bims-moremu Biomed News
on Molecular regulators of muscle mass
Issue of 2022‒03‒20
34 papers selected by
Anna Vainshtein
Craft Science Inc.
  1. Muscle Wasting in COPD: Not Enough Autophagy?
  2. Therapeutic effects of recreational exercise on skeletal muscle aging - how much is enough?
  3. MiR-208b Regulates the Conversion of Skeletal Muscle Fiber Types by Inhibiting Mettl8 Expression.
  4. Plasmonic fusion between fibroblasts and skeletal muscle cells for skeletal muscle regeneration.
  5. Association of Glycative Stress With Motor and Muscle Function.
  6. A Piezo1/KLF15/IL-6 axis mediates immobilization-induced muscle atrophy.
  7. Obesity and exercise training alter inflammatory pathway skeletal muscle small extracellular vesicle miRNAs.
  8. Involvement of muscle satellite cell dysfunction in neuromuscular disorders: Expanding the portfolio of satellite cell-opathies.
  9. Mitochondrial uncoupling attenuates sarcopenic obesity by enhancing skeletal muscle mitophagy and quality control.
  10. Adiponectin receptor agonist AdipoRon improves skeletal muscle function in aged mice.
  11. The circadian clock regulates metabolic responses to physical exercise.
  12. Mechanical unloading in 3D-engineered muscle leads to muscle atrophy by suppressing protein synthesis.
  13. AMP-activated protein kinase activation in skeletal muscle modulates exercise-induced uncoupled protein 1 expression in brown adipocyte in mouse model.
  14. Skeletal muscle proteome expression differentiates severity of cancer cachexia in mice and identifies loss of fragile X mental retardation syndrome-related protein 1.
  15. Argonaute 2 is lost from neuromuscular junctions affected with amyotrophic lateral sclerosis in SOD1G93A mice.
  16. Selective ablation of Nfix in macrophages attenuates muscular dystrophy by inhibiting fibro-adipogenic progenitor-dependent fibrosis.
  17. CD38-NADase is a new major contributor to Duchenne muscular dystrophic phenotype.
  18. Mass spectrometry imaging reveals local metabolic changes in skeletal muscle due to chronic training.
  19. Editorial: Nutrition in the Regulation of Muscle Development and Repair.
  20. Benefits of therapy by dynamin-2-mutant-specific silencing are maintained with time in a mouse model of dominant centronuclear myopathy.
  21. PGC-1α affects skeletal muscle and adipose tissue development by regulating mitochondrial biogenesis.
  22. Primary cilia on muscle stem cells are critical to maintain regenerative capacity and are lost during aging.
  23. Piezo1 regulates the regenerative capacity of skeletal muscles via orchestration of stem cell morphological states.
  24. Driving an Oxidative Phenotype Protects Myh4 Null Mice From Myofiber Loss During Postnatal Growth.
  25. EZH2 modulates retinoic acid signaling to ensure myotube formation during development.
  26. Maternal exercise before and during pregnancy facilitates embryonic myogenesis by enhancing thyroid hormone signaling.
  27. Decoding the role of inflammation-related microRNAs in cancer cachexia: a study using HPV16-transgenic mice and in silico approaches.
  28. Loss of mouse Stmn2 function causes motor neuropathy.
  29. Hyperphosphatemia increases inflammation to exacerbate anemia and skeletal muscle wasting independently of FGF23-FGFR4 signaling.
  30. Bridging the muscle genome to phenome across multiple biological scales.
  31. Targeting MuRF1 by small molecules in a HFpEF rat model improves myocardial diastolic function and skeletal muscle contractility.
  32. Characterization of a novel zebrafish model of SPEG-related centronuclear myopathy.
  33. Exerkines in health, resilience and disease.
  34. Mapping ongoing nutrition intervention trials in muscle, sarcopenia, and cachexia: a scoping review of future research.
  1. Am J Respir Cell Mol Biol. 2022 Mar 16.
    Muscle Wasting in COPD: Not Enough Autophagy?
    Jean-Philippe Leduc-Gaudet, Sabah N A Hussain.
      
    Keywords:  Autophagy; COPD; Myogenesis; Satellite Cells; Skeletal muscle
    DOI:  https://doi.org/10.1165/rcmb.2022-0064ED
  2. J Physiol. 2022 Mar 19.
    Therapeutic effects of recreational exercise on skeletal muscle aging - how much is enough?
    Davis A Englund.
      
    Keywords:  aging; exercise; innervation; satellite cell
    DOI:  https://doi.org/10.1113/JP283015
  3. Front Genet. 2022 ;13 820464
    MiR-208b Regulates the Conversion of Skeletal Muscle Fiber Types by Inhibiting Mettl8 Expression.
    Xiang Li, Hanfang Bi, Shanshan Xie, Wentao Cui.
      Skeletal muscle, the main source of animal meat products, contains muscle fiber as a key unit. It is well known that transformation takes place between different types of muscle fibers, however, the conversion mechanism is not clear. In a previous study, our lab has demonstrated that there is a decrease in type I muscle fibers and an increase in type IIB muscle fibers in skeletal muscle of myostatin gene-edited Meishan pigs. Very interestingly, we observed the down regulation of miR-208b expression and an increase in expression the predicted target gene Mettl8 (Methyltransferase like 8) in skeletal muscle of MSTN gene-edited Meishan pigs. These results reveal that there is a potential connection between the conversion of skeletal muscle fiber types and miR-208b and Mettl8 expression. In this study, we first explored the expression patterns of miR-208b and Mettl8 in skeletal muscle in Meishan pigs; and then C2C12 cells were used to simulate the development and maturation of muscle fibers. Our results indicated that Myh4 expression level decreased and Myh7 expression level increased following overexpression of miR-208b in C2C12 cells. We therefore speculate that miR-208b can promote the conversion of fast-twitch fibers to slow-twitch fibers. The targeting relationship between Mettl8 and miR-208b was confirmed by results obtained using dual luciferase assay, RT-qPCR, and WB analysis. Following the transfection of Mettl8 siRNA into C2C12 cells, we observed that Mettl8 expression decreased significantly while Myh7 expression increased and Myh4 expression decreased, indicating that Mettl8 promotes the conversion of slow muscle fibers to fast muscle fibers. Additionally, changes in skeletal muscle fiber types are observed in those mice where miR-208b and Mettl8 genes are knocked out. The miR-208b knockout inhibits the formation of slow muscle fibers, and the Mettl8 knockout inhibits the formation of fast muscle fibers. In conclusion, our research results show that miR-208b regulates the conversion of different muscle fiber types by inhibiting Mettl8 expression.
    Keywords:  Mettl8; miR-208b; miRNA; muscle fiber type conversion; myostatin; skeletal muscle
    DOI:  https://doi.org/10.3389/fgene.2022.820464
  4. Biomed Opt Express. 2022 Feb 01. 13(2): 608-619
    Plasmonic fusion between fibroblasts and skeletal muscle cells for skeletal muscle regeneration.
    Limor Minai, Dvir Yelin.
      Normal regeneration of skeletal muscle takes place by the differentiation of muscle-specific stem cells into myoblasts that fuse with existing myofibers for muscle repair. This natural repair mechanism could be ineffective in some cases, for example in patients with genetic muscular dystrophies or massive musculoskeletal injuries that lead to volumetric muscle loss. In this study we utilize the effect of plasmonic cell fusion, i.e. the fusion between cells conjugated by gold nanospheres and irradiated by resonant femtosecond laser pulses, for generating human heterokaryon cells of myoblastic and fibroblastic origin, which further develop into viable striated myotubes. The heterokaryon cells were found to express the myogenic transcription factors MyoD and Myogenin, as well as the Desmin protein that is essential in the formation of sarcomeres, and could be utilized in various therapeutic approaches that involve transplantation of cells or engineered tissue into the damaged muscle.
    DOI:  https://doi.org/10.1364/BOE.445290
  5. Front Physiol. 2022 ;13 855358
    Association of Glycative Stress With Motor and Muscle Function.
    Tatsuro Egawa, Tatsuya Hayashi.
