bims-moremu Biomed News
on Molecular regulators of muscle mass
Issue of 2021‒07‒25
forty papers selected by
Anna Vainshtein
Craft Science Inc.

  1. Biochem Biophys Res Commun. 2021 Jul 15. pii: S0006-291X(21)01018-4. [Epub ahead of print]570 96-102
      Glucocorticoids are known to induce skeletal muscle atrophy by suppressing protein synthesis and promoting protein degradation. Tauroursodeoxycholic acid (TUDCA) has beneficial effects in several diseases, such as hepatobiliary disorders, hindlimb ischemia and glucocorticoid-induced osteoporosis. However, the effects of TUDCA on glucocorticoid -induced skeletal muscle atrophy remains unknown. Therefore, in the present research, we explored the effects of TUDCA on dexamethasone (DEX)-induced loss and the potential mechanisms involved. We found TUDCA alleviated DEX-induced muscle wasting in C2C12 myotubes, identified by improved myotube differentiation index and expression of myogenin and MHC. And it showed that TUDCA activated the Akt/mTOR/S6K signaling pathway and inhibited FoxO3a transcriptional activity to decreased expression of MuRF1 and Atrogin-1, while blocking Akt by MK2206 blocked these effects of TUDCA on myotubes. Besides, TUDCA also attenuated DEX-induced apoptosis of myotubes. Furthermore, TUDCA was administrated to the mouse model of DEX-induced skeletal muscle atrophy. The results showed that TUDCA improved DEX-induced skeletal muscle atrophy and weakness (identified by increased grip strength and prolonged running exhaustive time) in mice by suppression of apoptosis, reduction of protein degradation and promotion of protein synthesis. Taken together, our research proved for the first time that TUDCA protected against DEX-induced skeletal muscle atrophy not only by improving myogenic differentiation and protein synthesis, but also through decreasing protein degradation and apoptosis of skeletal muscle.
    Keywords:  AKT; Apoptosis; Dexamethasone; Skeletal muscle atrophy; Tauroursodeoxycholic acid
  2. Front Cell Neurosci. 2021 ;15 663384
      Denervation can activate the catabolic pathway in skeletal muscle and lead to progressive skeletal muscle atrophy. At present, there is no effective treatment for muscle atrophy. Histone deacetylase 4 (HDAC4) has recently been found to be closely related to muscle atrophy, but the underlying mechanism of HDAC4 in denervation-induced muscle atrophy have not been described clearly yet. In this study, we found that the expression of HDAC4 increased significantly in denervated skeletal muscle. HDAC4 inhibition can effectively diminish denervation-induced muscle atrophy, reduce the expression of muscle specific E3 ubiquitin ligase (MuRF1 and MAFbx) and autophagy related proteins (Atg7, LC3B, PINK1 and BNIP3), inhibit the transformation of type I fibers to type II fibers, and enhance the expression of SIRT1 and PGC-1 α. Transcriptome sequencing and bioinformatics analysis was performed and suggested that HDAC4 may be involved in denervation-induced muscle atrophy by regulating the response to denervation involved in the regulation of muscle adaptation, cell division, cell cycle, apoptotic process, skeletal muscle atrophy, and cell differentiation. STRING analysis showed that HDAC4 may be involved in the process of muscle atrophy by directly regulating myogenin (MYOG), cell cycle inhibitor p21 (CDKN1A) and salt induced kinase 1 (SIK1). MYOG was significantly increased in denervated skeletal muscle, and MYOG inhibition could significantly alleviate denervation-induced muscle atrophy, accompanied by the decreased MuRF1 and MAFbx. MYOG overexpression could reduce the protective effect of HDAC4 inhibition on denervation-induced muscle atrophy, as evidenced by the decreased muscle mass and cross-sectional area of muscle fibers, and the increased mitophagy. Taken together, HDAC4 inhibition can alleviate denervation-induced muscle atrophy by reducing MYOG expression, and HDAC4 is also directly related to CDKN1A and SIK1 in skeletal muscle, which suggests that HDAC4 inhibitors may be a potential drug for the treatment of neurogenic muscle atrophy. These results not only enrich the molecular regulation mechanism of denervation-induced muscle atrophy, but also provide the experimental basis for HDAC4-MYOG axis as a new target for the prevention and treatment of muscular atrophy.
    Keywords:  CDKN1A; HDAC4; SIK1; muscle atrophy; myogenin
  3. J Clin Invest. 2021 Jul 20. pii: 143737. [Epub ahead of print]
      Skeletal muscle can undergo a regenerative process from injury or disease to preserve muscle mass and function, which is critically influenced by cellular stress responses. Inositol-requiring enzyme 1 (IRE1) is an ancient endoplasmic reticulum (ER) stress sensor and mediates a key branch of the unfolded protein response (UPR). In mammals, IRE1α is implicated in the homeostatic control of stress responses during tissue injury and regeneration. Here, we show that IRE1α serves as a myogenic regulator in skeletal muscle regeneration in response to injury and muscular dystrophy. We found in mice that IRE1α was activated during injury-induced muscle regeneration, and muscle-specific IRE1α ablation resulted in impaired regeneration upon cardiotoxin-induced injury. Gain- and loss-of-function studies in myocytes demonstrated that IRE1αacts to sustain both differentiation in myoblasts and hypertrophy in myotubes through regulated IRE1-dependent decay (RIDD) of mRNA encoding Myostatin, a key negative regulator of muscle repair and growth. Furthermore, in the mouse model of Duchenne muscular dystrophy (DMD), loss of muscle IRE1α resulted in augmented Myostatin signaling and exacerbated the dystrophic phenotypes. Thus, these results reveal a pivotal role for the RIDD output of IRE1α in muscle regeneration, offering new insight into potential therapeutic strategies for muscle loss diseases.
    Keywords:  Cell stress; Molecular pathology; Muscle Biology; Skeletal muscle
  4. Nutr Res. 2021 Jun 24. pii: S0271-5317(21)00036-1. [Epub ahead of print]92 99-108
      A large number of studies have shown that polyphenols can regulate skeletal muscle fiber type transformation through AMPK signal. However, the effects and mechanism of naringin (a natural polyphenol) on muscle fiber type transformation still remains unclear. Thus, we hypothesized that naringin would induce the transformation of skeletal muscle fibers from type II to type I by AMPK signaling. C2C12 myotubes and BALB/c mice models were used to test this hypothesis. We found that naringin significantly increased the protein expression of slow myosin heavy chain (MyHC), myoglobin and troponin I type I slow skeletal (Troponin I-SS) and the activities of succinate dehydrogenase (SDH) and malate dehydrogenase (MDH), and significantly decreased fast MyHC protein expression and lactate dehydrogenase (LDH) activity, accompanied by the activation of AMPK and the activity of peroxisome proliferator activated receptor-γ coactivator-1α (PGC-1α) in mice and C2C12 myotubes. Further inhibition of AMPK activity by compound C showed that the above effects were significantly inhibited in C2C12 myotubes. In conclusion, naringin promotes the transformation of skeletal muscle fibers from type II to type I through AMPK/PGC-1α signaling pathway, which not only enriches the nutritional and physiological functions of naringin, but also provides a theoretical basis for the regulation of muscle fiber type transformation by nutritional approaches.
