bims-moremu Biomed News
on Molecular regulators of muscle mass
Issue of 2022‒06‒05
34 papers selected by
Anna Vainshtein
Craft Science Inc.

  1. Elife. 2022 May 31. pii: e69802. [Epub ahead of print]11
      Exercise is an effective strategy in the prevention and treatment of metabolic diseases. Alterations in the skeletal muscle proteome, including post-translational modifications, regulate its metabolic adaptations to exercise. Here, we examined the effect of high-intensity interval training (HIIT) on the proteome and acetylome of human skeletal muscle, revealing the response of 3168 proteins and 1263 lysine acetyl-sites on 464 acetylated proteins. We identified global protein adaptations to exercise training involved in metabolism, excitation-contraction coupling, and myofibrillar calcium sensitivity. Furthermore, HIIT increased the acetylation of mitochondrial proteins, particularly those of complex V. We also highlight the regulation of exercise-responsive histone acetyl-sites. These data demonstrate the plasticity of the skeletal muscle proteome and acetylome, providing insight into the regulation of contractile, metabolic and transcriptional processes within skeletal muscle. Herein, we provide a substantial hypothesis-generating resource to stimulate further mechanistic research investigating how exercise improves metabolic health.
    Keywords:  acetylation; biochemistry; calcium sensitivity; chemical biology; computational biology; exercise; human; mitochondria; proteomics; skeletal muscle; systems biology
  2. Am J Physiol Cell Physiol. 2022 Jun 01.
      Muscle fiber denervation is a major contributor to the decline in muscle mass and function during aging. Heavy resistance exercise is an effective tool for increasing muscle mass and strength, but whether it can rescue denervated muscle fibers remains unclear. Therefore, the purpose of this study was to investigate the potential of heavy resistance exercise to modify indices of denervation in healthy elderly individuals. 38 healthy elderly men (72±5 years) underwent 16 weeks of heavy resistance exercise while 20 healthy elderly men (72±6 years) served as non-exercising sedentary controls. Muscle biopsies were obtained pre and post training, and midway at eight weeks. Biopsies were analysed by immunofluorescence for the prevalence of myofibers expressing embryonic myosin (MyHCe), neonatal myosin (MyHCn), nestin, and neural cell adhesion molecule (NCAM), and by RT-qPCR for gene expression levels of acetylcholine receptor (AChR) subunits, MyHCn, MyHCe, p16 and Ki67. In addition to increases in strength and type II fiber hypertrophy, heavy resistance exercise training led to a decrease in AChR α1 and ε subunit mRNA (at eight weeks). Changes in gene expression levels of the α1 and ε AChR subunits with eight weeks of heavy resistance exercise supports the role of this type of exercise in targeting stability of the neuromuscular junction. The number of fibers positive for NCAM, nestin, and MyHCn was not affected, suggesting that a longer timeframe is needed for adaptations to manifest at the protein level.
    Keywords:  Heavy resistance exercise; acetylcholine receptor; ageing human muscle; denervation; satellite cells
  3. Skelet Muscle. 2022 May 31. 12(1): 11
      BACKGROUND: As the interest in manned spaceflight increases, so does the requirement to understand the transcriptomic mechanisms that underlay the detrimental physiological adaptations of skeletal muscle to microgravity. While microgravity-induced differential gene expression (DGE) has been extensively investigated, the contribution of differential alternative splicing (DAS) to the plasticity and functional status of the skeletal muscle transcriptome has not been studied in an animal model. Therefore, by evaluating both DGE and DAS across spaceflight, we set out to provide the first comprehensive characterization of the transcriptomic landscape of skeletal muscle during exposure to microgravity.METHODS: RNA-sequencing, immunohistochemistry, and morphological analyses were conducted utilizing total RNA and tissue sections isolated from the gastrocnemius and quadriceps muscles of 30-week-old female BALB/c mice exposed to microgravity or ground control conditions for 9 weeks.
    RESULTS: In response to microgravity, the skeletal muscle transcriptome was remodeled via both DGE and DAS. Importantly, while DGE showed variable gene network enrichment, DAS was enriched in structural and functional gene networks of skeletal muscle, resulting in the expression of alternatively spliced transcript isoforms that have been associated with the physiological changes to skeletal muscle in microgravity, including muscle atrophy and altered fiber type function. Finally, RNA-binding proteins, which are required for regulation of pre-mRNA splicing, were themselves differentially spliced but not differentially expressed, an upstream event that is speculated to account for the downstream splicing changes identified in target skeletal muscle genes.
    CONCLUSIONS: Our work serves as the first investigation of coordinate changes in DGE and DAS in large limb muscles across spaceflight. It opens up a new opportunity to understand (i) the molecular mechanisms by which splice variants of skeletal muscle genes regulate the physiological adaptations of skeletal muscle to microgravity and (ii) how small molecule splicing regulator therapies might thwart muscle atrophy and alterations to fiber type function during prolonged spaceflight.