      Glycative stress is a type of biological stress caused by non-enzymatic glycation reactions, which include advanced glycation end product (AGE) formation, AGE accumulation, glycation-driven dysfunction of proteins and cellular signaling, inflammation, oxidation, and tissue damage. Increased glycative stress derived from hyperglycemia and lifestyle disorders is a risk factor in metabolic and age-related diseases, such as type 2 diabetes, cardiovascular disease, cancer, Alzheimer's disease, osteoporosis, and dementia. Studies have shown that AGE accumulation is correlated with the age-related loss of muscle mass and power output, also called sarcopenia. Mechanistically, dysfunctions of contractile proteins, myogenic capacity, and protein turnover can cause glycative stress-induced skeletal muscle dysfunction. Because the skeletal muscle is the largest metabolic organ in the body, maintaining skeletal muscle health is essential for whole-body health. Increasing awareness and understanding of glycative stress in the skeletal muscle in this review will contribute to the maintenance of better skeletal muscle function.
    Keywords:  advanced glycation end products; aging; diabetes; exercise; frailty; glycation stress; sarcopenia; skeletal muscle
    DOI:  https://doi.org/10.3389/fphys.2022.855358
  6. J Clin Invest. 2022 Mar 15. pii: e154611. [Epub ahead of print]
    A Piezo1/KLF15/IL-6 axis mediates immobilization-induced muscle atrophy.
    Yu Hirata, Kazuhiro Nomura, Daisuke Kato, Yoshihisa Tachibana, Takahiro Niikura, Kana Uchiyama, Tetsuya Hosooka, Tomoaki Fukui, Keisuke Oe, Ryosuke Kuroda, Yuji Hara, Takahiro Adachi, Koji Shibasaki, Hiroaki Wake, Wataru Ogawa.
      Whereas immobility is a common cause of muscle atrophy, the mechanism underlying this causality is unclear. We here show that KLF15 and IL-6 are up-regulated in skeletal muscle of limb-immobilized mice and that mice with KLF15 deficiency in skeletal muscle or with systemic IL-6 deficiency are protected from immobility-induced muscle atrophy. A newly developed Ca2+ bioimaging revealed that the Ca2+ concentration ([Ca2+]i) of skeletal muscle is reduced to below the basal level by immobilization, which is associated with the down-regulation of Piezo1. Acute disruption of Piezo1 in skeletal muscle induced Klf15 and Il6 expression as well as muscle atrophy, which was prevented by antibodies to IL-6. A role for the Piezo1/KLF15/IL-6 axis in immobility-induced muscle atrophy was validated by human samples. Our results thus uncover a paradigm for Ca2+ signaling in that a decrease in [Ca2+]i from the basal level triggers a defined biological event.
    Keywords:  Calcium signaling; Metabolism; Muscle Biology; Skeletal muscle
    DOI:  https://doi.org/10.1172/JCI154611
  7. Exp Physiol. 2022 Mar 15.
    Obesity and exercise training alter inflammatory pathway skeletal muscle small extracellular vesicle miRNAs.
    Brian P Sullivan, Yaohui Nie, Sheelagh Evans, Chris K Kargl, Zach R Hettinger, Ron T Garner, Monica J Hubal, Shihuan Kuang, Julianne Stout, Timothy P Gavin.
      NEW FINDINGS: What are the central questions of this study? Is one week of exercise training sufficient to reduce local and systemic inflammation? Do obesity and short term concurrent exercise training alter skeletal muscle extracellular vesicle contents? What is the main finding and its importance? Obesity alters skeletal muscle small EV miR targeting inflammatory and growth pathways. Exercise training alters skeletal muscle small EV miR targeting inflammatory pathways, indicative of reduced inflammation. Our findings provide support for the hypotheses that EVs play a vital role in intercellular communication during health and disease and that EVs mediate many of the beneficial effects of exercise.ABSTRACT: Obesity is associated with chronic inflammation characterized by increased levels of inflammatory cytokines, while exercise training reduces inflammation. Small EVs (30-150 nm) participate in cell-to-cell communication in part through miRNA post-transcriptional regulation of mRNA.
    PURPOSE: The current study examined if obesity and concurrent exercise training alter skeletal muscle: (1) EV miRNA content and (2) inflammatory signaling.
    METHODS: Vastus lateralis biopsies were obtained from sedentary individuals with (OB) and without obesity (LN). Before and after seven days of concurrent aerobic and resistance training, muscle-derived small EV miRNA and whole muscle mRNA were measured.
    RESULTS: Pathway analysis revealed that obesity alters small EV miRNA that target inflammatory (PEDF, Death Receptor, and Gαi) and growth pathways (Wnt/β-catenin, PTEN, PI3K/AKT, IGF-1). In addition, exercise training alters small EV miRNA in an anti-inflammatory manner targeting the IL-10, IL-8, toll-like receptor (TLR), and NF-κB signaling pathways. In whole muscle, IL-8 mRNA was reduced 50% and Jun mRNA was reduced 25% after exercise training consistent with the anti-inflammatory effects of exercise on skeletal muscle.
    CONCLUSIONS: Obesity and seven days of concurrent exercise training differentially alter skeletal muscle-derived small EV miRNA contents targeting inflammatory and anabolic pathways. This article is protected by copyright. All rights reserved.
    Keywords:  Exercise Training; Extracellular vesicles; Inflammation; Obesity; microRNA
    DOI:  https://doi.org/10.1113/EP090062
  8. Eur J Transl Myol. 2022 Mar 18.
    Involvement of muscle satellite cell dysfunction in neuromuscular disorders: Expanding the portfolio of satellite cell-opathies.
    Massimo Ganassi, Peter S Zammit.
      Neuromuscular disorders are a heterogeneous group of acquired or hereditary conditions that affect striated muscle function. The resulting decrease in muscle strength and motility irreversibly impacts quality of life. In addition to directly affecting skeletal muscle, pathogenesis can also arise from dysfunctional crosstalk between nerves and muscles, and may include cardiac impairment. Muscular weakness is often progressive and paralleled by continuous decline in the ability of skeletal muscle to functionally adapt and regenerate. Normally, the skeletal muscle resident stem cells, named satellite cells, ensure tissue homeostasis by providing myoblasts for growth, maintenance, repair and regeneration. We recently defined 'Satellite Cell-opathies' as those inherited neuromuscular conditions presenting satellite cell dysfunction in muscular dystrophies and myopathies (doi:10.1016/j.yexcr.2021.112906). Here, we expand the portfolio of Satellite Cell-opathies by evaluating the potential impairment of satellite cell function across all 16 categories of neuromuscular disorders, including those with mainly neurogenic and cardiac involvement. We explore the expression dynamics of myopathogenes, genes whose mutation leads to skeletal muscle pathogenesis, using transcriptomic analysis. This revealed that 45% of myopathogenes are differentially expressed during early satellite cell activation (0 - 5 hours). Of these 271 myopathogenes, 83 respond to Pax7, a master regulator of satellite cells. Our analysis suggests possible perturbation of satellite cell function in many neuromuscular disorders across all categories, including those where skeletal muscle pathology is not predominant. This characterisation further aids understanding of pathomechanisms and informs on development of prognostic and diagnostic tools, and ultimately, new therapeutics.
    DOI:  https://doi.org/10.4081/ejtm.2022.10064
  9. J Cachexia Sarcopenia Muscle. 2022 Mar 19.
    Mitochondrial uncoupling attenuates sarcopenic obesity by enhancing skeletal muscle mitophagy and quality control.
    Wagner S Dantas, Elizabeth R M Zunica, Elizabeth C Heintz, Bolormaa Vandanmagsar, Z Elizabeth Floyd, Yongmei Yu, Hisashi Fujioka, Charles L Hoppel, Kathryn P Belmont, Christopher L Axelrod, John P Kirwan.
      BACKGROUND: Sarcopenic obesity is a highly prevalent disease with poor survival and ineffective medical interventions. Mitochondrial dysfunction is purported to be central in the pathogenesis of sarcopenic obesity by impairing both organelle biogenesis and quality control. We have previously identified that a mitochondrial-targeted furazano[3,4-b]pyrazine named BAM15 is orally available and selectively lowers respiratory coupling efficiency and protects against diet-induced obesity in mice. Here, we tested the hypothesis that mitochondrial uncoupling simultaneously attenuates loss of muscle function and weight gain in a mouse model of sarcopenic obesity.METHODS: Eighty-week-old male C57BL/6J mice with obesity were randomized to 10 weeks of high fat diet (CTRL) or BAM15 (BAM15; 0.1% w/w in high fat diet) treatment. Body weight and food intake were measured weekly. Body composition, muscle function, energy expenditure, locomotor activity, and glucose tolerance were determined after treatment. Skeletal muscle was harvested and evaluated for histology, gene expression, protein signalling, and mitochondrial structure and function.