    Keywords:  AMPK/PGC-1α signaling pathway; C2C12 myotubes; Mice; Naringin; Skeletal muscle fiber type
  5. Int J Mol Sci. 2021 Jul 06. pii: 7282. [Epub ahead of print]22(14):
      Skeletal muscle has an outstanding capacity for regeneration in response to injuries, but there are disorders in which this process is seriously impaired, such as sarcopenia. Pharmacological treatments to restore muscle trophism are not available, therefore, the identification of suitable therapeutic targets that could be useful for the treatment of skeletal reduced myogenesis is highly desirable. In this in vitro study, we explored the expression and function of the calcium-sensing receptor (CaSR) in human skeletal muscle tissues and their derived satellite cells. The results obtained from analyses with various techniques of gene and protein CaSR expression and of its secondary messengers in response to calcium (Ca2+) and CaSR drugs have demonstrated that this receptor is not present in human skeletal muscle tissues, neither in the established satellite cells, nor during in vitro myogenic differentiation. Taken together, our data suggest that, although CaSR is a very important drug target in physiology and pathology, this receptor probably does not have any physiological role in skeletal muscle in normal conditions.
    Keywords:  G protein-coupled receptors; calcium-sensing receptor; myogenesis; satellite cells; skeletal muscle
  6. J Cell Sci. 2021 Jul 15. pii: jcs256388. [Epub ahead of print]134(14):
      Skeletal muscle myofibers are large and elongated cells with multiple and evenly distributed nuclei. Nuclear distribution suggests that each nucleus influences a specific compartment within the myofiber and implies a functional role for nuclear positioning. Compartmentalization of specific mRNAs and proteins has been reported at the neuromuscular and myotendinous junctions, but mRNA distribution in non-specialized regions of the myofibers remains largely unexplored. We report that the bulk of mRNAs are enriched around the nucleus of origin and that this perinuclear accumulation depends on recently transcribed mRNAs. Surprisingly, mRNAs encoding large proteins - giant mRNAs - are spread throughout the cell and do not exhibit perinuclear accumulation. Furthermore, by expressing exogenous transcripts with different sizes we found that size contributes to mRNA spreading independently of mRNA sequence. Both these mRNA distribution patterns depend on microtubules and are independent of nuclear dispersion, mRNA expression level and stability, and the characteristics of the encoded protein. Thus, we propose that mRNA distribution in non-specialized regions of skeletal muscle is size selective to ensure cellular compartmentalization and simultaneous long-range distribution of giant mRNAs.
    Keywords:  Compartmentalization; Multinucleation; Skeletal muscle; mRNA distribution; mRNA size; mRNA transport
  7. Front Physiol. 2021 ;12 696039
      Minocycline, a tetracycline-class of antibiotic, has been tested with mixed effectiveness on neuromuscular disorders such as amyotrophic lateral sclerosis, autoimmune neuritis and muscular dystrophy. The independent effect of minocycline on skeletal muscle force production and signalling remain poorly understood. Our aim here is to investigate the effects of minocycline on muscle mass, force production, myosin heavy chain abundance and protein synthesis. Mice were injected with minocycline (40 mg/kg i.p.) daily for 5 days and sacrificed at day six. Fast-twitch EDL, TA muscles and slow-twitch soleus muscles were dissected out, the TA muscle was snap-frozen and the remaining muscles were attached to force transducer whilst maintained in an organ bath. In C2C12 myotubes, minocycline was applied to the media at a final concentration of 10 μg/mL for 48 h. In minocycline treated mice absolute maximal force was lower in fast-twitch EDL while in slow-twitch soleus there was an increase in the time to peak and relaxation of the twitch. There was no effect of minocycline treatment on the other contractile parameters measured in isolated fast- and slow-twitch muscles. In C2C12 cultured cells, minocycline treatment significantly reduced both myosin heavy chain content and protein synthesis without visible changes to myotube morphology. In the TA muscle there was no significant changes in myosin heavy chain content. These results indicate that high dose minocycline treatment can cause a reduction in maximal isometric force production and mass in fast-twitch EDL and impair protein synthesis during myogenesis in C2C12 cultured cells. These findings have important implications for future studies investigating the efficacy of minocycline treatment in neuromuscular or other muscle-atrophy inducing conditions.
    Keywords:  C2C12 myotubes; minocycline; muscle force; protein production; skeletal muscle function
  8. JPEN J Parenter Enteral Nutr. 2021 Jul 22.
      Muscle wasting is common and persistent in severely burned patients, worsened by immobilization during treatment. In this review, we posit two major phenotypes of muscle wasting after severe burn, cachexia and sarcopenia, each with distinguishing characteristics to result in muscle atrophy; these characteristics are also likely present in other critically ill populations. An online search was conducted from the PubMed database and other available online resources and we manually extracted published articles in a systematic mini review. We describe the current definitions and characteristics of cachexia and sarcopenia and relate these to muscle wasting after severe burn. We then discuss these putative mechanisms of muscle atrophy in this condition. Severe burn and immobilization have distinctive patterns in mediating muscle wasting and muscle atrophy. In considering these two pathological phenotypes (cachexia and sarcopenia), we propose two independent principal causes and mechanisms of muscle mass loss after burns: 1) inflammation-induced cachexia leading to proteolysis and protein degradation, and 2) sarcopenia/immobility that signals inhibition of expected increases in protein synthesis in response to protein loss. Because both are present following severe burn, these should be considered independently in devising treatments. Discussing cachexia and sarcopenia as independent mechanisms of severe burn-initiated muscle wasting is explored. Recognition of these associated mechanisms will likely improve outcomes. This article is protected by copyright. All rights reserved.
    Keywords:  cachexia; immobilization; muscle atrophy; sarcopenia; thermal injury
  9. Cancers (Basel). 2021 Jul 19. pii: 3615. [Epub ahead of print]13(14):
      Cancer cachexia is a debilitating multi-factorial wasting syndrome characterised by severe skeletal muscle wasting and dysfunction (i.e., myopathy). In the oncology setting, cachexia arises from synergistic insults from both cancer-host interactions and chemotherapy-related toxicity. The majority of studies have surrounded the cancer-host interaction side of cancer cachexia, often overlooking the capability of chemotherapy to induce cachectic myopathy. Accumulating evidence in experimental models of cachexia suggests that some chemotherapeutic agents rapidly induce cachectic myopathy, although the underlying mechanisms responsible vary between agents. Importantly, we highlight the capacity of specific chemotherapeutic agents to induce cachectic myopathy, as not all chemotherapies have been evaluated for cachexia-inducing properties-alone or in clinically compatible regimens. Furthermore, we discuss the experimental evidence surrounding therapeutic strategies that have been evaluated in chemotherapy-induced cachexia models, with particular focus on exercise interventions and adjuvant therapeutic candidates targeted at the mitochondria.
    Keywords:  cachexia; chemotherapy; exercise therapy; mitoprotection; muscle wasting; myopathy; pharmaceutical adjuvants; skeletal muscle
  10. Biochem Biophys Res Commun. 2021 Jul 19. pii: S0006-291X(21)01076-7. [Epub ahead of print]570 184-190
      OBJECTIVE: Inflammation contributes to skeletal muscle atrophy via protein degradation induced by p38 mitogen-activated protein kinase (MAPK) phosphorylation. Meanwhile, pulsed ultrasound irradiation provides the mechanical stimulation to the target tissue, and has been reported to show anti-inflammatory effects. This study investigated the preventive effects of pulsed ultrasound irradiation on muscle atrophy induced by lipopolysaccharide (LPS) in C2C12 myotubes.METHODS: C2C12 myotubes were used in this research. The pulsed ultrasound (a frequency of 3 MHz, duty cycle of 20%, intensity of 0.5 W/cm2) was irradiated to myotube before LPS administration.
