strength (p = 0.034). AGRN and PRSS12 are associated with muscle strength and mass in single-variant analyses, while PRSS12 has further associations with muscle strength in gene-burden tests. Our findings provide novel evidence of the relevance of AGRN and PRSS12 to sarcopenia phenotypes and support existing physiological data illustrating the importance of the NMJ in maintaining muscle health during ageing.
    Keywords:  Agrin; Genes; Muscle mass; Muscle strength; Neuromuscular junction; Sarcopenia
    DOI:  https://doi.org/10.1007/s11357-022-00721-1
  37. J Appl Microbiol. 2022 Dec 20. pii: lxac014. [Epub ahead of print]
    The critical role of gut microbiota dysbiosis in skeletal muscle wasting: a systematic review.
    Amirabbas Nikkhah, Hanieh-Sadat Ejtahed, Fateme Ettehad Marvasti, MinaSadat Taghavi, Azin Pakmehr, Firouzeh Hajipour, Bagher Larijani.
       AIMS: Skeletal muscle wasting is affected by the gut microbiota dysbiosis through multiple pathways, including inflammatory process, defected immune system, and anabolic resistance. We aimed to systematically review the studies investigating the gut microbiota composition in sarcopenic and cachexic humans and animals.
    METHODS: We carried out a comprehensively systematic search using relevant keywords on PubMed, Web of Science, and Scopus databases until July 2021. Original human observational research and animal studies related to our research topics published in English were selected.
    RESULTS: Seven human studies and five animal studies were included. Three human studies were case-control, whereas the other four were cross-sectional studies that investigated three different conditions, including age-related sarcopenia, as well as liver cirrhosis and cancer cachexia. The principal alteration in age-related sarcopenia and liver cirrhosis-induced sarcopenia was a reduction in short-chain fatty acids (SCFAs) -producing bacteria. Lachnospiraceae family, consisting of Lachnospira, Fusicatenibacter,Roseburia, and Lachnoclostridium, significantly decreased in age-related sarcopenia, while in liver cirrhosis-induced sarcopenia, the alpha diversity of gut microbiota decreased compared with the control group. Moreover, Enterobacteriaceae, which has a pro-inflammatory effect increased in muscle-wasted animals.
    CONCLUSION: This systematic review presents associations between the gut microbiota alterations and skeletal muscle wasting as a consequence of various pathologies, including aging sarcopenia, renal failure, and cancer cachexia in both human and animal studies.
    Keywords:  Gut microbiota; cachexia; dysbiosis; muscle wasting; sarcopenia; skeletal muscle
    DOI:  https://doi.org/10.1093/jambio/lxac014
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