    RESULTS: BAM15 decreased body weight (54.0 ± 2.0 vs. 42.3 ± 1.3 g, P < 0.001) which was attributable to increased energy expenditure (10.1 ± 0.1 vs. 11.3 ± 0.4 kcal/day, P < 0.001). BAM15 increased muscle mass (52.7 ± 0.4 vs. 59.4 ± 1.0%, P < 0.001), strength (91.1 ± 1.3 vs. 124.9 ± 1.2 g, P < 0.0001), and locomotor activity (347.0 ± 14.4 vs. 432.7 ± 32.0 m, P < 0.001). Improvements in physical function were mediated in part by reductions in skeletal muscle inflammation (interleukin 6 and gp130, both P < 0.05), enhanced mitochondrial function, and improved endoplasmic reticulum homeostasis. Specifically, BAM15 activated mitochondrial quality control (PINK1-ubiquitin binding and LC3II, P < 0.01), increased mitochondrial activity (citrate synthase and complex II activity, all P < 0.05), restricted endoplasmic reticulum (ER) misfolding (decreased oligomer A11 insoluble/soluble ratio, P < 0.0001) while limiting ER stress (decreased PERK signalling, P < 0.0001), apoptotic signalling (decreased cytochrome C release and Caspase-3/9 activation, all P < 0.001), and muscle protein degradation (decreased 14-kDa actin fragment insoluble/soluble ratio, P < 0.001).
    CONCLUSIONS: Mitochondrial uncoupling by agents such as BAM15 may mitigate age-related decline in muscle mass and function by molecular and cellular bioenergetic adaptations that confer protection against sarcopenic obesity.
    Keywords:  Ageing; BAM15; Bioenergetics; Mitochondrial uncoupling; Obesity; Sarcopenia
    DOI:  https://doi.org/10.1002/jcsm.12982
  10. Elife. 2022 Mar 17. pii: e71282. [Epub ahead of print]11
    Adiponectin receptor agonist AdipoRon improves skeletal muscle function in aged mice.
    Priya Balasubramanian, Anne E Schaar, Grace E Gustafson, Alex B Smith, Porsha R Howell, Angela Greenman, Scott Baum, Ricki J Colman, Dudley W Lamming, Gary M Diffee, Rozalyn M Anderson.
      The loss of skeletal muscle function with age, known as sarcopenia, significantly reduces independence and quality of life and can have significant metabolic consequences. Although exercise is effective in treating sarcopenia it is not always a viable option clinically, and currently there are no pharmacological therapeutic interventions for sarcopenia. Here we show that chronic treatment with pan-adiponectin receptor agonist AdipoRon improved muscle function in male mice by a mechanism linked to skeletal muscle metabolism and tissue remodeling. In aged mice, 6 weeks of AdipoRon treatment improved skeletal muscle functional measures in vivo and ex vivo. Improvements were linked to changes in fiber type, including an enrichment of oxidative fibers, and an increase in mitochondrial activity. In young mice, 6 weeks of AdipoRon treatment improved contractile force and activated the energy sensing kinase AMPK and the mitochondrial regulator PGC-1a (peroxisome proliferator activated receptor gamma coactivator 1 alpha). In cultured cells, the AdipoRon induced stimulation of AMPK and PGC-1a was associated with increased mitochondrial membrane potential, reorganization of mitochondrial architecture, increased respiration, and increased ATP production. Furthermore, the ability of AdipoRon to stimulate AMPK and PGC1a was conserved in nonhuman primate cultured cells. These data show that AdipoRon is an effective agent for the prevention of sarcopenia in mice and indicate that its effects translate to primates, suggesting it may also be a suitable therapeutic for sarcopenia in clinical application.
    Keywords:  cell biology; mouse; rhesus macaque
    DOI:  https://doi.org/10.7554/eLife.71282
  11. Chronobiol Int. 2022 Mar 14. 1-11
    The circadian clock regulates metabolic responses to physical exercise.
    Qianyun Cheng, Chao Lu, Ruizhe Qian.
      It has been proposed for years that physical exercise ameliorates metabolic diseases. Optimal exercise timing in humans and mammals has indicated that circadian clocks play a vital role in exercise and body metabolism. Skeletal muscle metabolism exhibits a robust circadian rhythm under the control of the suprachiasmatic nucleus of the hypothalamus. Clock genes also control the development, differentiation, and function of skeletal muscles. In this review, we aimed to clarify the relationship between exercise, skeletal muscles, and the circadian clock. Health benefits can be attained by the scheduling of exercise at the best circadian time. Exercise therapy for metabolic diseases and cardiovascular health is a key adjuvant method. This review highlights the importance of exercise timing in maintaining healthy metabolism and circadian clocks.
    Keywords:  Circadian clock; aging; metabolic syndrome; physical exercise; skeletal muscle metabolism
    DOI:  https://doi.org/10.1080/07420528.2022.2050384
  12. J Appl Physiol (1985). 2022 Mar 17.
    Mechanical unloading in 3D-engineered muscle leads to muscle atrophy by suppressing protein synthesis.
    Takeshi Sugimoto, Shoma Imai, Maki Yoshikawa, Toshia Fujisato, Takeshi Hashimoto, Tomohiro Nakamura.
      Three dimensional (3D)-engineered muscle is an useful approach to a more comprehensive understanding of molecular mechanisms underlying unloading-induced muscle atrophy. We investigated the effects of mechanical unloading on molecular muscle protein synthesis (MPS)- and muscle protein breakdown (MPB)-related signaling pathways involved in muscle atrophy in 3D-engineered muscle, and to better understand in vitro model of muscle disuse. The 3D-engineered muscle consisting of C2C12 myoblasts and type-1 collagen gel was allowed to differentiate for 2 weeks and divided into three groups: 0 days of stretched-on control (CON), 2 and/or 7 days of stretched-on (ON), in which both ends of the muscle were fixed with artificial tendons, and the stretched-off group (OFF), in which one side of the artificial tendon was detached. Muscle weight (-38.1 to -48.4%), length (-67.0 to -73.5%), twitch contractile force (-70.5 to -75.0%) and myosin heavy chain expression (-32.5 to -50.5%) in the OFF group were significantly decreased on days 2 and 7 compared with the ON group (P < 0.05, respectively), despite that ON group was stable over time. Although determinative molecular signaling could not be identified, the MPS rate reflected by puromysin labeled protein was significantly decreased following mechanical unloading (P < 0.05, -38.5 to -51.1%). Meanwhile, MPB, particularly the ubiquitin-proteasome pathway, was not impacted. Hence, mechanical unloading of 3D-engineered muscle in vitro leads to muscle atrophy by suppressing MPS, cell differentiation, and cell growth rather than the promotion of MPB.
    Keywords:  C2C12; Tissue-engineered muscle; mechanical unloading; muscle disuse atrophy; muscle protein synthesis
    DOI:  https://doi.org/10.1152/japplphysiol.00323.2021
  13. J Physiol. 2022 Mar 17.
    AMP-activated protein kinase activation in skeletal muscle modulates exercise-induced uncoupled protein 1 expression in brown adipocyte in mouse model.
    Hye Jin Kim, Youn Ju Kim, Je Kyung Seong.