    RESULTS: The LPS increased phosphorylation of p38 MAPK and decreased the myofibril and myosin heavy chain protein (P < 0.05), followed by atrophy in C2C12 myotubes. The pulsed ultrasound irradiation attenuated p38 MAPK phosphorylation and myotube atrophy induced by LPS (P < 0.05).
    CONCLUSIONS: Pulsed ultrasound irradiation has the preventive effects on inflammation-induced muscle atrophy through inhibiting phosphorylation of p38 MAPK.
    Keywords:  C2C12 myotubes; Lipopolysaccharide; Muscle atrophy; Pulsed ultrasound irradiation; p38 MAPK
  11. Front Physiol. 2021 ;12 676265
      The role of microRNAs in metabolic diseases has been recognized and modulation of them could be a promising strategy to treat obesity and obesity-related diseases. The major purpose of this study was to test the hypothesis that intramuscular miR-1 precursor replacement therapy could improve metabolic parameters of mice fed a high-fat diet. To this end, we first injected miR-1 precursor intramuscularly in high-fat diet-fed mice and evaluated glucose tolerance, insulin sensitivity, and adiposity. miR-1-treated mice did not lose weight but had improved insulin sensitivity measured by insulin tolerance test. Next, using an in vitro model of insulin resistance by treating C2C12 cells with palmitic acid (PA), we overexpressed miR-1 and measured p-Akt content and the transcription levels of a protein related to fatty acid oxidation. We found that miR-1 could not restore insulin sensitivity in C2C12 cells, as indicated by p-Akt levels and that miR-1 increased expression of Pgc1a and Cpt1b in PA-treated cells, suggesting a possible role of miR-1 in mitochondrial respiration. Finally, we analyzed mitochondrial oxygen consumption in primary skeletal muscle cells treated with PA and transfected with or without miR-1 mimic. PA-treated cells showed reduced basal respiration, oxygen consumption rate-linked ATP production, maximal and spare capacity, and miR-1 overexpression could prevent impairments in mitochondrial respiration. Our data suggest a role of miR-1 in systemic insulin sensitivity and a new function of miR-1 in regulating mitochondrial respiration in skeletal muscle.
    Keywords:  high-fat diet; microRNA; mitochondrial dysfunction; obesity; skeletal muscle
  12. Pak J Pharm Sci. 2021 Jan;34(1(Special)): 447-455
      By analyzing the effects of P53 inhibitors and ladder climbing exercise on P53 mRNA transcription in skeletal muscle of mice, the application of P53 mRNA in signal transduction mechanism of skeletal muscle cells was studied. Several clean ICR mice were fed for experiment. The experimental mice were divided into groups to analyze the effect of P53 inhibitor on P53 mRNA transcription in gastrocnemius muscle of mice. The mice were randomly divided into The application of P53 mRNA in signal transduction mechanism of skeletal muscle cells was studied, and the corresponding endurance exercise program and ladder climbing training program were designed. According to the research, exercise is to some extent a stimulating factor affecting P53 inhibitor. Endurance training and injection of P53 inhibitor affect P53 mRNA content. Exercise has a benign effect on ICR mice injected with P53 inhibitor. The expression of P53 mRNA in skeletal muscle was significantly affected by climbing training in youth, and decreased by climbing training in old age. However, there was no difference between long-term climbing training and short-term climbing training in the expression of P53 mRNA in skeletal muscle.
  13. Nucleic Acids Res. 2021 Jul 21. pii: gkab617. [Epub ahead of print]
      Skeletal muscle regeneration is mediated by myoblasts that undergo epigenomic changes to establish the gene expression program of differentiated myofibers. mSWI/SNF chromatin remodeling enzymes coordinate with lineage-determining transcription factors to establish the epigenome of differentiated myofibers. Bromodomains bind to acetylated lysines on histone N-terminal tails and other proteins. The mutually exclusive ATPases of mSWI/SNF complexes, BRG1 and BRM, contain bromodomains with undefined functional importance in skeletal muscle differentiation. Pharmacological inhibition of mSWI/SNF bromodomain function using the small molecule PFI-3 reduced differentiation in cell culture and in vivo through decreased myogenic gene expression, while increasing cell cycle-related gene expression and the number of cells remaining in the cell cycle. Comparative gene expression analysis with data from myoblasts depleted of BRG1 or BRM showed that bromodomain function was required for a subset of BRG1- and BRM-dependent gene expression. Reduced binding of BRG1 and BRM after PFI-3 treatment showed that the bromodomain is required for stable chromatin binding at target gene promoters to alter gene expression. Our findings demonstrate that mSWI/SNF ATPase bromodomains permit stable binding of the mSWI/SNF ATPases to promoters required for cell cycle exit and establishment of muscle-specific gene expression.
  14. Gene. 2021 Jul 16. pii: S0378-1119(21)00431-5. [Epub ahead of print] 145836
      Skeletal muscle atrophy can result from a range of physiological conditions, including denervation, immobilization, hindlimb unweighting, and aging. To better characterize the molecular genetic events of atrophy, a microarray analysis revealed that FGGY carbohydrate kinase domain containing (Fggy) is expressed in skeletal muscle and is induced in response to denervation. Bioinformatic analysis of the Fggy gene locus revealed two validated isoforms with alternative transcription initiation sites that we have designated Fggy-L-552 and Fggy-S-387. Additionally, we cloned two novel alternative splice variants, designated Fggy-L-482 and Fggy-S-344, from cultured muscle cells suggesting that at least four Fggy splice variants are expressed in skeletal muscle. Quantitative RT-PCR was performed using RNA isolated from muscle cells and primers designed to distinguish the four alternative Fggy transcripts and found that the Fggy-L transcripts are more highly expressed during myoblast differentiation, while the Fggy-S transcripts show relatively stable expression in proliferating myoblasts and differentiated myotubes. Confocal fluorescent microscopy revealed that the Fggy-L variants appear to localize evenly throughout the cytoplasm, while the Fggy-S variants produce a more punctuate cytoplasmic localization pattern in proliferating muscle cells. Finally, ectopic expression of Fggy-L-552 and Fggy-S-387 resulted in inhibition of muscle cell differentiation and attenuation of the MAP kinase and Akt signaling pathways. The identification and characterization of novel genes such as Fggy helps to improve our understanding of the molecular and cellular events that lead to atrophy and may eventually result in the identification of new therapeutic targets for the treatment of muscle wasting.
    Keywords:  Akt; Erk1/2; Fggy carbohydrate kinase domain containing; atrophy; skeletal muscle
  15. Endocrinol Diabetes Metab. 2021 Jul;4(3): e00253
      Aim: Heparin, a widely used antithrombotic drug has many other anticoagulant-independent physiological functions. Here, we elucidate a novel role of heparin in glucose homeostasis, suggesting an approach for developing heparin-targeted therapies for diabetes.Methods: For serum heparin levels and correlation analysis, 122 volunteer's plasma, DIO (4 weeks HFD) and db/db mice serums were collected and used for spectrophotometric determination. OGTT, ITT, 2-NBDG uptake and muscle GLUT4 immunofluorescence were detected in chronic intraperitoneal injection of heparin or heparinase (16 days) and muscle-specific loss-of-function mice. In 293T cells, the binding of insulin to its receptor was detected by fluorescence resonance energy transfer (FRET), Myc-GLUT4-mCherry plasmid was used in GLUT4 translocation. In vitro, C2C12 cells as mouse myoblast cells were further verified the effects of heparin on glucose homeostasis through 2-NBDG uptake, Western blot and co-immunoprecipitation.