    Keywords:  Alternative splicing; Microgravity; Skeletal muscle; Spaceflight; Transcriptome
  4. Aging Cell. 2022 Jun 02. e13650
      Microphysiological systems (MPS), also referred to as tissue chips, incorporating 3D skeletal myobundles are a novel approach for physiological and pharmacological studies to uncover new medical treatments for sarcopenia. We characterize a MPS in which engineered skeletal muscle myobundles derived from donor-specific satellite cells that model aged phenotypes are encapsulated in a perfused tissue chip platform containing platinum electrodes. Our myobundles were derived from CD56+ myogenic cells obtained via percutaneous biopsy of the vastus lateralis from adults phenotyped by age and physical activity. Following 17 days differentiation including 5 days of a 3 V, 2 Hz electrical stimulation regime, the myobundles exhibited fused myotube alignment and upregulation of myogenic, myofiber assembly, signaling and contractile genes as demonstrated by gene array profiling and localization of key components of the sarcomere. Our results demonstrate that myobundles derived from the young, active (YA) group showed high intensity immunofluorescent staining of α-actinin proteins and responded to electrical stimuli with a ~1 μm displacement magnitude compared with non-stimulated myobundles. Myobundles derived from older sedentary group (OS) did not display a synchronous contraction response. Hypertrophic potential is increased in YA-derived myobundles in response to stimulation as shown by upregulation of insulin growth factor (IGF-1), α-actinin (ACTN3, ACTA1) and fast twitch troponin protein (TNNI2) compared with OS-derived myobundles. Our MPS mimics disease states of muscle decline and thus provides an aged system and experimental platform to investigate electrical stimulation mimicking exercise regimes and may be adapted to long duration studies of compound efficacy and toxicity for therapeutic evaluation against sarcopenia.
    Keywords:  bioengineered skeletal muscle; cellular electrical stimulation; human CD56+ primary cells; muscle myogenesis gene expression; sarcomere immunofluorescence
  5. Front Genet. 2022 ;13 835099
      Single-cell RNA-seq (scRNA-seq) has revolutionized modern genomics, but the large size of myotubes and myofibers has restricted use of scRNA-seq in skeletal muscle. For the study of muscle, single-nucleus RNA-seq (snRNA-seq) has emerged not only as an alternative to scRNA-seq, but as a novel method providing valuable insights into multinucleated cells such as myofibers. Nuclei within myofibers specialize at junctions with other cell types such as motor neurons. Nuclear heterogeneity plays important roles in certain diseases such as muscular dystrophies. We survey current methods of high-throughput single cell and subcellular resolution transcriptomics, including single-cell and single-nucleus RNA-seq and spatial transcriptomics, applied to satellite cells, myoblasts, myotubes and myofibers. We summarize the major myonuclei subtypes identified in homeostatic and regenerating tissue including those specific to fiber type or at junctions with other cell types. Disease-specific nucleus populations were found in two muscular dystrophies, FSHD and Duchenne muscular dystrophy, demonstrating the importance of performing transcriptome studies at the single nucleus level in muscle.
    Keywords:  myonuclei heterogeneity; single-cell RNA-seq; single-nucleus RNA-seq; skeletal muscle; spatial transcriptomics
  6. Exp Mol Pathol. 2022 May 27. pii: S0014-4800(22)00061-2. [Epub ahead of print] 104798
      Sirt2 regulates various biological processes by deacetylating target genes. Despite roles in regulating proliferation, cell cycle, and glucose metabolism, which are closely associated with skeletal muscle physiology, Sirt2 functions in this tissue remain unclear. In this study, genetic deletion of Sirt2 delayed muscle regeneration after Notexin-induced muscle injury. Gene expressions of myogenic regulatory factors, including Myf5, MyoD, and Myogenin, and cell cycle regulators, such as cyclin D1 and CDK2, were repressed in Sirt2 knockout mice after injury. Also, Sirt2 knockout mice presented muscle atrophy after muscle injury which is associated with the down-regulation of anabolic signaling and the up-regulation of catabolic signaling, in particular, increased atrogin1 transcriptional expression. Thus, Sirt2 positively regulated skeletal muscle regeneration after muscle injury by regulating transcriptional expression involved in myogenesis, cell cycle, and anabolic and catabolic signaling. Based on the in vivo analyses, Sirt2 could function as an interventional therapeutic for chronic myopathy, which is characterized by impaired muscle regeneration and muscle atrophy.
    Keywords:  Muscle atrophy; Muscle regeneration; Notexin-induced muscle injury; Sirt2; Sirt2 knockout mice
  7. Biochim Biophys Acta Mol Cell Res. 2022 May 27. pii: S0167-4889(22)00092-1. [Epub ahead of print] 119300
      Exercise-induced physical endurance enhancement and skeletal muscle remodeling can prevent and delay the development of multiple diseases, especially metabolic syndrome. Herein, the study explored the association between glucagon-like peptide-1 (GLP-1) secretion and exercise, and its effect on skeletal muscle remodeling to enhance endurance capacity. We found both acute exercise and short-term endurance training significantly increased the secretion of GLP-1 in mice. Recombinant adeno-associated virus (AAV) encoding Gcg (proglucagon) was used to induce the overexpression of GLP-1 in skeletal muscle of mice. Overexpression of GLP-1 in skeletal muscle enhanced endurance capacity. Meanwhile, glycogen synthesis, glucose uptake, type I fibers proportion, and mitochondrial biogenesis were augmented in GLP-1-AAV skeletal muscle. Furthermore, the in vitro experiment showed that exendin-4 (a GLP-1 receptor agonist) treatment remarkably promoted glucose uptake, type I fibers formation, and mitochondrial respiration. Mechanistically, the knockdown of AMPK could reverse the effects imposed by GLP-1R activation in vitro. Taken together, these results verify that GLP-1 regulates skeletal muscle remodeling to enhance exercise endurance possibly via GLP-1R signaling-mediated phosphorylation of AMPK.