      KEY POINTS: Exercise promotes thermogenesis by activating uncoupling protein 1 (UCP1), which leads to a decrease in the body weight gain and body fat content. However, little is known about the role of exerkines in modulating UCP1 expression and subsequent brown adipose tissue (BAT) activation. Four weeks of voluntary wheel running exercise reduces body weight and fat content. Exercise induces the increase in AMP-activated protein kinase (AMPK) and slow-type muscle fibre marker genes in skeletal muscles and promotes UCP1 expression in white and brown adipose tissues. Incubation of brown adipocytes with serum isolated from exercise-trained mice significantly increased their UCP1 gene and protein levels; moreover, conditioned media of AMPK-activator-treated C2C12 myotubes induces increased UCP1 expression in brown adipocytes. These results highlight that aerobic exercise-induced skeletal muscle AMPK has a significant effect on UCP1 expression in BAT.ABSTRACT: Aerobic exercise is an effective intervention in preventing obesity and is, also an important factor associated with thermogenesis. There is an increasing interest in factors and mechanisms induced by aerobic exercise that can influence the metabolism and thermogenic activity in an individual. Recent studies suggest that exercise-induced circulating factors, which are (known as "exerkines") able to modulate activation of brown adipose tissue (BAT) and browning of white adipose tissue. However, the underlying molecular mechanisms associated with the effect of exercise-induced peripheral factors on BAT activation remain poorly understood. Furthermore, the role of exercise training in BAT activation is still debatable. Hence, the purpose of our study is to assess whether exercise training affects the expression of uncoupled protein 1 (UCP1) in brown adipocytes via release of different blood factors. Four weeks of exercise training significantly decreased the body weight gain and fat mass gain. Furthermore, trained mice exhibit higher levels of energy expenditure and UCP1 expression compared with untrained mice. Surprisingly, treatment with serum from exercise-trained mice increased the expression of UCP1 in differentiated brown adipocytes. To gain a better understanding of these mechanisms, we analysed the conditioned media obtained after treating the C2C12 myotubes with an AMP-activated protein kinase (AMPK) activator (AICAR; 5-aminoimidazole-4-carboxamide ribonucleotide), which leads to an increased expression of UCP1 when added to brown adipocytes. Our observations suggest the possibility of aerobic exercise-induced BAT activation via activation of AMPK in skeletal muscles. Abstract figure legend Exercise induces the release of several factors called 'exerkines' that can help to modulate the metabolic as well as thermogenic activity of an individual. However, there is limited knowledge regarding the underlying molecular mechanisms that enable these factors to stimulate brown adipose tissue activity. Our study demonstrates that exercise-induces activation of AMP-activated protein kinase in skeletal muscles, which, in turn, presumably through the release of exerkines from muscles, can modulate the uncoupled protein 1 expression in brown adipocytes. We believe that this paper provides an understanding of the molecular basis of adipocyte browning during aerobic exercise, and this knowledge may be useful in developing novel strategies for preventing the onset of/overcoming obesity. This article is protected by copyright. All rights reserved.
    Keywords:  AMPK; BAT activation; UCP1; brown adipocyte; exercise; exerkine; myokine
    DOI:  https://doi.org/10.1113/JP282999
  14. Proteomics. 2022 Mar 15. e2100157
    Skeletal muscle proteome expression differentiates severity of cancer cachexia in mice and identifies loss of fragile X mental retardation syndrome-related protein 1.
    Andy V Khamoui, Dorota Tokmina-Roszyk, Rafaela G Feresin, Gregg B Fields, Nishant P Visavadiya.
      TMT-based quantitative proteomics was used to examine protein expression in skeletal muscle from mice with moderate and severe cancer cachexia to study mechanisms underlying varied cachexia severity. Weight loss of 10% (moderate) and 20% (severe) was induced by injection of colon-26 cancer cells in 10-week old Balb/c mice. In moderate cachexia, enriched pathways reflected fibrin formation, integrin/MAPK signaling, and innate immune system, suggesting an acute phase response and fibrosis. These pathways remained enriched in severe cachexia, however, energy-yielding pathways housed in mitochondria were prominent additions to the severe state. These enrichments suggest distinct muscle proteome expression patterns that differentiate cachexia severity. When analyzed with two other mouse models, eight differentially expressed targets were shared including Serpina3n, Sypl2, Idh3a, Acox1, Col6a1, Myoz3, Ugp2, and Slc41a3. Acox1 and Idh3a control lipid oxidation and NADH generation in the TCA cycle, respectively, and Col6a1 comprises part of type VI collagen with reported profibrotic functions, suggesting influential roles in cachexia. A potential target was identified in FXR1, an RNA-binding protein not previously implicated in cancer cachexia. FXR1 decreased in cachexia and related linearly with weight change and myofiber size. These findings suggest distinct mechanisms associated with cachexia severity and potential biomarkers and therapeutic targets. This article is protected by copyright. All rights reserved.
    Keywords:  FXR1; Fragile X mental retardation autosomal homologue-1; Mitochondria; Muscle atrophy; RNA-binding protein
    DOI:  https://doi.org/10.1002/pmic.202100157
  15. Sci Rep. 2022 Mar 17. 12(1): 4630
    Argonaute 2 is lost from neuromuscular junctions affected with amyotrophic lateral sclerosis in SOD1G93A mice.
    Dillon Shapiro, Ryan Massopust, Thomas Taetzsch, Gregorio Valdez.
      miRNAs are necessary for neuromuscular junction (NMJ) health; however, little is known about the proteins required for their activity in this regard. We examined expression of Argonaute 2 (Ago2) and miRNA biogenesis genes in skeletal muscles during development, following nerve injury and in the SOD1G93A ALS mouse model. We found that these genes are enriched in neonate muscles and in adult muscles following nerve injury. Despite widespread NMJ deterioration, these genes were not increased in muscles of SOD1G93A mice. We also found that Ago2 distribution is linked to maturation, innervation, and health of NMJs. Ago2 increasingly concentrates in synaptic regions during NMJ maturation, disperses following experimental denervation and reconcentrates at the NMJ upon reinnervation. Similar to experimentally denervated muscles, a homogenous distribution of Ago2 was observed in SOD1G93A muscle fibers. To determine if Ago2 is necessary for the health of adult muscles, we excised Ago2 from Ago2fl/fl mice using adeno-associated virus mediated Cre recombinase expression. We observed modest changes in muscle histology after 3 months of Ago2 knockdown. Together, these data provide critical insights into the role of Ago2 and miRNA biogenesis genes in healthy and ALS-afflicted skeletal muscles and NMJs.
    DOI:  https://doi.org/10.1038/s41598-022-08455-y
  16. J Pathol. 2022 Mar 17.
    Selective ablation of Nfix in macrophages attenuates muscular dystrophy by inhibiting fibro-adipogenic progenitor-dependent fibrosis.
    Marielle Saclier, Giuseppe Angelini, Chiara Bonfanti, Giada Mura, Giulia Temponi, Graziella Messina.
      Muscular dystrophies are genetic diseases characterized by chronic inflammation and fibrosis. Macrophages are immune cells that sustain muscle regeneration upon acute injury but seem deleterious in the context of chronic muscle injury such as in muscular dystrophies. Here we observed that the number of macrophages expressing the transcription factor Nfix increases in two distinct mouse models of muscular dystrophies. We showed that the deletion of Nfix in macrophages in dystrophic mice delays the establishment of fibrosis and muscle wasting and increases grasp force. Macrophages lacking Nfix expressed more TNFα and less TGFβ1 thus promoting apoptosis of fibro-adipogenic progenitors. Moreover, pharmacological treatment of dystrophic mice with a ROCK inhibitor accelerated fibrosis through the increase of Nfix expression by macrophages. Thus, we have identified Nfix as a macrophage profibrotic factor in muscular dystrophies, whose inhibition could be a therapeutic route to reduce severity of the dystrophic disease. This article is protected by copyright. All rights reserved.
    Keywords:  Nfix; fibro-adipogenic progenitors; fibrosis; inflammation; macrophage; muscular dystrophy
    DOI:  https://doi.org/10.1002/path.5895
  17. EMBO Mol Med. 2022 Mar 17. e12860
    CD38-NADase is a new major contributor to Duchenne muscular dystrophic phenotype.
    Antoine de Zélicourt, Abdallah Fayssoil, Mbarka Dakouane-Giudicelli, Isley De Jesus, Ahmed Karoui, Faouzi Zarrouki, Florence Lefebvre, Arnaud Mansart, Jean-Marie Launay, Jerome Piquereau, Mariana G Tarragó, Marcel Bonay, Anne Forand, Sophie Moog, France Piétri-Rouxel, Elise Brisebard, Claudia C S Chini, Sonu Kashyap, Matthew J Fogarty, Gary C Sieck, Mathias Mericskay, Eduardo N Chini, Ana Maria Gomez, José-Manuel Cancela, Sabine de la Porte.
      Duchenne muscular dystrophy (DMD) is characterized by progressive muscle degeneration. Two important deleterious features are a Ca2+ dysregulation linked to Ca2+ influxes associated with ryanodine receptor hyperactivation, and a muscular nicotinamide adenine dinucleotide (NAD+ ) deficit. Here, we identified that deletion in mdx mice of CD38, a NAD+ glycohydrolase-producing modulators of Ca2+ signaling, led to a fully restored heart function and structure, with skeletal muscle performance improvements, associated with a reduction in inflammation and senescence markers. Muscle NAD+ levels were also fully restored, while the levels of the two main products of CD38, nicotinamide and ADP-ribose, were reduced, in heart, diaphragm, and limb. In cardiomyocytes from mdx/CD38-/- mice, the pathological spontaneous Ca2+ activity was reduced, as well as in myotubes from DMD patients treated with isatuximab (SARCLISA® ) a monoclonal anti-CD38 antibody. Finally, treatment of mdx and utrophin-dystrophin-deficient (mdx/utr-/- ) mice with CD38 inhibitors resulted in improved skeletal muscle performances. Thus, we demonstrate that CD38 actively contributes to DMD physiopathology. We propose that a selective anti-CD38 therapeutic intervention could be highly relevant to develop for DMD patients.