    Results: Serum concentrations of heparin are positively associated with blood glucose levels in humans and are significantly increased in diet-induced and db/db obesity mouse models. Consistently, a chronic intraperitoneal injection of heparin results in hyperglycaemia, glucose intolerance and insulin resistance. These effects are independent of heparin's anticoagulant function and associated with decreases in glucose uptake and translocation of glucose transporter type 4 (GLUT4) in skeletal muscle. By using a muscle-specific loss-of-function mouse model, we further demonstrated that muscle GLUT4 is required for the detrimental effects of heparin on glucose homeostasis.
    Conclusions: Heparin reduced insulin binding to its receptor by interacting with insulin and inhibited insulin-mediated activation of the PI3K/Akt signalling pathway in skeletal muscle, which leads to impaired glucose uptake and hyperglycaemia.
    Keywords:  GLUT4 activity; heparin; hyperglycaemia; insulin resistance; muscle glucose uptake
  16. Int J Mol Sci. 2021 Jul 08. pii: 7349. [Epub ahead of print]22(14):
      Mitochondrial dysfunction is considered the major contributor to skeletal muscle wasting in different conditions. Genetically determined neuromuscular disorders occur as a result of mutations in the structural proteins of striated muscle cells and therefore are often combined with cardiac phenotype, which most often manifests as a cardiomyopathy. The specific roles played by mitochondria and mitochondrial energetic metabolism in skeletal muscle under muscle-wasting conditions in cardiomyopathies have not yet been investigated in detail, and this aspect of genetic muscle diseases remains poorly characterized. This review will highlight dysregulation of mitochondrial representation and bioenergetics in specific skeletal muscle disorders caused by mutations that disrupt the structural and functional integrity of muscle cells.
    Keywords:  cardiomyopathies; mitochondrial dysfunction; neuromuscular disorders
  17. Geroscience. 2021 Jul 20.
      Skeletal muscle mass losses with age are associated with negative health consequences, including an increased risk of developing metabolic disease and the loss of independence. Athletes adopt numerous nutritional strategies to maximize the benefits of exercise training and enhance recovery in pursuit of improving skeletal muscle quality, mass, or function. Importantly, many of the principles applied to enhance skeletal muscle health in athletes may be applicable to support active aging and prevent sarcopenia in the healthy (non-clinical) aging population. Here, we discuss the anabolic properties of protein supplementation in addition to ingredients that may enhance the anabolic effects of protein (e.g. omega 3 s, creatine, inorganic nitrate) in older persons. We conclude that nutritional strategies used in pursuit of performance enhancement in athletes are often applicable to improve skeletal muscle health in the healthy older population when implemented as part of a healthy active lifestyle. Further research is required to elucidate the mechanisms by which these nutrients may induce favourable changes in skeletal muscle and to determine the appropriate dosing and timing of nutrient intakes to support active aging.
    Keywords:  Carbohydrate periodization; Creatine; Protein; Skeletal muscle; n-3PUFA
  18. Stem Cells Transl Med. 2021 Jul 22.
      Duchenne muscular dystrophy (DMD) is a progressive and lethal disease, caused by X-linked mutations of the dystrophin encoding gene. The lack of dystrophin leads to muscle weakness, degeneration, fibrosis, and progressive loss of skeletal, cardiac, and respiratory muscle function resulting in premature death due to the cardiac and respiratory failure. There is no cure for DMD and current therapies neither cure nor arrest disease progression. Thus, there is an urgent need to develop new approaches and safer therapies for DMD patients. We have previously reported functional improvements which correlated with increased dystrophin expression following transplantation of dystrophin expressing chimeric (DEC) cells of myoblast origin to the mdx mouse models of DMD. In this study, we demonstrated that systemic-intraosseous transplantation of DEC human cells derived from myoblasts of normal and DMD-affected donors, increased dystrophin expression in cardiac, respiratory, and skeletal muscles of the mdx/scid mouse model of DMD. DEC transplant correlated with preservation of ejection fraction and fractional shortening on echocardiography, improved respiratory function on plethysmography, and improved strength and function of the limb skeletal muscles. Enhanced function was associated with improved muscle histopathology, revealing reduced mdx pathology, fibrosis, decreased inflammation, and preserved muscle morphology and architecture. Our findings confirm that DECs generate a systemic protective effect in DMD-affected target organs. Therefore, DECs represents a novel therapeutic approach with the potential to preserve or enhance multiorgan function of the skeletal, cardiac, and respiratory muscles critical for the well-being of DMD patients.
    Keywords:  DEC therapy; Duchenne muscular dystrophy; cardiac protection/function; cellular therapy; dystrophin expressing chimeric cells; muscle regeneration; myoblasts; pulmonary protection/function
  19. Int J Mol Sci. 2021 Jul 05. pii: 7228. [Epub ahead of print]22(13):
      Urinary acrolein adduct levels have been reported to be increased in both habitual smokers and type-2 diabetic patients. The impairment of glucose transport in skeletal muscles is a major factor responsible for glucose uptake reduction in type-2 diabetic patients. The effect of acrolein on glucose metabolism in skeletal muscle remains unclear. Here, we investigated whether acrolein affects muscular glucose metabolism in vitro and glucose tolerance in vivo. Exposure of mice to acrolein (2.5 and 5 mg/kg/day) for 4 weeks substantially increased fasting blood glucose and impaired glucose tolerance. The glucose transporter-4 (GLUT4) protein expression was significantly decreased in soleus muscles of acrolein-treated mice. The glucose uptake was significantly decreased in differentiated C2C12 myotubes treated with a non-cytotoxic dose of acrolein (1 μM) for 24 and 72 h. Acrolein (0.5-2 μM) also significantly decreased the GLUT4 expression in myotubes. Acrolein suppressed the phosphorylation of glucose metabolic signals IRS1, Akt, mTOR, p70S6K, and GSK3α/β. Over-expression of constitutive activation of Akt reversed the inhibitory effects of acrolein on GLUT4 protein expression and glucose uptake in myotubes. These results suggest that acrolein at doses relevant to human exposure dysregulates glucose metabolism in skeletal muscle cells and impairs glucose tolerance in mice.
    Keywords:  Akt; acrolein; glucose metabolism; glucose transporter; skeletal muscle
  20. Int J Mol Sci. 2021 Jul 15. pii: 7588. [Epub ahead of print]22(14):
      Despite the intensive investigation of the molecular mechanism of skeletal muscle hypertrophy, the underlying signaling processes are not completely understood. Therefore, we used an overload model, in which the main synergist muscles (gastrocnemius, soleus) of the plantaris muscle were surgically removed, to cause a significant overload in the remaining plantaris muscle of 8-month-old Wistar male rats. SIRT1-associated pro-anabolic, pro-catabolic molecular signaling pathways, NAD and H2S levels of this overload-induced hypertrophy were studied. Fourteen days of overload resulted in a significant 43% (p < 0.01) increase in the mass of plantaris muscle compared to sham operated animals. Cystathionine-β-synthase (CBS) activities and bioavailable H2S levels were not modified by overload. On the other hand, overload-induced hypertrophy of skeletal muscle was associated with increased SIRT1 (p < 0.01), Akt (p < 0.01), mTOR, S6 (p < 0.01) and suppressed sestrin 2 levels (p < 0.01), which are mostly responsible for anabolic signaling. Decreased FOXO1 and SIRT3 signaling (p < 0.01) suggest downregulation of protein breakdown and mitophagy. Decreased levels of NAD+, sestrin2, OGG1 (p < 0.01) indicate that the redox milieu of skeletal muscle after 14 days of overloading is reduced. The present investigation revealed novel cellular interactions that regulate anabolic and catabolic processes in the hypertrophy of skeletal muscle.