    Keywords:  Endurance capacity; GLP-1; Glycogen storage; Mitochondrial biogenesis; Muscle fiber type
  8. Cell Commun Signal. 2022 May 31. 20(1): 77
      BACKGROUND: Natural antisense RNAs are RNA molecules that are transcribed from the opposite strand of either protein-coding or non-protein coding genes and have the ability to regulate the expression of their sense gene or several related genes. However, the roles of natural antisense RNAs in the maintenance and myogenesis of muscle stem cells remain largely unexamined.METHODS: We analysed myoblast differentiation and regeneration by overexpression and knockdown of Foxk1-AS using lentivirus and adeno-associated virus infection in C2C12 cells and damaged muscle tissues. Muscle injury was induced by BaCl2 and the regeneration and repair of damaged muscle tissues was assessed by haematoxylin-eosin staining and quantitative real-time PCR. The expression of myogenic differentiation-related genes was verified via quantitative real-time PCR, Western blotting and immunofluorescence staining.
    RESULTS: We identified a novel natural antisense RNA, Foxk1-AS, which is transcribed from the opposite strand of Foxk1 DNA and completely incorporated in the 3' UTR of Foxk1. Foxk1-AS targets Foxk1 and functions as a regulator of myogenesis. Overexpression of Foxk1-AS strongly inhibited the expression of Foxk1 in C2C12 cells and in tibialis anterior muscle tissue and promoted myoblast differentiation and the regeneration of muscle fibres damaged by BaCl2. Furthermore, overexpression of Foxk1-AS promoted the expression of Mef2c, which is an important transcription factor in the control of muscle gene expression and is negatively regulated by Foxk1.
    CONCLUSION: The results indicated that Foxk1-AS represses Foxk1, thereby rescuing Mef2c activity and promoting myogenic differentiation of C2C12 cells and regeneration of damaged muscle fibres. Video Abstract.
    Keywords:  Foxk1; Foxk1-AS; Mef2c; Myogenic differentiation; Natural antisense RNA
  9. J Endocrinol. 2022 May 01. pii: JOE-22-0057. [Epub ahead of print]
      Estrogen deficiency causes metabolic disorders in humans and rodents, including in part due to changes in energy expenditure. We have shown previously that skeletal muscle mitochondrial function is compromised in ovariectomized rats. Since physical exercise is a powerful strategy to improve skeletal muscle mitochondrial content and function, we hypothesize that exercise training would counteract the deficiency-induced skeletal muscle mitochondrial dysfunction in ovariectomized rats. We report that exercised ovariectomized rats, at 60-65% of maximal exercise capacity for eight weeks, exhibited less fat accumulation and body-weight gain compared with sedentary controls. Treadmill exercise training decreased muscle lactate production, indicating a shift to mitochondrial oxidative metabolism. Furthermore, reduced soleus muscle mitochondrial oxygen consumption confirmed that estrogen deficiency is detrimental to mitochondrial function. However, exercise restored mitochondrial oxygen consumption in ovariectomized rats, achieving similar levels as in exercised control rats. Exercise-induced skeletal muscle peroxisome proliferator-activated receptor-γ coactivator-1α, expression was similar in both groups. Therefore, the mechanisms by which exercise improves mitochondrial oxygen consumption appears to be different in ovariectomized-exercised and sham-exercised rats. While there was an increase in mitochondrial content in sham-exercised rats, demonstrated by a greater citrate synthase activity, no induction was observed in ovariectomized-exercised rats. Normalizing mitochondrial respiratory capacity by citrate synthase activity indicates a better oxidative phosphorylation efficiency in the ovariectomized-exercised group. In conclusion, physical exercise sustains mitochondrial function in ovarian hormone-deficient rats through a non-conventional mitochondrial content-independent manner.
  10. J Physiol. 2022 Jun 02.
    Keywords:  denervation; lysosomes; mitochondria; mitophagy; muscle atrophy
  11. Aging Dis. 2022 Jun;13(3): 801-814
      Sarcopenia is a new type of senile syndrome with progressive skeletal muscle mass loss with age, accompanied by decreased muscle strength and/or muscle function. Sarcopenia poses a serious threat to the health of the elderly and increases the burden of family and society. The underlying pathophysiological mechanisms of sarcopenia are still unclear. Recent studies have shown that changes of skeletal muscle metabolism are the risk factors for sarcopenia. Furthermore, the importance of the skeletal muscle metabolic microenvironment in regulating satellite cells (SCs) is gaining significant attention. Skeletal muscle metabolism has intrinsic relationship with the regulation of skeletal muscle mass and regeneration. This review is to discuss recent findings regarding skeletal muscle metabolic alternation and the development of sarcopenia, hoping to contribute better understanding and treatment of sarcopenia.
    Keywords:  Sarcopenia; metabolic alternation; regeneration; signaling pathways
  12. Front Physiol. 2022 ;13 851789
      Clinical evidence suggests that resistance exercise exerts health benefit. The mechanisms underlying such health benefits is largely explored in experimental animals. Available experimental models have several shortcomings such as the need for noxious stimuli that could affect the physiological readouts. In this study, we describe a simple-to-use experimental model of resistance exercise. In this resistance exercise, rats pull pre-determined weights using a tunnel and pulley system. We show that resistance-exercised rats developed a larger pulling strength when compared to those seen in either control rats or in rats subjected to traditional treadmill exercise. Histological examination revealed that resistance exercise led to a larger fiber cross-sectional area in the plantaris muscle, but not in the gastrocnemius or the soleus muscles. Similarly, the percentage of type-II muscle fibers in the plantaris was increased in resistance exercised rats when compared to those seen in plantaris muscles of either control or treadmill-exercised rat groups. Furthermore, this resistance exercise led to a significant increase in the expression levels of the phosphorylated protein kinase B; a marker of muscle hypertrophy in the plantaris muscle. Such effects were not seen in treadmill-trained rats. In conclusion, we developed an experimental model that can be amenable for experimental exploration of the mechanisms underlying the beneficial effects of resistance exercise. We further provide evidence that this resistance exercise model enhanced muscle strength and muscle hypertrophy.