    Keywords:  CD38; DMD; NAD+; calcium; cardiomyopathy
    DOI:  https://doi.org/10.15252/emmm.202012860
  18. Biosci Biotechnol Biochem. 2022 Mar 14. pii: zbac037. [Epub ahead of print]
    Mass spectrometry imaging reveals local metabolic changes in skeletal muscle due to chronic training.
    Naoko Goto-Inoue, Mizuki Morisasa, Keisuke Kimura, Tsukasa Mori, Yasuro Furuichi, Yasuko Manabe, Nobuharu L Fujii.
      Muscle atrophy is a major health problem that needs effective prevention and treatment approaches. Chronic exercise, an effective treatment strategy for atrophy, promotes muscle hypertrophy, which leads to dynamic metabolic changes; however, the metabolic changes vary among myofiber types. To investigate local metabolic changes due to chronic exercise, we utilized comprehensive proteome and mass spectrometry (MS) imaging analyses. Our training model exhibited hypertrophic features only in glycolytic myofibers. The proteome analyses demonstrated that exercise promoted anabolic pathways, such as protein synthesis, and significant changes in lipid metabolism, but not in glucose metabolism. Furthermore, the fundamental energy sources, glycogen, neutral lipids, and ATP, were sensitive to exercise, and the changes in these sources differed between glycolytic and oxidative myofibers. MS imaging revealed that the lipid composition differs among myofibers; arachidonic acid might be an effective target for promoting lipid metabolism during muscle hypertrophy in oxidative myofibers.
    Keywords:  exercise; mass spectrometry imaging; metabolites; muscle hypertrophy
    DOI:  https://doi.org/10.1093/bbb/zbac037
  19. Front Physiol. 2022 ;13 853007
    Editorial: Nutrition in the Regulation of Muscle Development and Repair.
    Olasunkanmi A J Adegoke, Yan Huang, Xing Fu, Stephen Mora.
      
    Keywords:  amino acids; fatty acids; insulin resistance; micronutrients; regeneration; repair; satellite cells; skeletal muscle
    DOI:  https://doi.org/10.3389/fphys.2022.853007
  20. Mol Ther Nucleic Acids. 2022 Mar 08. 27 1179-1190
    Benefits of therapy by dynamin-2-mutant-specific silencing are maintained with time in a mouse model of dominant centronuclear myopathy.
    Delphine Trochet, Bernard Prudhon, Lylia Mekzine, Mégane Lemaitre, Maud Beuvin, Laura Julien, Sofia Benkhelifa-Ziyyat, Mai Thao Bui, Norma Romero, Marc Bitoun.
      Dominant dynamin 2 (DNM2) mutations are responsible for the autosomal dominant centronuclear myopathy (AD-CNM), a rare progressive neuromuscular disorder ranging from severe neonatal to mild adult forms. We previously demonstrated that mutant-specific RNA interference is an efficient therapeutic strategy to rescue the muscle phenotype at the onset of the symptoms in the AD-CNM knockin-Dnm2 R465W/+ mouse model. Our objective was to evaluate the long-term benefit of the treatment along with the disease time course. We demonstrate here that the complete rescue of the muscle phenotype is maintained for at least 1 year after a single injection of adeno-associated virus expressing the mutant-specific short hairpin RNA (shRNA). This was achieved by a maintained reduction of the mutant Dnm2 transcript. Moreover, this long-term study uncovers a pathological accumulation of DNM2 protein occurring with age in the mouse model and prevented by the treatment. Conversely, a physiological DNM2 protein decrease with age was observed in muscles from wild-type mice. Therefore, this study highlights a new potential pathophysiological mechanism linked to mutant protein accumulation and underlines the importance of DNM2 protein expression level for proper muscle function. Overall, these results strengthen the allele-specific silencing approach as a robust, safe, and efficient therapy for AD-CNM.
    Keywords:  RNA interference; allele-specific silencing; dominant centronuclear myopathy; dynamin 2; gene therapy; in vivo long-term benefits
    DOI:  https://doi.org/10.1016/j.omtn.2022.02.009
  21. Mol Genet Genomics. 2022 Mar 15.
    PGC-1α affects skeletal muscle and adipose tissue development by regulating mitochondrial biogenesis.
    Shaofen Kong, Bolin Cai, Qinghua Nie.
      The discovery and interpretation of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) protein in mitochondrial biogenesis, skeletal muscle and adipose tissue development has broad research prospects, so it is important to review the related studies of PGC-1α in detail and comprehensively. PGC-1α is a protein composed of 798 amino acids (aa) with a molecular weight of about 91 kDa. PGC-1α is involved in the operation of the respiratory chain by combining with deacetylase and phosphorylase to bind some nuclear receptors. In addition, PGC-1α affects skeletal muscle and adipose metabolism by regulating mitochondrial oxidative phosphorylation. Recently, new data suggest that regulating mitochondrial metabolism in adipose tissue may be an effective adjunct to the treatment of obesity. In addition, dietary resveratrol, which has an effective anti-obesity effect, has been shown to promote mitochondrial biosynthesis by activating AMPK/PGC-1α axis, as well as to regenerate muscle damaged by obesity. In this review, we combined previous studies to explore the latest studies, showing that PGC-1α can regulate mitochondrial biogenesis and is regulated by AMPK and SIRT1. Furthermore, PGC-1α is a favored protein, which not only regulates muscle fiber type, inhibits muscle atrophy, but also participates in browning of white adipose tissue (WAT) and regulates body heat production. So, we concluded that PGC-1α is a key gene in mitochondrial biogenesis and plays an important role in the regulation and regulation of mitochondrial biogenesis along with other genes involved in the process. Meanwhile, PGC-1α acts as a core metabolic regulator in adipose tissue and skeletal muscle. This review comprehensively summarizes a large number of research findings. First, the role of PGC-1α in mitochondrial biogenesis was clarified, and then the key role of PGC-1α in the development of skeletal muscle and adipose tissue was reevaluated. Furthermore, the role of PGC-1α in some human diseases was discussed. Finally, the role of PGC-1α as a major gene in poultry was pointed out, and the future research direction was proposed.
    Keywords:  Adipose tissue; Mitochondria; Mitochondrial biogenesis; PGC-1α; Skeletal muscle
    DOI:  https://doi.org/10.1007/s00438-022-01878-2
  22. Nat Commun. 2022 Mar 17. 13(1): 1439
    Primary cilia on muscle stem cells are critical to maintain regenerative capacity and are lost during aging.
    Adelaida R Palla, Keren I Hilgendorf, Ann V Yang, Jaclyn P Kerr, Aaron C Hinken, Janos Demeter, Peggy Kraft, Nancie A Mooney, Nora Yucel, David M Burns, Yu Xin Wang, Peter K Jackson, Helen M Blau.
      During aging, the regenerative capacity of muscle stem cells (MuSCs) decreases, diminishing the ability of muscle to repair following injury. We found that the ability of MuSCs to regenerate is regulated by the primary cilium, a cellular protrusion that serves as a sensitive sensory organelle. Abolishing MuSC cilia inhibited MuSC proliferation in vitro and severely impaired injury-induced muscle regeneration in vivo. In aged muscle, a cell intrinsic defect in MuSC ciliation was associated with the decrease in regenerative capacity. Exogenous activation of Hedgehog signaling, known to be localized in the primary cilium, promoted MuSC expansion, both in vitro and in vivo. Delivery of the small molecule Smoothened agonist (SAG1.3) to muscles of aged mice restored regenerative capacity leading to increased strength post-injury. These findings provide fresh insights into the signaling dysfunction in aged MuSCs and identify the ciliary Hedgehog signaling pathway as a potential therapeutic target to counter the loss of muscle regenerative capacity which accompanies aging.
    DOI:  https://doi.org/10.1038/s41467-022-29150-6
  23. Sci Adv. 2022 Mar 18. 8(11): eabn0485
    Piezo1 regulates the regenerative capacity of skeletal muscles via orchestration of stem cell morphological states.