    Keywords:  anabolic signaling pathways; overload-induced hypertrophy; redox regulation; skeletal muscle
  21. Curr Biol. 2021 Jul 10. pii: S0960-9822(21)00881-2. [Epub ahead of print]
      Skeletal muscle contraction depends on activation of clustered acetylcholine receptors (AchRs) and muscle-specific Na+ channels (Nav1.4). Some Nav1.4 channels are highly enriched at the neuromuscular junction (NMJ), and their clustering is thought to be essential for effective muscle excitation. However, this has not been experimentally tested, and how NMJ Na+ channels are clustered is unknown. Here, using muscle-specific ankyrinR, ankyrinB, and ankyrinG single, double, and triple-conditional knockout mice, we show that Nav1.4 channels fail to cluster only after deletion of all three ankyrins. Remarkably, ankyrin-deficient muscles have normal NMJ morphology, AchR clustering, sarcolemmal levels of Nav1.4, and muscle force, and they show no indication of degeneration. However, mice lacking clustered NMJ Na+ channels have significantly reduced levels of motor activity and their NMJs rapidly fatigue after repeated nerve-dependent stimulation. Thus, the triple redundancy of ankyrins facilitates NMJ Na+ channel clustering to prevent neuromuscular synapse fatigue.
    Keywords:  cytoskeleton; ion channel; neuromuscular junction; scaffold
  22. Biofabrication. 2021 Jul 20.
      Three-dimensional engineering of skeletal muscle is becoming increasingly relevant for tissue engineering, disease modeling and bio-hybrid robotics, where flexible, versatile and multidisciplinary approaches for the evaluation of tissue differentiation, functionality and force measurement are required. This works presents a 3D-printed platform of bioengineered human skeletal muscle which can efficiently model the three-dimensional structure of native tissue, while providing information about force generation and contraction profiles. Proper differentiation and maturation of myocytes is demonstrated by the expression of key myo-proteins using immunocytochemistry and analyzed by confocal microscopy, and the functionality assessed via electrical stimulation and analysis of contraction kinetics. To validate the flexibility of this platform for complex tissue modelling, the bioengineered muscle is treated with tumor necrosis factor α to mimic the conditions of aging, which is supported by morphological and functional changes. Moreover, as a proof of concept, the effects of Argireline® Amplified peptide, a cosmetic ingredient that causes muscle relaxation, are evaluated in both healthy and aged tissue models. Therefore, the results demonstrate that this 3D-bioengineered human muscle platform could be used to assess morphological and functional changes in the aging process of muscular tissue with potential applications in biomedicine, cosmetics and bio-hybrid robotics.
    Keywords:  3D bioprinting; bio-actuator; drug testing; human skeletal muscle; muscle ageing
  23. Int J Mol Sci. 2021 Jul 02. pii: 7175. [Epub ahead of print]22(13):
      Thyroid hormones (THs) are key regulators of different biological processes. Their action involves genomic and non-genomic mechanisms, which together mediate the final effects of TH in target tissues. However, the proportion of the two processes and their contribution to the TH-mediated effects are still poorly understood. Skeletal muscle is a classical target tissue for TH, which regulates muscle strength and contraction, as well as energetic metabolism of myofibers. Here we address the different contribution of genomic and non-genomic action of TH in skeletal muscle cells by specifically silencing the deiodinase Dio2 or the β3-Integrin expression via CRISPR/Cas9 technology. We found that myoblast proliferation is inversely regulated by integrin signal and the D2-dependent TH activation. Similarly, inhibition of the nuclear receptor action reduced myoblast proliferation, confirming that genomic action of TH attenuates proliferative rates. Contrarily, genomic and non-genomic signals promote muscle differentiation and the regulation of the redox state. Taken together, our data reveal that integration of genomic and non-genomic signal pathways finely regulates skeletal muscle physiology. These findings not only contribute to the understanding of the mechanisms involved in TH modulation of muscle physiology but also add insight into the interplay between different mechanisms of action of TH in muscle cells.
    Keywords:  deiodinase; genomic and non-genomic action; thyroid hormone
  24. Front Physiol. 2021 ;12 697121
      DNA methylation is a key epigenetic mechanism involved in embryonic muscle development and plays an important role in early muscle development. In this study, we sought to investigate the effects of genome-wide DNA methylation by combining the expression profiles of the chicken embryonic muscle. Genome-wide DNA methylation maps and transcriptomes of muscle tissues collected from different embryonic development points (E7, E11, E17, and D1) were used for whole-genome bisulfite sequencing (WGBS) and RNA sequencing, respectively. We found that the differentially methylated genes (DMGs) were significantly associated with muscle organ development, regulation of skeletal muscle satellite cell proliferation, and actin filament depolymerization. Furthermore, genes TBX1, MEF2D, SPEG, CFL2, and TWF2 were strongly correlated with the methylation-caused expression switch. Therefore, we chose the CFL2 gene to explore its function in skeletal muscle satellite cells, and the in vitro experiments showed that CFL2 acts as a negative regulator of chicken skeletal muscle satellite cell proliferation and can induce cell apoptosis. These results provide valuable data for future genome and epigenome studies of chicken skeletal muscle and may help reveal the molecular mechanisms of potential economic traits.
    Keywords:  DNA methylation; chicken; embryonic; muscle development; transcriptome
  25. J Neuromuscul Dis. 2021 Jul 10.
      BACKGROUND: Duchenne muscular dystrophy is a degenerative muscle disease that results from impairment of the dystrophin gene. The disease causes progressive loss in muscle mass and function.OBJECTIVE: The anti-aging protein, α-klotho, has been implicated in the regulation of muscle regeneration. We previously discovered that mice harboring reduced α-klotho levels exhibited a decline in muscle strength and running endurance.
    METHOD: To investigate the ability of α-klotho to improve overall endurance in a dystrophin null murine model, we examined the voluntary wheel running performance of dystrophin-null, mdx4cv mice overexpressing an α-klotho transgene.
    RESULTS: As expected, compared to wild type, both male and female dystrophic mice exhibited reduced running ability that was characterized by shorter running duration and longer periods of rest between cycles of activity. While our results did not detect an improvement in running performance with α-klotho overexpression, we identified distinct differences in the running patterns between females and males from all mouse strains analyzed (i.e., mdx4cv, mdx4cv overexpressing α-klotho, α-klotho overexpressing, α-klotho hypomorph, and wild type). For all strains, male mice displayed significantly reduced voluntary running ability compared to females. Further analysis of the mdx4cv strains demonstrated that male mice ran for shorter lengths of time and took longer breaks. However, we did not identify gender-associated differences in the actual speed at which mdx4cv mice ran.
    CONCLUSION: Our data suggest key differences in the running capabilities of female and male mice, which are of particularly relevant to studies of dystrophin-null mice.
    Keywords:  Running wheel; mdx; mdx4cv; α-klotho
  26. J Appl Physiol (1985). 2021 07 22.
      Muscle atrophy occurs as a result of prolonged periods of reduced mechanical stimulation associated with injury or disease. The growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis and load sensing pathways can both aid in recovery from disuse through their shared downstream signaling, but their relative contributions to these processes are not fully understood. The goal of this study was to determine if reduced muscle IGF-1 altered the response to disuse and reloading. Adult male mice with inducible muscle-specific IGF-1 deletion (MID) induced 1 week before suspension and age-matched controls (CON) were subjected to hindlimb suspension and reloading. Analysis of muscle force, morphology, gene expression, signaling, and tissue weights were performed in non-suspended mice, and those suspended for 7 days, or reloaded following suspension for 3-, 7-, and 14 days. MID mice displayed diminished IGF-1 protein levels and muscle atrophy prior to suspension. Muscles from suspended CON mice displayed a similar extent of atrophy and depletion of IGF-1, yet combined loss of load and IGF-1 was not additive with respect to muscle mass. In contrast, soleus force generation capacity was diminished to the greatest extent when both suspension and IGF-1 deletion occurred. Recovery of mass, force, and gene expression patterns following suspension were similar in CON and MID mice, even though IGF-1 levels increased only in muscles from CON mice. Diminished strength in disuse atrophy is exacerbated with the loss of muscle IGF-1 production, whereas recovery of mass and strength upon reloading can occur even IGF-1 is low.