    Keywords:  fast-twitch muscle fiber; muscle hypertrophy; strength training; treadmill exercise; tunnel-pulley system
  13. J Clin Invest. 2022 Jun 01. pii: e159002. [Epub ahead of print]132(11):
      Skeletal muscle fibers contain hundreds of nuclei, which increase the overall transcriptional activity of the tissue and perform specialized functions. Multinucleation occurs through myoblast fusion, mediated by the muscle fusogens Myomaker (MYMK) and Myomixer (MYMX). We describe a human pedigree harboring a recessive truncating variant of the MYMX gene that eliminates an evolutionarily conserved extracellular hydrophobic domain of MYMX, thereby impairing fusogenic activity. Homozygosity of this human variant resulted in a spectrum of abnormalities that mimicked the clinical presentation of Carey-Fineman-Ziter syndrome (CFZS), caused by hypomorphic MYMK variants. Myoblasts generated from patient-derived induced pluripotent stem cells displayed defective fusion, and mice bearing the human MYMX variant died perinatally due to muscle abnormalities. In vitro assays showed that the human MYMX variant conferred minimal cell-cell fusogenicity, which could be restored with CRISPR/Cas9-mediated base editing, thus providing therapeutic potential for this disorder. Our findings identify MYMX as a recessive, monogenic human disease gene involved in CFZS, and provide new insights into the contribution of myoblast fusion to neuromuscular diseases.
    Keywords:  Monogenic diseases; Muscle; Muscle Biology; Neuromuscular disease
  14. Front Genet. 2022 ;13 892136
    Keywords:  cachexia; cancer; extracellular vesicles; microRNAs; muscle; muscle wasting (atrophy)
  15. JCI Insight. 2022 May 31. pii: e158397. [Epub ahead of print]
      LAMA2-deficiency, resulting from a defective or absent laminin α2-subunit, is a common cause of congenital muscular dystrophy. It is characterized by muscle weakness from myofiber degeneration and neuropathy from Schwann cell amyelination. Previously it was shown that transgenic muscle-specific expression of αLNNd, a laminin-γ1-binding linker protein that ena-bles polymerization in defective laminins, selectively ameliorates the muscle abnormality in mouse disease models. Here, adeno-associated virus (AAV) was used to deliver linker mini-genes to dystrophic dy2J/dy2J mice for expression of either αLNNd in muscle, or αLNNdΔG2', a shortened linker, in muscle, nerve and other tissues. Linker and laminin-α2 levels were higher in αLNNdΔG2'-treated mice. Both αLNNd- and αLNNdΔG2'-treated mice exhibited increased fore-limb grip strength. Further, αLNNdΔG2'-treated mice achieved hindlimb and all-limb grip strength levels approaching those of wild-type mice as well as ablation of hindlimb paresis and contractures. Improvement of muscle histology was evident in the muscle-specific αLNNd-ex-pressing mice but more extensive in the αLNNdΔG2'-expressing mice, along with restoration of sciatic nerve axonal envelopment and myelination. The results reveal that an αLN-linker mini-gene, driven by a ubiquitous promoter is superior to muscle-specific delivery through higher ex-pression that extends to peripheral nerve. These studies support a novel approach of somatic gene therapy.
    Keywords:  Extracellular matrix; Laminin; Muscle Biology; Neuroscience
  16. J Histochem Cytochem. 2022 Jun;70(6): 415-426
      We previously demonstrated that 8 weeks of moderate-intensity endurance training is safe and improves muscle function and characteristics of sickle cell disease (SCD) patients. Here, we investigated skeletal muscle satellite cells (SCs) in SCD patients and their responses to a training program. Fifteen patients followed the training program while 18 control patients maintained a normal lifestyle. Biopsies of the vastus lateralis muscle were performed before and after training. After training, the cross-sectional area and myonuclear content in type I fibers were slightly increased in the training patients compared to non-training patients. The SC pool was unchanged in type I fibers while it was slightly decreased in type II fibers in the training patients compared to non-training patients. No necrotic fibers were detected in patients before or after training. Therefore, the slight myonuclear accretion in type I fibers in trained SCD patients may highlight the contribution of SCs to training-induced slight type I fiber hypertrophy without expansion of the SC pool. The low training intensity and the short duration of training sessions could explain the low SC response to the training program. However, the lack of necrotic fibers suggests that the training program seemed to be safe for patients' muscle tissue.
    Keywords:  CD56; Ki67; exercise; satellite cells; sickle cell anemia
  17. J Physiol. 2022 May 31.
    Keywords:  muscle atrophy; muscle recovery; oxidative stress; pericytes
  18. J Appl Physiol (1985). 2022 Jun 02.
      Eccentric muscle contractions are fundamental to everyday life. They occur markedly in jumping, running, and accidents. Following an initial force rise, stretching of a fully activated muscle can result in a phase of decreasing force ('Give') followed by force redevelopment. However, how the stretch velocity affects 'Give' and force redevelopment remains largely unknown. We investigated the force produced by fully activated single skinned fibers of rat extensor digitorum longus muscles during long stretches. Fibers were pulled from length .85 to 1.3 optimal fiber length at a rate of 1, 10 and 100% of the estimated maximum shortening velocity. 'Give' was absent in slow stretches. Medium and fast stretches yielded a clear 'Give'. After the initial force peak, forces decreased by 11.2% and 27.8% relative to the initial peak force before rising again. During the last half of the stretch (from 1.07 to 1.3 optimal fiber length, which is within the range of the expected descending limb of the force-length relationship), the linear force slope tripled from slow to medium stretch and increased further by 60% from medium to fast stretch. These results are compatible with forcible cross-bridge detachment and re-development of a cross-bridge distribution, and a viscoelastic titin contribution to fiber force. Accounting for these results can improve muscle models and predictions of multi-body simulations.