    Nuoying Ma, Delia Chen, Ji-Hyung Lee, Paola Kuri, Edward Blake Hernandez, Jacob Kocan, Hamd Mahmood, Elisia D Tichy, Panteleimon Rompolas, Foteini Mourkioti.
      Muscle stem cells (MuSCs) are essential for tissue homeostasis and regeneration, but the potential contribution of MuSC morphology to in vivo function remains unknown. Here, we demonstrate that quiescent MuSCs are morphologically heterogeneous and exhibit different patterns of cellular protrusions. We classified quiescent MuSCs into three functionally distinct stem cell states: responsive, intermediate, and sensory. We demonstrate that the shift between different stem cell states promotes regeneration and is regulated by the sensing protein Piezo1. Pharmacological activation of Piezo1 is sufficient to prime MuSCs toward more responsive cells. Piezo1 deletion in MuSCs shifts the distribution toward less responsive cells, mimicking the disease phenotype we find in dystrophic muscles. We further demonstrate that Piezo1 reactivation ameliorates the MuSC morphological and regenerative defects of dystrophic muscles. These findings advance our fundamental understanding of how stem cells respond to injury and identify Piezo1 as a key regulator for adjusting stem cell states essential for regeneration.
    DOI:  https://doi.org/10.1126/sciadv.abn0485
  24. Front Physiol. 2021 ;12 785151
    Driving an Oxidative Phenotype Protects Myh4 Null Mice From Myofiber Loss During Postnatal Growth.
    Caiyun Zeng, Hao Shi, Laila T Kirkpatrick, Aymeric Ricome, Sungkwon Park, Jason M Scheffler, Kevin M Hannon, Alan L Grant, David E Gerrard.
      Postnatal muscle growth is accompanied by increases in fast fiber type compositions and hypertrophy, raising the possibility that a slow to fast transition may be partially requisite for increases in muscle mass. To test this hypothesis, we ablated the Myh4 gene, and thus myosin heavy chain IIB protein and corresponding fibers in mice, and examined its consequences on postnatal muscle growth. Wild-type and Myh4 -/- mice had the same number of muscle fibers at 2 weeks postnatal. However, the gastrocnemius muscle lost up to 50% of its fibers between 2 and 4 weeks of age, though stabilizing thereafter. To compensate for the lack of functional IIB fibers, type I, IIA, and IIX(D) fibers increased in prevalence and size. To address whether slowing the slow-to-fast fiber transition process would rescue fiber loss in Myh4 -/- mice, we stimulated the oxidative program in muscle of Myh4 -/- mice either by overexpression of PGC-1α, a well-established model for fast-to-slow fiber transition, or by feeding mice AICAR, a potent AMP kinase agonist. Forcing an oxidative metabolism in muscle only partially protected the gastrocnemius muscle from loss of fibers in Myh4 -/- mice. To explore whether traditional means of stimulating muscle hypertrophy could overcome the muscling deficits in postnatal Myh4 -/- mice, myostatin null mice were bred with Myh4 -/- mice, or Myh4 -/- mice were fed the growth promotant clenbuterol. Interestingly, both genetic and pharmacological stimulations had little impact on mice lacking a functional Myh4 gene suggesting that the existing muscle fibers have maximized its capacity to enlarge to compensate for the lack of its neighboring IIB fibers. Curiously, however, cell signaling events responsible for IIB fiber formation remained intact in the tissue. These findings further show disrupting the slow-to-fast transition of muscle fibers compromises muscle growth postnatally and suggest that type IIB myosin heavy chain expression and its corresponding fiber type may be necessary for fiber maintenance, transition and hypertrophy in mice. The fact that forcing muscle metabolism toward a more oxidative phenotype can partially compensates for the lack of an intact Myh4 gene provides new avenues for attenuating the loss of fast-twitch fibers in aged or diseased muscles.
    Keywords:  PGC-1α; clenbuterol; clenbuterol (CB); muscle fiber type; myosin heavy chain; myostatin; oxidative metabolism
    DOI:  https://doi.org/10.3389/fphys.2021.785151
  25. FEBS Lett. 2022 Mar 16.
    EZH2 modulates retinoic acid signaling to ensure myotube formation during development.
    Venkata Thulabandu, James W Ferguson, Melissa Phung, Radhika P Atit.
      Sequential differentiation of pre-somitic progenitors into myocytes and subsequently into myotubes and myofibers is essential for the myogenic differentiation program (MDP) crucial for muscle development. Signaling factors involved in MDP are Polycomb Repressive Complex 2 (PRC2) targets in various developmental contexts. PRC2 is active in the developing myotomes during MDP, but how it regulates MDP is unclear. Here, we found that myocyte differentiation to myotubes requires Enhancer of Zeste 2 (EZH2), the catalytic component of PRC2. We observed elevated retinoic-acid (RA) signaling in the prospective myocytes in the Ezh2 mutants (E8.5-MusEzh2 ), and its inhibition can partially rescue the myocyte differentiation defect. Together, our data demonstrate a new role for PRC2-EZH2 during myocyte differentiation into myotubes by modulating RA signaling.
    Keywords:  Muscle Development; Muscle Differentiation Program; Myotube Formation; Polycomb Repressive Complex2; Retinoic Acid Signaling
    DOI:  https://doi.org/10.1002/1873-3468.14334
  26. Thyroid. 2022 Mar 14.
    Maternal exercise before and during pregnancy facilitates embryonic myogenesis by enhancing thyroid hormone signaling.
    Yao Gao, Liang Zhao, Jun Seok Son, Xiangdong Liu, Yanting Chen, Jeanene Marie Deavila, Mei-Jun Zhu, Gordon K Murdoch, Min Du.
      BACKGROUND: Maternal exercise (ME) improves fetal and offspring muscle development, but mechanisms remain to be established. Since thyroid hormone (TH) is critical for cell differentiation during embryonic development, we hypothesized that ME elevates TH receptor (THR) signaling in embryos, which promotes embryonic myogenesis.METHODS: Female mice were exercised daily on a treadmill or received a daily TH injection (T3I). Embryos (E12.5) and P19 cells were used for studying effects of TH on embryonic myogenesis. TH levels in serum and embryos after ME or T3I were analyzed. Expression of TH signaling related genes and myogenic genes were assessed. THRα binding to the promoters of myogenic genes was investigated by CHIP-qPCR. A CRISPR/CAS9 plasmid was utilized to knock out THRα in P19 cells.
    RESULTS: ME elevated TH levels in both maternal circulation and embryos, which were correlated with enhanced TH signaling and myogenesis. At E12.5, both myogenic determinants (Pax3, Pax7) and myogenic regulatory factors (Myf5, Myod) were upregulated in ME embryos. ME increased THRα content and elevated mRNA expression of TH transporter Slc16a2 and deiodinase Dio2. In addition, the THRα binding to the promoters of Pax3/7 was increased. In P19 embryoid bodies, T3 promoted myogenic differentiation, which was abolished by ablating THRα. Further, maternal daily injection of T3 at a level matching exercised mothers promoted embryonic myogenesis.
    CONCLUSIONS: ME promotes TH delivery to the embryos and enhances embryonic myogenesis, which is partially mediated by enhanced TH signaling in ME embryos.
    DOI:  https://doi.org/10.1089/thy.2021.0639
  27. J Physiol Biochem. 2022 Mar 17.
    Decoding the role of inflammation-related microRNAs in cancer cachexia: a study using HPV16-transgenic mice and in silico approaches.
    Joana M O Santos, Sara Peixoto da Silva, Margarida M S M Bastos, Paula A Oliveira, Rui M Gil da Costa, Rui Medeiros.