    Keywords:  Atrogenes; Disuse Atrophy; IGF-1; Muscle
  27. PLoS One. 2021 ;16(7): e0255006
      Fish muscle growth is a complex process regulated by multiple pathways, resulting on the net accumulation of proteins and the activation of myogenic progenitor cells. Around 350-320 million years ago, teleost fish went through a specific whole genome duplication (WGD) that expanded the existent gene repertoire. Duplicated genes can be retained by different molecular mechanisms such as subfunctionalization, neofunctionalization or redundancy, each one with different functional implications. While the great majority of ohnolog genes have been identified in the teleost genomes, the effect of gene duplication in the fish physiology is still not well characterized. In the present study we studied the effect of WGD on the transcription of the duplicated components controlling muscle growth. We compared the expression of lineage-specific ohnologs related to myogenesis and protein balance in the fast-skeletal muscle of pacus (Piaractus mesopotamicus-Ostariophysi) and Nile tilapias (Oreochromis niloticus-Acanthopterygii) fasted for 4 days and refed for 3 days. We studied the expression of 20 ohnologs and found that in the great majority of cases, duplicated genes had similar expression profiles in response to fasting and refeeding, indicating that their functions during growth have been conserved during the period after the WGD. Our results suggest that redundancy might play a more important role in the retention of ohnologs of regulatory pathways than initially thought. Also, comparison to non-duplicated orthologs showed that it might not be uncommon for the duplicated genes to gain or loss new regulatory elements simultaneously. Overall, several of duplicated ohnologs have similar transcription profiles in response to pro-growth signals suggesting that evolution tends to conserve ohnolog regulation during muscle development and that in the majority of ohnologs related to muscle growth their functions might be very similar.
  28. Integr Cancer Ther. 2021 Jan-Dec;20:20 15347354211035442
      PURPOSE: Prostate cancer survivors (PCS) receive androgen deprivation therapy (ADT) as treatment for recurrent cancer, yet ADT is associated with loss of skeletal muscle and physical function. Resistance training can counter both muscle and physical function loss; however, an understanding of the molecular responses of skeletal muscle to resistance training during ADT is still undefined. This sub-analysis of the original randomized, controlled pilot trial investigated effects of 12 weeks of periodized resistance training on mRNA expression of the anabolic genes IGF-1, myogenin, PGC-1α4 and the catabolic genes myostatin and MuRF-1 in skeletal muscle of PCS on ADT. Secondary aims investigated if changes in lean mass and physical function correlated with changes in mRNA expression.METHODS: PCS on ADT (n = 17) were randomized to 12 weeks of supervised resistance training (EXE, n = 9) or home-based stretching (STRETCH, n = 8) 3 days per week. Outcomes were assessed at baseline and post-intervention. Muscle biopsies were analyzed by RT-PCR for mRNA expression. Body composition was assessed through dual-energy X-ray absorptiometry, and physical function through muscular strength, timed up and go, stair climb, and 400 m walk.
    RESULTS: MuRF-1 mRNA expression was significantly greater in EXE compared to STRETCH post-intervention (P = .005). Change in MuRF-1 mRNA expression significantly correlated with improvements in strength and physical function (P < .05), while change in IGF-1 expression correlated with change in lean mass (P = .015).
    CONCLUSION: Twelve weeks of resistance training increased mRNA expression of MuRF-1 in skeletal muscle of PCS on ADT. Elevations in resting mRNA expression of IGF-1, myogenin and PGC-1α4, and reduction in mRNA expression of myostatin that are typically expected following resistance training were not observed.
    Keywords:  gene expression; prostate cancer; sarcopenia; strength training
  29. APL Bioeng. 2021 Sep;5(3): 036101
      To develop effective cures for neuromuscular diseases, human-relevant in vitro models of neuromuscular tissues are critically needed to probe disease mechanisms on a cellular and molecular level. However, previous attempts to co-culture motor neurons and skeletal muscle have resulted in relatively immature neuromuscular junctions (NMJs). In this study, NMJs formed by human induced pluripotent stem cell (hiPSC)-derived motor neurons were improved by optimizing the maturity of the co-cultured muscle tissue. First, muscle tissues engineered from the C2C12 mouse myoblast cell line, cryopreserved primary human myoblasts, and freshly isolated primary chick myoblasts on micromolded gelatin hydrogels were compared. After three weeks, only chick muscle tissues remained stably adhered to hydrogels and exhibited progressive increases in myogenic index and stress generation, approaching values generated by native muscle tissue. After three weeks of co-culture with hiPSC-derived motor neurons, engineered chick muscle tissues formed NMJs with increasing co-localization of pre- and postsynaptic markers as well as increased frequency and magnitude of synaptic activity, surpassing structural and functional maturity of previous in vitro models. Engineered chick muscle tissues also demonstrated increased expression of genes related to sarcomere maturation and innervation over time, revealing new insights into the molecular pathways that likely contribute to enhanced NMJ formation. These approaches for engineering advanced neuromuscular tissues with relatively mature NMJs and interrogating their structure and function have many applications in neuromuscular disease modeling and drug development.
  30. J Mech Behav Biomed Mater. 2021 Jul 03. pii: S1751-6161(21)00347-7. [Epub ahead of print]122 104670
      Skeletal muscles ensure the mobility of mammals and are complex natural fiber-matrix-composites with a hierarchical microstructure. In this work, we analyze the muscle's mechanical behavior on the level of fascicles and muscle fibers. We introduce continuum mechanics hyperelastic material models for the connective tissue endomysium and the embedded muscle fibers. The coupled electrical, chemical and mechanical processes taking place in activated contracting muscle fibers are captured including the temporal change of the activation level and the spatial propagation of the activation potential in fibers. In our model, we investigate the material behavior of fascicle, fiber and endomysium in the fiber direction and examine interactions between muscle fiber and endomysium by considering the temporal and spatial change of muscle fiber activation. In addition, a loading case of normal and shear forces is applied to analyze the fiber lifting force and the lifting height of unipennate muscles with different pennation angles. Moreover, the development of local stresses and strains in fibers and endomysium for different strains are studied. The simulation results allow to identify regions in high risk of damage. Optimal arrangements of unipennate muscle microstructure are found for either very small or very large pennation angles.
    Keywords:  Electromechanical coupling; Extensor digitorum longus; Finite element method; Multiscale modeling; Skeletal muscle; Unipennate muscles
  31. Front Neurol. 2021 ;12 649452
      Regular exercise plays an essential role in maintaining healthy neurocognitive function and central nervous system (CNS) immuno-metabolism in the aging CNS. Physical activity decreases the risk of developing Alzheimer's Disease (AD), is associated with better AD prognosis, and positively affects cognitive function in AD patients. Skeletal muscle is an important secretory organ, communicating proteotoxic and metabolic stress to distant tissues, including the CNS, through the secretion of bioactive molecules collectively known as myokines. Skeletal muscle undergoes significant physical and metabolic remodeling during exercise, including alterations in myokine expression profiles. This suggests that changes in myokine and myometabolite secretion may underlie the well-documented benefits of exercise in AD. However, to date, very few studies have focused on specific alterations in skeletal muscle-originating secreted factors and their potential neuroprotective effects in AD. In this review, we discuss exercise therapy for AD prevention and intervention, and propose the use of circulating myokines as novel therapeutic tools for modifying AD progression.