    Keywords:  Contractile behavior; muscle physiology; skeletal muscle; stretch; velocity dependence
  19. Diabetes Metab J. 2022 May;46(3): 402-413
      Low levels of mitochondrial stress are beneficial for organismal health and survival through a process known as mitohormesis. Mitohormetic responses occur during or after exercise and may mediate some salutary effects of exercise on metabolism. Exercise-related mitohormesis involves reactive oxygen species production, mitochondrial unfolded protein response (UPRmt), and release of mitochondria-derived peptides (MDPs). MDPs are a group of small peptides encoded by mitochondrial DNA with beneficial metabolic effects. Among MDPs, mitochondrial ORF of the 12S rRNA type-c (MOTS-c) is the most associated with exercise. MOTS-c expression levels increase in skeletal muscles, systemic circulation, and the hypothalamus upon exercise. Systemic MOTS-c administration increases exercise performance by boosting skeletal muscle stress responses and by enhancing metabolic adaptation to exercise. Exogenous MOTS-c also stimulates thermogenesis in subcutaneous white adipose tissues, thereby enhancing energy expenditure and contributing to the anti-obesity effects of exercise training. This review briefly summarizes the mitohormetic mechanisms of exercise with an emphasis on MOTS-c.
    Keywords:  Exercise; Hormesis; MOTS-c peptide, human; Mitochondria; Mitochondrial proteins; Obesity
  20. Oxid Med Cell Longev. 2022 ;2022 2151191
      Skeletal muscle is one of the largest organs in the body and is essential for maintaining quality of life. Loss of skeletal muscle mass and function can lead to a range of adverse consequences. The gut microbiota can interact with skeletal muscle by regulating a variety of processes that affect host physiology, including inflammatory immunity, protein anabolism, energy, lipids, neuromuscular connectivity, oxidative stress, mitochondrial function, and endocrine and insulin resistance. It is proposed that the gut microbiota plays a role in the direction of skeletal muscle mass and work. Even though the notion of the gut microbiota-muscle axis (gut-muscle axis) has been postulated, its causal link is still unknown. The impact of the gut microbiota on skeletal muscle function and quality is described in detail in this review.
  21. Clin Interv Aging. 2022 ;17 857-872
      Sarcopenia, an age-related disease characterized by loss of muscle strength and muscle mass, has attracted the attention of medical experts due to its severe morbidity, low living quality, high expenditure of health care, and mortality. Traditionally, persistent aerobic exercise (PAE) is considered as a valid way to attenuate muscular atrophy. However, nowadays, high intensity interval training (HIIT) has emerged as a more effective and time-efficient method to replace traditional exercise modes. HIIT displays comprehensive effects on exercise capacity and skeletal muscle metabolism, and it provides a time-out for the recovery of cardiopulmonary and muscular functions without causing severe adverse effects. Studies demonstrated that compared with PAE, HIIT showed similar or even higher effects in improving muscle strength, enhancing physical performances and increasing muscle mass of elder people. Therefore, HIIT might become a promising way to cope with the age-related loss of muscle mass and muscle function. However, it is worth mentioning that no study of HIIT was conducted directly on sarcopenia patients, which is attributed to the suspicious of safety and validity. In this review, we will assess the effects of different training parameters on muscle and sarcopenia, summarize previous papers which compared the effects of HIIT and PAE in improving muscle quality and function, and evaluate the potential of HIIT to replace the status of PAE in treating old people with muscle atrophy and low modality; and point out drawbacks of temporary experiments. Our aim is to discuss the feasibility of HIIT to treat sarcopenia and provide a reference for clinical scientists who want to utilize HIIT as a new way to cope with sarcopenia.
    Keywords:  Sarcopenia; aging; high intensity interval training; persistent aerobic exercise
  22. Proc Biol Sci. 2022 Jun 08. 289(1976): 20220622
      Muscle spindle abundance is highly variable within and across species, but we currently lack any clear picture of the mechanistic causes or consequences of this variation. Previous use of spindle abundance as a correlate for muscle function implies a mechanical underpinning to this variation, but these ideas have not been tested. Herein, we use integrated medical imaging and subject-specific musculoskeletal models to investigate the relationship between spindle abundance, muscle architecture and in vivo muscle behaviour in the human locomotor system. These analyses indicate that muscle spindle number is tightly correlated with muscle fascicle length, absolute fascicle length change, velocity of fibre lengthening and active muscle forces during walking. Novel correlations between functional indices and spindle abundance are also recovered, where muscles with a high abundance predominantly function as springs, compared to those with a lower abundance mostly functioning as brakes during walking. These data demonstrate that muscle fibre length, lengthening velocity and fibre force are key physiological signals to the central nervous system and its modulation of locomotion, and that muscle spindle abundance may be tightly correlated to how a muscle generates work. These insights may be combined with neuromechanics and robotic studies of motor control to help further tease apart the functional drivers of muscle spindle composition.