      Cachexia is associated with poor prognosis in cancer patients, and inflammation is one of its main drive factors. MicroRNAs have recently emerged as important players in cancer cachexia and are involved in reciprocal regulation networks with pro-inflammatory signaling pathways. We hypothesize that inflammation-driven cancer cachexia is regulated by specific microRNAs. The aim of this study is to explore the expression and role of inflammation-related microRNAs in muscle wasting. HPV16-transgenic mice develop systemic inflammation and muscle wasting and are a model for cancer cachexia. We employed gastrocnemius muscle samples from these mice to study the expression of microRNAs. Bioinformatic tools were then used to explore their potential role in muscle wasting. Among the microRNAs studied, miR-223-3p (p = 0.004), let-7b-5p (p = 0.034), miR-21a-5p (p = 0.034), miR-150-5p (p = 0.027), and miR-155-5p (p = 0.011) were significantly upregulated in muscles from cachectic mice. In silico analysis showed that these microRNAs participate in several processes related to muscle wasting, including muscle structure development and regulation of the MAPK pathway. When analyzing protein-protein interactions (PPI)-networks, two major clusters and the top 10 hubs were obtained. From the top 10, Kras (p = 0.050) and Ccdn1 (p = 0.009) were downregulated in cachectic muscles, as well as Map2k3 (p = 0.007). These results show that miR-223-3p, let-7b-5p, miR-21a-5p, miR-150-5p, and miR-155-5p, play a role in muscle wasting in HPV16 transgenic mice, possible through regulating the MAPK cascades. Future experimental studies are required to validate our in silico analysis, and to explore the usefulness of these microRNAs and MAPK signaling as new potential biomarkers or therapy targets for cancer cachexia.
    Keywords:  Cancer cachexia; HPV16; Inflammation; K14-HPV16; MicroRNAs; Muscle wasting
    DOI:  https://doi.org/10.1007/s13105-021-00866-1
  28. Neuron. 2022 Mar 11. pii: S0896-6273(22)00176-3. [Epub ahead of print]
    Loss of mouse Stmn2 function causes motor neuropathy.
    Irune Guerra San Juan, Leslie A Nash, Kevin S Smith, Marcel F Leyton-Jaimes, Menglu Qian, Joseph R Klim, Francesco Limone, Alexander B Dorr, Alexander Couto, Greta Pintacuda, Brian J Joseph, D Eric Whisenant, Caroline Noble, Veronika Melnik, Deirdre Potter, Amie Holmes, Aaron Burberry, Matthijs Verhage, Kevin Eggan.
      Amyotrophic lateral sclerosis (ALS) is characterized by motor neuron degeneration accompanied by aberrant accumulation and loss of function of the RNA-binding protein TDP43. Thus far, it remains unresolved to what extent TDP43 loss of function directly contributes to motor system dysfunction. Here, we employed gene editing to find whether the mouse ortholog of the TDP43-regulated gene STMN2 has an important function in maintaining the motor system. Both mosaic founders and homozygous loss-of-function Stmn2 mice exhibited neuromuscular junction denervation and fragmentation, resulting in muscle atrophy and impaired motor behavior, accompanied by an imbalance in neuronal microtubule dynamics in the spinal cord. The introduction of human STMN2 through BAC transgenesis was sufficient to rescue the motor phenotypes observed in Stmn2 mutant mice. Collectively, our results demonstrate that disrupting the ortholog of a single TDP43-regulated RNA is sufficient to cause substantial motor dysfunction, indicating that disruption of TDP43 function is likely a contributor to ALS.
    Keywords:  ALS; CRISPR; SCG10; TARDBP; TDP43; microtubules; motor neuron; motor neuropathy; neuromuscular junction; stathmin 2
    DOI:  https://doi.org/10.1016/j.neuron.2022.02.011
  29. Elife. 2022 Mar 18. pii: e74782. [Epub ahead of print]11
    Hyperphosphatemia increases inflammation to exacerbate anemia and skeletal muscle wasting independently of FGF23-FGFR4 signaling.
    Brian Czaya, Kylie Heitman, Isaac Campos, Christopher Yanucil, Dominik Kentrup, David Westbrook, Orlando Gutierrez, Jodie L Babitt, Grace Jung, Isidro B Salusky, Mark Hanudel, Christian Faul.
      Elevations in plasma phosphate concentrations (hyperphosphatemia) occur in chronic kidney disease (CKD), in certain genetic disorders, and following the intake of a phosphate-rich diet. Whether hyperphosphatemia and/or associated changes in metabolic regulators, including elevations of fibroblast growth factor 23 (FGF23) directly contribute to specific complications of CKD is uncertain. Here we report that similar to patients with CKD, mice with adenine-induced CKD develop inflammation, anemia and skeletal muscle wasting. These complications are also observed in mice fed high phosphate diet even without CKD. Ablation of pathologic FGF23-FGFR4 signaling did not protect mice on an increased phosphate diet or mice with adenine-induced CKD from these sequelae. However, low phosphate diet ameliorated anemia and skeletal muscle wasting in a genetic mouse model of CKD. Our mechanistic in vitro studies indicate that phosphate elevations induce inflammatory signaling and increase hepcidin expression in hepatocytes, a potential causative link between hyperphosphatemia, anemia and skeletal muscle dysfunction. Our study suggests that high phosphate intake, as caused by the consumption of processed food, may have harmful effects irrespective of pre-existing kidney injury, supporting not only the clinical utility of treating hyperphosphatemia in CKD patients but also arguing for limiting phosphate intake in healthy individuals.
    Keywords:  cell biology; immunology; inflammation; mouse
    DOI:  https://doi.org/10.7554/eLife.74782
  30. J Exp Biol. 2022 Mar 15. pii: jeb.243630. [Epub ahead of print]
    Bridging the muscle genome to phenome across multiple biological scales.
    SaiLavanyaa Sundar, Barbora Rimkus, Prabath S Meemaduma, Samuel deLap, Nicholas LaFave, Alice W Racca, Pabodha Hettige, Jeffrey Moore, Matthew Gage, Andrea Shehaj, Nicolai Konow.
      Muscle is highly hierarchically organized, with functions shaped by genetically controlled expression of protein ensembles with different isoform profiles at the sarcomere scale. However, it remains unclear how isoform profiles shape whole muscle performance. We compared two mouse hind limb muscles, the slow, relatively parallel-fibered soleus (SOL) and the faster, more pennate-fibered tibialis anterior (TA), across scales: from gene regulation, isoform expression and translation speed, to force-length-velocity-power for intact muscles. Expression of myosin heavy-chain (MHC) isoforms directly corresponded with contraction velocity. The fast-twitch TA with fast MHC isoforms had faster unloaded velocities (actin sliding velocity, VACTIN; peak fiber velocity, VMAX) than slow-twitch SOL. For SOL, VACTIN was biased towards VACTIN for purely slow MHC I, despite this muscle's even fast and slow MHC isoform composition. Our multi-scale results clearly identified a consistent and significant dampening in fiber shortening velocities for both muscles, underscoring an indirect correlation between VACTIN and fiber VMAX that may be influenced by differences in fiber architecture, along with internal loading due to both passive and active effects. These influences correlate with the increased peak force and power in the slightly more pennate TA, leading to a broader length range of near-optimal force production. Conversely, a greater force-velocity curvature in the near-parallel fibered SOL highlights the fine-tuning by molecular-scale influences including myosin heavy and light chain expression along with whole muscle characteristics. Our results demonstrate that the individual gene, protein, and whole fiber characteristics do not directly reflect overall muscle performance but that intricate fine-tuning across scales shapes specialized muscle function.
    Keywords:  Mouse; Myosin isoforms; Shortening velocity; Soleus; Tibialis anterior; Transcriptomics
    DOI:  https://doi.org/10.1242/jeb.243630
  31. J Cachexia Sarcopenia Muscle. 2022 Mar 17.
    Targeting MuRF1 by small molecules in a HFpEF rat model improves myocardial diastolic function and skeletal muscle contractility.
    Volker Adams, Antje Schauer, Antje Augstein, Virginia Kirchhoff, Runa Draskowski, Anett Jannasch, Keita Goto, Gemma Lyall, Anita Männel, Peggy Barthel, Norman Mangner, Ephraim B Winzer, Axel Linke, Siegfried Labeit.
      BACKGROUND: About half of heart failure (HF) patients, while having preserved left ventricular function, suffer from diastolic dysfunction (so-called HFpEF). No specific therapeutics are available for HFpEF in contrast to HF where reduced ejection fractions (HFrEF) can be treated pharmacologically. Myocardial titin filament stiffening, endothelial dysfunction, and skeletal muscle (SKM) myopathy are suspected to contribute to HFpEF genesis. We previously described small molecules interfering with MuRF1 target recognition thereby attenuating SKM myopathy and dysfunction in HFrEF animal models. The aim of the present study was to test the efficacy of one small molecule (MyoMed-205) in HFpEF and to describe molecular changes elicited by MyoMed-205.METHODS: Twenty-week-old female obese ZSF1 rats received the MuRF1 inhibitor MyoMed-205 for 12 weeks; a comparison was made to age-matched untreated ZSF1-lean (healthy) and obese rats as controls. LV (left ventricle) function was assessed by echocardiography and by invasive haemodynamic measurements until week 32. At week 32, SKM and endothelial functions were measured and tissues collected for molecular analyses. Proteome-wide analysis followed by WBs and RT-PCR was applied to identify specific genes and affected molecular pathways. MuRF1 knockout mice (MuRF1-KO) SKM tissues were included to validate MuRF1-specificity.