    Keywords:  aging; exercise; exerkines; myokines; neuroprotection
  32. Int J Mol Sci. 2021 Jul 10. pii: 7412. [Epub ahead of print]22(14):
      Mitoflashes are spontaneous transients of the biosensor mt-cpYFP. In cardiomyocytes, mitoflashes are associated with the cyclophilin D (CypD) mediated opening of mitochondrial permeability transition pore (mPTP), while in skeletal muscle they are considered hallmarks of mitochondrial respiration burst under physiological conditions. Here, we evaluated the potential association between mitoflashes and the mPTP opening at different CypD levels and phosphorylation status by generating three CypD derived fusion constructs with a red shifted, pH stable Ca2+ sensor jRCaMP1b. We observed perinuclear mitochondrial Ca2+ efflux accompanying mitoflashes in CypD and CypDS42A (a phosphor-resistant mutation at Serine 42) overexpressed myofibers but not the control myofibers expressing the mitochondria-targeting sequence of CypD (CypDN30). Assisted by a newly developed analysis program, we identified shorter, more frequent mitoflash activities occurring over larger areas in CypD and CypDS42A overexpressed myofibers than the control CypDN30 myofibers. These observations provide an association between the elevated CypD expression and increased mitoflash activities in hindlimb muscles in an amyotrophic lateral sclerosis (ALS) mouse model previously observed. More importantly, feeding the mice with sodium butyrate reversed the CypD-associated mitoflash phenotypes and protected against ectopic upregulation of CypD, unveiling a novel molecular mechanism underlying butyrate mediated alleviation of ALS progression in the mouse model.
    Keywords:  amyotrophic lateral sclerosis; butyrate; cyclopilin D; jRCaMP1b; mPTP; supervised inspection of Ca2+ transients
  33. Skelet Muscle. 2021 Jul 22. 11(1): 19
      BACKGROUND: In the search of genetic determinants of Duchenne muscular dystrophy (DMD) severity, LTBP4, a member of the latent TGF-β binding protein family, emerged as an important predictor of functional outcome trajectories in mice and humans. Nonsynonymous single-nucleotide polymorphisms in LTBP4 gene associate with prolonged ambulation in DMD patients, whereas an in-frame insertion polymorphism in the mouse LTBP4 locus modulates disease severity in mice by altering proteolytic stability of the Ltbp4 protein and release of transforming growth factor-β (TGF-β). Givinostat, a pan-histone deacetylase inhibitor currently in phase III clinical trials for DMD treatment, significantly reduces fibrosis in muscle tissue and promotes the increase of the cross-sectional area (CSA) of muscles in mdx mice. In this study, we investigated the activity of Givinostat in mdx and in D2.B10 mice, two mouse models expressing different Ltbp4 variants and developing mild or more severe disease as a function of Ltbp4 polymorphism.METHODS: Givinostat and steroids were administrated for 15 weeks in both DMD murine models and their efficacy was evaluated by grip strength and run to exhaustion functional tests. Histological examinations of skeletal muscles were also performed to assess the percentage of fibrotic area and CSA increase.
    RESULTS: Givinostat treatment increased maximal normalized strength to levels that were comparable to those of healthy mice in both DMD models. The effect of Givinostat in both grip strength and exhaustion tests was dose-dependent in both strains, and in D2.B10 mice, Givinostat outperformed steroids at its highest dose. The in vivo treatment with Givinostat was effective in improving muscle morphology in both mdx and D2.B10 mice by reducing fibrosis.
    CONCLUSION: Our study provides evidence that Givinostat has a significant effect in ameliorating both muscle function and histological parameters in mdx and D2.B10 murine models suggesting a potential benefit also for patients with a poor prognosis LTBP4 genotype.
    Keywords:  D2.B10; Duchenne nuscular dystrophy; Givinostat; HDAC inhibitor; LTBP4; mdx
  34. NPJ Microgravity. 2021 Jul 23. 7(1): 28
      With the reignited push for manned spaceflight and the development of companies focused on commercializing spaceflight, increased human ventures into space are inevitable. However, this venture would not be without risk. The lower gravitational force, known as microgravity, that would be experienced during spaceflight significantly disrupts many physiological systems. One of the most notably affected systems is the musculoskeletal system, where exposure to microgravity causes both bone and skeletal muscle loss, both of which have significant clinical implications. In this review, we focus on recent advancements in our understanding of how exposure to microgravity affects the musculoskeletal system. We will focus on the catabolic effects microgravity exposure has on both bone and skeletal muscle cells, as well as their respective progenitor stem cells. Additionally, we report on the mechanisms that underlie bone and muscle tissue loss resulting from exposure to microgravity and then discuss current countermeasures being evaluated. We reveal the gaps in the current knowledge and expound upon how current research is filling these gaps while also identifying new avenues of study as we continue to pursue manned spaceflight.
  35. Ageing Res Rev. 2021 Jul 17. pii: S1568-1637(21)00158-6. [Epub ahead of print] 101411
      Telomeres protect genomic stability and shortening is one of the hallmarks of ageing. Telomerase reverse transcriptase (TERT) is the major protein component of telomerase, which elongates telomeres. Given that short telomeres are linked to a host of chronic diseases and the therapeutic potential of telomerase-based therapies as treatments and a strategy to extend lifespan, lifestyle factors that increase TERT gene expression and telomerase activity could attenuate telomere attrition and contribute to healthy biological ageing. Physical activity and maximal aerobic fitness are associated with telomere maintenance, yet the molecular mechanisms remain unclear. Therefore, the purpose of this systematic review and meta-analysis was to identify the influence of a single bout of exercise and long-term exercise training on TERT expression and telomerase activity. A search of human and rodent trials using the PubMed, Scopus, Science Direct and Embase databases was performed. Based on findings from the identified and eligible trials, both a single bout of exercise (n; standardised mean difference [95%CI]: 5; SMD: 1.19 [0.41-1.97], p = 0.003) and long-term exercise training (10; 0.31 [0.03-0.60], p = 0.03) up-regulates TERT and telomerase activity in non-cancerous somatic cells. As human and rodent studies were included in both meta-analyses both exhibited heterogeneity (I2 = 55-87%, p < 0.05). Endurance athletes also exhibited increased leukocyte TERT and telomerase activity compared to their inactive counterparts. These findings suggest exercise training as an inexpensive lifestyle factor that increases TERT expression and telomerase activity. Regular exercise training could attenuate telomere attrition through a telomerase-dependent mechanism and ultimately extend health-span and longevity.
    Keywords:  TERT; Telomere; biological ageing; senescence
  36. Cryobiology. 2021 Jul 15. pii: S0011-2240(21)00119-X. [Epub ahead of print]
      Mammalian hibernation is a period that involves substantial metabolic change in order to promote survival in harsh conditions, with animals typically relying on non-carbohydrate fuel stores during long bouts of torpor. However, the use and maintenance of carbohydrate fuel stores remains important during periods of arousal from torpor as well as when exiting hibernation. Gluconeogenesis plays a key role in maintaining glucose stores; however, little is known about this process within the muscles of hibernating mammals. Here, we used 13-lined ground squirrels (Ictidomys tridecemlineatus) as our model for mammalian hibernation, and showed that skeletal muscle fructose-1,6-bisphosphatse (FBPase; EC, the rate-limiting enzyme for the gluconeogenic pathway, was suppressed during torpor as compared to the euthermic control. A physical assessment of partially purified FBPase via exposure to increasing concentrations of the denaturant urea indicated that FBPase from the two conditions were structurally distinct. Western blot analysis suggests that the kinetic and physical differences between euthermic and torpid FBPase may be derived from differential acetylation, whereby increased acetylation of the torpid enzyme makes FBPase more rigid and less active. This study increases our understanding of skeletal muscle carbohydrate metabolism during mammalian hibernation and sets forth a potentially novel mechanism for the regulation of FBPase during environmental stress.