    Keywords:  MRI; biomechanics; muscle spindle; physics simulation; proprioception
  23. J Funct Morphol Kinesiol. 2022 May 11. pii: 40. [Epub ahead of print]7(2):
      Huntington's disease (HD) is a rare, hereditary, and progressive neurodegenerative disease, characterized by involuntary choreatic movements with cognitive and behavioral disturbances. In order to mitigate impairments in motor function, physical exercise was integrated in HD rehabilitative interventions, showing to be a powerful tool to ameliorate the quality of life of HD-affected patients. This review aims to describe the effects of physical exercise on HD-related skeletal muscle disorders in both murine and human models. We performed a literature search using PubMed, Scopus, and Web of Science databases on the role of physical activity in mouse models of HD and human patients. Fifteen publications fulfilled the criteria and were included in the review. Studies performed on mouse models showed a controversial role played by exercise, whereas in HD-affected patients, physical activity appeared to have positive effects on gait, motor function, UHDMRS scale, cognitive function, quality of life, postural stability, total body mass, fatty acid oxidative capacity, and VO2 max. Physical activity seems to be feasible, safe, and effective for HD patients. However, further studies with longer follow-up and larger cohorts of patients will be needed to draw firm conclusions on the positive effects of exercise for HD patients.
    Keywords:  Huntington’s disease; exercise; motor function; mouse models; rehabilitation; skeletal muscles
  24. J Rehabil Med. 2022 Jan 11. 54 jrm00250
      OBJECTIVE:  To evaluate the effects and safety of exercise training, and to determine the most effective exercise intervention for people with Duchenne muscular dystrophy. Exercise training was compared with no training, placebo or alternative exercise training. Primary outcomes were functioning and health-related quality of life. Secondary outcomes were muscular strength, endurance and lung function.  Data sources: A systematic literature search was conducted in Medline, EMBASE, CINAHL, Cochrane Central, PEDro and Scopus.  Study selection and data extraction: Screening, data extraction, risk of bias and quality assessment were carried out. Risk of bias was assessed using the Cochrane Collaborations risk of bias tools. The certainty of evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation.DATA SYNTHESIS: Twelve studies with 282 participants were included. A narrative synthesis showed limited or no improvements in functioning compared with controls. Health-related quality of life was assessed in only 1 study. A meta-analysis showed a significant difference in muscular strength and endurance in favour of exercise training compared with no training and placebo. However, the certainty of evidence was very low.
    CONCLUSION: Exercise training may be beneficial in Duchenne muscular dystrophy, but the evidence remains uncertain. Further research is needed on exercise training to promote functioning and health-related quality of life in Duchenne muscular dystrophy.
  25. Front Endocrinol (Lausanne). 2022 ;13 886243
      Background: Charcot-Marie-Tooth (CMT) indicates a group of inherited polyneuropathies whose clinical phenotypes primarily include progressive distal weakness and muscle atrophy. Compelling evidence showed that the exercise-mimetic myokine irisin protects against muscle wasting in an autocrine manner, thus possibly preventing the onset of musculoskeletal atrophy. Therefore, we sought to determine if irisin serum levels correlate with biochemical and muscle parameters in a cohort of CMT patients.Methods: This cohort study included individuals (N=20) diagnosed with CMT disease. Irisin and biochemical markers were quantified in sera. Skeletal muscle mass (SMM) was evaluated by bioelectric impedance analysis, muscle strength by handgrip, and muscle quality was derived from muscle strength and muscle mass ratio.
    Results: CMT patients (m/f, 12/8) had lower irisin levels than age and sex matched healthy subjects (N=20) (6.51 ± 2.26 vs 9.34 ± 3.23 μg/ml; p=0.003). SMM in CMT patients was always lower compared to SMM reference values reported in healthy Caucasian population matched for age and sex. Almost the totality of CMT patients (19/20) showed low muscle quality and therefore patients were evaluated on the basis of muscle strength. Irisin was lower in presence of pathological compared to normal muscle strength (5.56 ± 1.26 vs 7.67 ± 2.72 μg/ml; p=0.03), and directly correlated with the marker of bone formation P1PN (r= 0.669; 95%CI 0.295 to 0.865; p=0.002), but inversely correlated with Vitamin D (r=-0.526; 95%CI -0,791 to -0,095; p=0.017). Surprisingly, in women, irisin levels were higher than in men (7.31 ± 2.53 vs 5.31 ± 1.02 μg/ml, p=0.05), and correlated with both muscle strength (r=0.759; 95%CI 0.329 to 0.929; p=0.004) and muscle quality (r=0.797; 95%CI 0.337 to 0.950; p=0.006).
    Conclusion: Our data demonstrate lower irisin levels in CMT patients compared to healthy subjects. Moreover, among patients, we observed, significantly higher irisin levels in women than in men, despite the higher SMM in the latter. Future studies are necessary to establish whether, in this clinical contest, irisin could represent a marker of the loss of muscle mass and strength and/or bone loss.