    RESULTS: By week 32, untreated obese rats had normal LV ejection fraction but augmented E/e' ratios and increased end diastolic pressure and myocardial fibrosis, all typical features of HFpEF. Furthermore, SKM myopathy (both atrophy and force loss) and endothelial dysfunction were detected. In contrast, MyoMed-205 treated rats had markedly improved diastolic function, less myocardial fibrosis, reduced SKM myopathy, and increased SKM function. SKM extracts from MyoMed-205 treated rats had reduced MuRF1 content and lowered total muscle protein ubiquitination. In addition, proteomic profiling identified eight proteins to respond specifically to MyoMed-205 treatment. Five out of these eight proteins are involved in mitochondrial metabolism, dynamics, or autophagy. Consistent with the mitochondria being a MyoMed-205 target, the synthesis of mitochondrial respiratory chain complexes I + II was increased in treated rats. MuRF1-KO SKM controls also had elevated mitochondrial complex I and II activities, also suggesting mitochondrial activity regulation by MuRF1.
    CONCLUSIONS: MyoMed-205 improved myocardial diastolic function and prevented SKM atrophy/function in the ZSF1 animal model of HFpEF. Mechanistically, SKM benefited from an attenuated ubiquitin proteasome system and augmented synthesis/activity of proteins of the mitochondrial respiratory chain while the myocardium seemed to benefit from reduced titin modifications and fibrosis.
    Keywords:  Diastolic dysfunction; HFpEF; MuRF1; Muscle atrophy; Skeletal muscle dysfunction; ZSF1
    DOI:  https://doi.org/10.1002/jcsm.12968
  32. Dis Model Mech. 2022 Mar 16. pii: dmm.049437. [Epub ahead of print]
    Characterization of a novel zebrafish model of SPEG-related centronuclear myopathy.
    Karla G Espinosa, Salma Geissah, Linda Groom, Jonathan Volpatti, Ian C Scott, Robert T Dirksen, Mo Zhao, James J Dowling.
      Centronuclear myopathy (CNM) is a congenital neuromuscular disorder caused by pathogenic variation in genes associated with membrane trafficking and excitation-contraction coupling (ECC). Bi-allelic autosomal recessive mutations in striated muscle enriched protein kinase (SPEG) account for a subset of CNM patients. Previous research has been limited by the perinatal lethality of constitutive Speg knockout mice. Thus, the precise biological role of SPEG in developing skeletal muscle remains unknown. To address this issue, we generated zebrafish spega, spegb, and spega;spegb (speg-DKO) mutant lines. We demonstrate that speg-DKO zebrafish faithfully recapitulate multiple phenotypes associated with CNM, including disruption of the ECC machinery, dysregulation of calcium homeostasis during ECC, and impairment of muscle performance. Taking advantage of zebrafish models of multiple CNM genetic subtypes, we compared novel and known disease markers in speg-DKO with mtm1-KO and DNM2-S619L transgenic zebrafish. We observed desmin accumulation common to all CNM subtypes, and DNM2 upregulation in muscle of both speg-DKO and mtm1-KO zebrafish. In all, we establish a new model of SPEG-related CNM, and identify abnormalities in this model suitable for defining disease pathomechanisms and evaluating potential therapies.
    Keywords:  Centronuclear myopathy; Disease model; Excitation-contraction coupling; Muscle; SPEG; Zebrafish
    DOI:  https://doi.org/10.1242/dmm.049437
  33. Nat Rev Endocrinol. 2022 Mar 18.
    Exerkines in health, resilience and disease.
    Lisa S Chow, Robert E Gerszten, Joan M Taylor, Bente K Pedersen, Henriette van Praag, Scott Trappe, Mark A Febbraio, Zorina S Galis, Yunling Gao, Jacob M Haus, Ian R Lanza, Carl J Lavie, Chih-Hao Lee, Alejandro Lucia, Cedric Moro, Ambarish Pandey, Jeremy M Robbins, Kristin I Stanford, Alice E Thackray, Saul Villeda, Matthew J Watt, Ashley Xia, Juleen R Zierath, Bret H Goodpaster, Michael P Snyder.
      The health benefits of exercise are well-recognized and are observed across multiple organ systems. These beneficial effects enhance overall resilience, healthspan and longevity. The molecular mechanisms that underlie the beneficial effects of exercise, however, remain poorly understood. Since the discovery in 2000 that muscle contraction releases IL-6, the number of exercise-associated signalling molecules that have been identified has multiplied. Exerkines are defined as signalling moieties released in response to acute and/or chronic exercise, which exert their effects through endocrine, paracrine and/or autocrine pathways. A multitude of organs, cells and tissues release these factors, including skeletal muscle (myokines), the heart (cardiokines), liver (hepatokines), white adipose tissue (adipokines), brown adipose tissue (baptokines) and neurons (neurokines). Exerkines have potential roles in improving cardiovascular, metabolic, immune and neurological health. As such, exerkines have potential for the treatment of cardiovascular disease, type 2 diabetes mellitus and obesity, and possibly in the facilitation of healthy ageing. This Review summarizes the importance and current state of exerkine research, prevailing challenges and future directions.
    DOI:  https://doi.org/10.1038/s41574-022-00641-2
  34. J Cachexia Sarcopenia Muscle. 2022 Mar 17.
    Mapping ongoing nutrition intervention trials in muscle, sarcopenia, and cachexia: a scoping review of future research.
    Camila E Orsso, Montserrat Montes-Ibarra, Merran Findlay, Barbara S van der Meij, Marian A E de van der Schueren, Francesco Landi, Alessandro Laviano, Carla M Prado.
      Muscle loss alone, or in the context of sarcopenia or cachexia, is a prevalent condition and a predictor of negative outcomes in aging and disease. As adequate nutrition is essential for muscle maintenance, a growing number of studies has been conducted to explore the role of specific nutrients on muscle mass or function. Nonetheless, more research is needed to guide evidence-based recommendations. This scoping review aimed to compile and document ongoing clinical trials investigating nutrition interventions as a strategy to prevent or treat low muscle mass or function (strength and physical performance), sarcopenia, or cachexia. ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform were searched up to 21 April 2021 for planned and ongoing trials. Randomized controlled trials with ≥20 participants per arm were included based on intent to explore the effects of nutrition interventions on muscle-related outcomes (i.e. muscle mass or strength, physical performance, or muscle synthesis rate) in both clinical and non-clinical conditions (i.e. aging). Two reviewers independently screened records for eligibility, and a descriptive synthesis of trials characteristics was conducted. A total of 113 trials were included in the review. Most trials (69.0%) enroll adults with clinical conditions, such as cancer (19.5%), obesity and metabolic diseases (16.8%), and musculoskeletal diseases (10.7%). The effects of nutrition interventions on age-related muscle loss are explored in 31% of trials. Although nutrition interventions of varied types were identified, food supplements alone (48.7%) or combined with dietary advice (11.5%) are most frequently reported. Protein (17.7%), amino acids (10.6%), and β-hydroxy-β-methylbutyrate (HMB, 6.2%) are the top three food supplements' nutrients under investigation. Primary outcome of most trials (54.9%) consists of measures of muscle mass alone or in combination with muscle strength and/or performance (as either primary or secondary outcomes). Muscle strength and physical performance are primary outcomes of 38% and 31.9% of the trials, respectively. These measurements were obtained using a variety of techniques. Only a few trials evaluate muscle synthesis rate either as a primary or secondary outcome (5.3%). Several nutrition studies focusing on muscle, sarcopenia, and cachexia are underway and can inform future research in this area. Although many trials have similar type of interventions, methodological heterogeneity may challenge study comparisons, and future meta-analyses aiming to provide evidence-based recommendations. Upcoming research in this area may benefit from guidelines for the assessment of therapeutic effects of nutrition interventions.
    Keywords:  Cachexia; Clinical trials; Dietary intervention; Muscle; Nutrition intervention; Sarcopenia
    DOI:  https://doi.org/10.1002/jcsm.12954
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