    Keywords:  gluconeogenesis; glucose metabolism; mammalian hibernation; muscle metabolism; posttranslational acetylation; torpor
  37. Front Genet. 2021 ;12 688526
      We here review the loss of muscle function and mass (sarcopenia) in the framework of human healthspan and lifespan, and mechanisms involved in aging. The rapidly changing composition of the human population will impact the incidence and the prevalence of aging-induced disorders such as sarcopenia and, henceforth, efforts to narrow the gap between healthspan and lifespan should have top priority. There are substantial knowledge gaps in our understanding of aging. Heritability is estimated to account for only 25% of lifespan length. However, as we push the expected lifespan at birth toward those that we consider long-lived, the genetics of aging may become increasingly important. Linkage studies of genetic polymorphisms to both the susceptibility and aggressiveness of sarcopenia are still missing. Such information is needed to shed light on the large variability in clinical outcomes between individuals and why some respond to interventions while others do not. We here make a case for the concept that sarcopenia has a neurogenic origin and that in manifest sarcopenia, nerve and myofibers enter into a vicious cycle that will escalate the disease progression. We point to gaps in knowledge, for example the crosstalk between the motor axon, terminal Schwann cell, and myofiber in the denervation processes that leads to a loss of motor units and muscle weakness. Further, we argue that the operational definition of sarcopenia should be complemented with dynamic metrics that, along with validated biomarkers, may facilitate early preclinical diagnosis of individuals vulnerable to develop advanced sarcopenia. We argue that preventive measures are likely to be more effective to counter act aging-induced disorders than efforts to treat manifest clinical conditions. To achieve compliance with a prescription of preventive measures that may be life-long, we need to identify reliable predictors to design rational and convincing interventions.
    Keywords:  aging; demography; genotype; heritability; muscle mass; muscle weakness; phenotype
  38. Nat Commun. 2021 Jul 23. 12(1): 4502
      Cells in many tissues, such as bone, muscle, and placenta, fuse into syncytia to acquire new functions and transcriptional programs. While it is known that fused cells are specialized, it is unclear whether cell-fusion itself contributes to programmatic-changes that generate the new cellular state. Here, we address this by employing a fusogen-mediated, cell-fusion system to create syncytia from undifferentiated cells. RNA-Seq analysis reveals VSV-G-induced cell fusion precedes transcriptional changes. To gain mechanistic insights, we measure the plasma membrane surface area after cell-fusion and observe it diminishes through increases in endocytosis. Consequently, glucose transporters internalize, and cytoplasmic glucose and ATP transiently decrease. This reduced energetic state activates AMPK, which inhibits YAP1, causing transcriptional-reprogramming and cell-cycle arrest. Impairing either endocytosis or AMPK activity prevents YAP1 inhibition and cell-cycle arrest after fusion. Together, these data demonstrate plasma membrane diminishment upon cell-fusion causes transient nutrient stress that may promote transcriptional-reprogramming independent from extrinsic cues.
  39. Sci Rep. 2021 Jul 23. 11(1): 15141
      Cytokines such as IL-6, TNF-α and IL-1β trigger inflammatory cascades which may play a role in the pathogenesis of chronic kidney disease (CKD)-associated cachexia. CKD was induced by 5/6 nephrectomy in mice. We studied energy homeostasis in Il1β-/-/CKD, Il6-/-/CKD and Tnfα-/-/CKD mice and compared with wild type (WT)/CKD controls. Parameters of cachexia phenotype were completely normalized in Il1β-/-/CKD mice but were only partially rescued in Il6-/-/CKD and Tnfα-/-/CKD mice. We tested the effects of anakinra, an IL-1 receptor antagonist, on CKD-associated cachexia. WT/CKD mice were treated with anakinra (2.5 mg/kg/day, IP) or saline for 6 weeks and compared with WT/Sham controls. Anakinra normalized food intake and weight gain, fat and lean mass content, metabolic rate and muscle function, and also attenuated molecular perturbations of energy homeostasis in adipose tissue and muscle in WT/CKD mice. Anakinra decreased serum and muscle expression of IL-6, TNF-α and IL-1β in WT/CKD mice. Anakinra attenuated browning of white adipose tissue in WT/CKD mice. Moreover, anakinra normalized gastrocnemius weight and fiber size as well as attenuated muscle fat infiltration in WT/CKD mice. This was accompanied by correcting the increased muscle wasting signaling pathways while promoting the decreased myogenesis process in gastrocnemius of WT/CKD mice. We performed qPCR analysis for the top 20 differentially expressed muscle genes previously identified via RNAseq analysis in WT/CKD mice versus controls. Importantly, 17 differentially expressed muscle genes were attenuated in anakinra treated WT/CKD mice. In conclusion, IL-1 receptor antagonism may represent a novel targeted treatment for adipose tissue browning and muscle wasting in CKD.
  40. J Physiol Biochem. 2021 Jul 22.
      The purpose of this study was to determine whether magnesium L-lactate is responsible for having a beneficial effect on the myocardium and the skeletal muscles and how this substrate acts at the molecular level. Twenty seven young male Wistar rats were supplied with a magnesium L-lactate (L) solution, a magnesium chloride (M) solution and/or water (W) as a vehicle for 10 weeks. The treated animals absorbed the L and M solutions as they wished since they also had free access to water. After 9 weeks of treatment, in vivo cardiac function was determined ultrasonically. The animals were sacrificed at the end of the tenth week of treatment and the heart was perfused according to the Langendorff method by using a technique allowing the determination of cardiomyocyte activity (same coronary flow in the two groups). Blood was collected and skeletal muscles of the hind legs were weighed. The myocardial expressions of the sodium/proton exchange 1 (NHE1) and sodium/calcium exchange 1 (NCX1), intracellular calcium accumulation, myocardial magnesium content, as well as systemic and tissue oxidative stress, were determined. Animals of the L group absorbed systematically a low dose of L-lactate (31.5 ± 4.3 µg/100 g of body weight/day) which was approximately four times higher than that ingested in the W group through the diet supplied. Ex vivo cardiomyocyte contractility and the mass of some skeletal muscles (tibialis anterior) were increased by the L treatment. Myocardial calcium was decreased, as was evidenced by an increase in total CaMKII expression, without any change in the ratio between phosphorylated CaMKII and total CaMKII. Cardiac magnesium tended to be elevated. Our results suggest that the increased intracellular magnesium concentration was related to L-lactate-induced cytosolic acidosis and to the activation of the NHE1/NCX1 axis. Interestingly, systemic oxidative stress was reduced by the L treatment whereas the lipid profile of the animals was unaltered. Taken together, these results suggest that a chronic low-dose L-lactate intake has a beneficial health effect on some skeletal muscles and the myocardium through the activation of the NHE1/NCX1 axis, a decrease in cellular calcium and an increase in cellular magnesium. The treatment can be beneficial for the health of young rodents in relation to chronic oxidative stress-related diseases.
    Keywords:  Calcium; Diet; Heart; L-lactate; Skeletal muscle