    Keywords:  CMT; irisin; muscle atrophy; myokine; osteoporosis
  26. Cell Rep. 2022 May 31. pii: S2211-1247(22)00659-3. [Epub ahead of print]39(9): 110884
      Muscle regeneration is known to be defective under diabetic conditions. However, the underlying mechanisms remain less clear. Adult quiescent muscle satellite cells (MuSCs) from leptin-receptor-deficient (i.e., db/db) diabetic mice are defective in early activation in vivo, but not in culture, suggesting the involvement of pathogenic niche factors. Elevated extracellular adenosine (eAdo) and AMP (eAMP) are detected under diabetic conditions. eAdo and eAMP potently inhibit cell cycle re-entry of quiescent MuSCs and injury-induced muscle regeneration. Mechanistically, eAdo and eAMP engage the equilibrative Ado transporters (ENTs)-Ado kinase (ADK)-AMPK signaling axis in MuSCs to inhibit the mTORC1-dependent cell growth checkpoint. eAdo and eAMP also inhibit early activation of quiescent fibroadipogenic progenitors and human MuSCs by the same mechanism. Treatment of db/db diabetic mice with an ADK inhibitor partially rescues the activation defects of MuSCs in vivo. Thus, both ADK and ENTs represent potential therapeutic targets for restoring the regenerative functions of tissue stem cells in patients with diabetes.
    Keywords:  AMPK; CP: Metabolism; adenosine kinase (ADK); diabetes; equilibrative nucleoside transporter (ENT); extracellular AMP; extracellular adenosine; mTORC1; muscle satellite cells (MuSCs)
  27. ACS Chem Biol. 2022 May 31.
      Manipulation of RNA splicing machinery has emerged as a drug modality. Here, we illustrate the potential of this novel paradigm to correct aberrant splicing events focused on the recent therapeutic advances in spinal muscular atrophy (SMA). SMA is an incurable neuromuscular disorder and at present the primary genetic cause of early infant death. This Review summarizes the exciting journey from the first reported SMA cases to the currently approved splicing-switching treatments, i.e., antisense oligonucleotides and small-molecule modifiers. We emphasize both chemical structures and molecular bases for recognition. We briefly discuss the advantages and disadvantages of these treatments and include the remaining challenges and future directions. Finally, we also predict that these success stories will contribute to further therapies for human diseases by RNA-splicing control.
  28. Front Cell Neurosci. 2022 ;16 916065
    Keywords:  AAV9; AVXS-101; Survival Motor Neuron (SMN); Zolgensma; gene therapy; onasemnogene abeparvovec; spinal muscular atrophy (SMA)
  29. Clin Exp Pharmacol Physiol. 2022 May 30.
      Regular endurance exercise is a non-pharmacological strategy to protect the liver against diseases. Conversely, exercise may be harmful when excessive, the so-called overtraining. As expected, mice who underwent an overtraining protocol presented higher levels of proinflammatory cytokines in the serum and liver. Based on the relationship among overtraining, inflammation, and mammalian target of rapamycin complex 1 (mTORC1) up-regulation, the present study verified if animals submitted to an overtraining protocol but with inhibition of the mTOR pathway via rapamycin injections could mitigate the liver and serum inflammation. Once autophagy can be linked to the improvement of hepatic dysfunction, we also investigated if the inhibition of mTORC1 by rapamycin can improve hepatic autophagy. The animals were randomized into four groups: Control (CT; sedentary mice), Overtraining by downhill running (OT; mice submitted to the downhill running-based overtraining protocol), Overtraining by downhill running with chronic administration of rapamycin (OT/Rapa; mice submitted to the downhill running-based overtraining protocol with intraperitoneal injections of rapamycin) and Aerobic (AER; submitted to aerobic training protocol). The serum and liver of the animals were used for biochemical analysis, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and immunoblotting. The main results are 1) OT and OT/Rapa protocols decreased the performance; 2) the protein levels of interleukin 6 (IL-6) were higher for the OT group; the OT/Rapa group reduced the autophagic genes, increased the Microtubule-associated protein light chain 3 II/I (LC3II/LC3I) protein ratio, and decreased the Sequestosome 1 (SQSTM1) protein. In conclusion, rapamycin appears efficiently to increase the autophagy proteins and decrease IL-6 protein in the liver of overtraining mice. This article is protected by copyright. All rights reserved.
    Keywords:  autophagy; exercise; liver; mTORC1; rapamycin
  30. Sci Transl Med. 2022 Jun;14(647): eabj5557
      How mechanical stress affects physical performance via tendons is not fully understood. Piezo1 is a mechanosensitive ion channel, and E756del PIEZO1 was recently found as a gain-of-function variant that is common in individuals of African descent. We generated tendon-specific knock-in mice using R2482H Piezo1, a mouse gain-of-function variant, and found that they had higher jumping abilities and faster running speeds than wild-type or muscle-specific knock-in mice. These phenotypes were associated with enhanced tendon anabolism via an increase in tendon-specific transcription factors, Mohawk and Scleraxis, but there was no evidence of changes in muscle. Biomechanical analysis showed that the tendons of R2482H Piezo1 mice were more compliant and stored more elastic energy, consistent with the enhancement of jumping ability. These phenotypes were replicated in mice with tendon-specific R2482H Piezo1 replacement after tendon maturation, indicating that PIEZO1 could be a target for promoting physical performance by enhancing function in mature tendon. The frequency of E756del PIEZO1 was higher in sprinters than in population-matched nonathletic controls in a small Jamaican cohort, suggesting a similar function in humans. Together, this human and mouse genetic and physiological evidence revealed a critical function of tendons in physical performance, which is tightly and robustly regulated by PIEZO1 in tenocytes.
  31. Prog Neurobiol. 2022 May 30. pii: S0301-0082(22)00074-0. [Epub ahead of print] 102288
      Duchenne muscular dystrophy (DMD) is a muscle disorder caused by DMD mutations and is characterized by neurobehavioural comorbidities due to dystrophin deficiency in the brain. The lack of Dp140, a dystrophin short isoform, is clinically associated with intellectual disability and autism spectrum disorders (ASDs), but its postnatal functional role is not well understood. To investigate synaptic function in the presence or absence of brain Dp140, we utilized two DMD mouse models, mdx23 and mdx52 mice, in which Dp140 is preserved or lacking, respectively. ASD-like behaviours were observed in pups and 8-week-old mdx52 mice lacking Dp140. Paired-pulse ratio of excitatory postsynaptic currents, glutamatergic vesicle number in basolateral amygdala neurons, and glutamatergic transmission in medial prefrontal cortex-basolateral amygdala projections were significantly reduced in mdx52 mice compared to those in wild-type and mdx23 mice. ASD-like behaviour and electrophysiological findings in mdx52 mice were ameliorated by restoration of Dp140 following intra-cerebroventricular injection of antisense oligonucleotide drug-induced exon 53 skipping or intra-basolateral amygdala administration of Dp140 mRNA-based drug. Our results implicate Dp140 in ASD-like behaviour via altered glutamatergic transmission in the basolateral amygdala of mdx52 mice.
    Keywords:  Basolateral amygdala (BLA); Dp140; Duchenne muscular dystrophy (DMD); Dystrophin protein (Dp) isoforms; Neurotransmission; RNA therapy
  32. Front Biosci (Landmark Ed). 2022 May 05. 27(5): 143
      BACKGROUND: Exercise is associated with health benefits, including the prevention and management of obesity. However, heterogeneity in the adaptive response to exercise training exists. Our objective was to evaluate if changes in extracellular vesicles (EVs) after acute aerobic exercise were associated with the responder phenotype following 6-weeks of resistance training (RT).METHODS: This is a secondary analysis of plasma samples from the EXIT trial (clinical trial#02204670). Eleven sedentary youth with obesity (15.7 ± 0.5 yrs, BMI ≥95th percentile) underwent acute exercise (60% HRR, 45 min). Blood was collected at baseline [AT0 min], during [AT15-45 min], and 75 min post-recovery [AT120], and EVs purified using size exclusion chromatography from extracted plasma. Afterward, youth participated in 6-weeks RT and were categorized into responders or non-responders based on changes in insulin sensitivity.
    RESULTS: We assessed EV biophysical profile (size, zeta potential, protein yield, and EV subtype protein expression) in a single-blind fashion. Overall, there was a general increase in EV production in both groups. Average EV size was larger in responders (~147 nm) vs. non-responders (~124 nm; p < 0.05). EV size was positively associated with absolute change in Matsuda index (insulin sensitivity) following RT (r = 0.44, p = 0.08). EV size distribution revealed responders predominantly expressed EVs sized 150-300 nm, whereas non-responders expressed EVs sized 50-150 nm (p < 0.05). At baseline, responders had ~25% lower TSG101, ~85% higher MMP2 levels. EV protein yield was higher in responders than non-responders at AT15 (p < 0.05).
    CONCLUSIONS: Our data suggest that youth with obesity that respond to RT produce larger EVs that are TSG101+ and CD63+, with increased EV protein yield during acute exercise.
    Keywords:  acute exercise; extracellular vesicles; insulin sensitivity; obesity; resistance exercise training; responders to exercise; youth
  33. Front Oncol. 2022 ;12 848394
      Cancer cachexia is a disorder of energy balance characterized by the wasting of adipose tissue and skeletal muscle resulting in severe weight loss with profound influence on morbidity and mortality. Treatment options for cancer cachexia are still limited. This multifactorial syndrome is associated with changes in several metabolic pathways in adipose tissue which is affected early in the course of cachexia. Adipose depots are involved in energy storage and consumption as well as endocrine functions. In this mini review, we discuss the metabolic reprogramming in all three types of adipose tissues - white, brown, and beige - under the influence of the tumor macro-environment. Alterations in adipose tissue lipolysis, lipogenesis, inflammation and adaptive thermogenesis of beige/brown adipocytes are highlighted. Energy-wasting circuits in adipose tissue impacts whole-body metabolism and particularly skeletal muscle. Targeting of key molecular players involved in the metabolic reprogramming may aid in the development of new treatment strategies for cancer cachexia.
    Keywords:  adipokines; adipose tissue; adipose tissue browning; cancer cachexia; inflammation; lipogenesis; lipolysis; non-shivering thermogenesis
  34. J Biol Chem. 2022 May 30. pii: S0021-9258(22)00534-8. [Epub ahead of print] 102093
      Autophagy is an essential cellular process involving degradation of superfluous or defective macromolecules and organelles as a form of homeostatic recycling. Initially proposed to be a 'bulk' degradation pathway, a more nuanced appreciation of selective autophagy pathways has developed in the literature in recent years. As a glycogen-selective autophagy process, 'glycophagy' is emerging as a key metabolic route of transport and delivery of glycolytic fuel substrate. Study of glycophagy is at an early stage. Enhanced understanding of this major non-canonical pathway of glycogen flux will provide important opportunities for new insights into cellular energy metabolism. In addition, glycogen metabolic mishandling is centrally involved in the pathophysiology of several metabolic diseases in a wide range of tissues, including liver, skeletal muscle, cardiac muscle, and brain. Thus, advances in this exciting new field are of broad multi-disciplinary interest relevant to many cell types and metabolic states. Here, we review the current evidence of glycophagy involvement in homeostatic cellular metabolic processes and of molecular mediators participating in glycophagy flux, We integrate information from a variety of settings including cell lines, primary cell culture systems, ex vivo tissue preparations, genetic disease models and clinical glycogen disease states.
    Keywords:  Atg8; Gabarapl1; Stbd1; autophagy; glycogen; glycophagy; lysosome