bims-moremu Biomed News
on Molecular regulators of muscle mass
Issue of 2021‒05‒30
thirty-nine papers selected by
Anna Vainshtein
Craft Science Inc.

  1. PLoS One. 2021 ;16(5): e0252135
      Skeletal muscle atrophy is a feature of aging (termed sarcopenia) and various diseases, such as cancer and kidney failure. Effective drug treatment options for muscle atrophy are lacking. The tapeworm medication, niclosamide is being assessed for repurposing to treat numerous diseases, including end-stage cancer metastasis and hepatic steatosis. In this study, we investigated the potential of niclosamide as a repurposing drug for muscle atrophy. In a myotube atrophy model using the glucocorticoid, dexamethasone, niclosamide did not prevent the reduction in myotube diameter or the decreased expression of phosphorylated FOXO3a, which upregulates the ubiquitin-proteasome pathway of muscle catabolism. Treatment of normal myotubes with niclosamide did not activate mTOR, a major regulator of muscle protein synthesis, and increased the expression of atrogin-1, which is induced in catabolic states. Niclosamide treatment also inhibited myogenesis in muscle precursor cells, enhanced the expression of myoblast markers Pax7 and Myf5, and downregulated the expression of differentiation markers MyoD, MyoG and Myh2. In an animal model of muscle atrophy, niclosamide did not improve muscle mass, grip strength or muscle fiber cross-sectional area. Muscle atrophy is also feature of cancer cachexia. IC50 analyses indicated that niclosamide was more cytotoxic for myoblasts than cancer cells. In addition, niclosamide did not suppress the induction of iNOS, a key mediator of atrophy, in an in vitro model of cancer cachexia and did not rescue myotube diameter. Overall, these results suggest that niclosamide may not be a suitable repurposing drug for glucocorticoid-induced skeletal muscle atrophy or cancer cachexia. Nevertheless, niclosamide may be employed as a compound to study mechanisms regulating myogenesis and catabolic pathways in skeletal muscle.
  2. Methods Mol Biol. 2021 ;2299 357-370
      Fibrosis in skeletal muscle is the natural tissue response to persistent damage and chronic inflammatory states, cursing with altered muscle stem cell regenerative functions and increased activation of fibrogenic mesenchymal stromal cells. Exacerbated deposition of extracellular matrix components is a characteristic feature of human muscular dystrophies, neurodegenerative diseases affecting muscle and aging. The presence of fibrotic tissue not only impedes normal muscle contractile functions but also hampers effective gene and cell therapies. There is a lack of appropriate experimental models to study fibrosis. In this chapter, we highlight recent developments on skeletal muscle fibrosis in mice and expand previously described methods by our group to exacerbate and accelerate fibrosis development in murine muscular dystrophy models and to study the presence of fibrosis in muscle samples. These methods will help understand the molecular and biological mechanisms involved in muscle fibrosis and to identify novel therapeutic strategies to limit the progression of fibrosis in muscular dystrophy.
    Keywords:  Chronic injury; Duchenne muscular dystrophy; Exercise; Fibrosis; Skeletal muscle regeneration; mdx mice
  3. Acta Biomater. 2021 May 25. pii: S1742-7061(21)00330-5. [Epub ahead of print]
      The biological basis of Duchenne muscular dystrophy (DMD) pathology is only partially characterized and there are still few disease-modifying therapies available, therein underlying the value of strategies to model and study DMD. Dystrophin, the causative gene of DMD, is responsible for linking the cytoskeleton of muscle fibers to the extracellular matrix beyond the sarcolemma. We posited that disease-associated phenotypes not yet captured by two-dimensional culture methods would arise by generating multinucleated muscle cells within a three-dimensional (3D) extracellular matrix environment. Herein we report methods to produce 3D human skeletal muscle microtissues (hMMTs) using clonal, immortalized myoblast lines established from healthy and DMD donors. We also established protocols to evaluate immortalized hMMT self-organization and myotube maturation, as well as calcium handling, force generation, membrane stability (i.e., creatine kinase activity and Evans blue dye permeability) and contractile apparatus organization following electrical-stimulation. In examining hMMTs generated with a cell line wherein the dystrophin gene possessed a duplication of exon 2, we observed rare dystrophin-positive myotubes, which were not seen in 2D cultures. Further, we show that treating DMD hMMTs with a β1-integrin activating antibody, improves contractile apparatus maturation and stability. Hence, immortalized myoblast-derived DMD hMMTs offer a pre-clinical system with which to investigate therapeutic strategies for duplicated exon 2 skipping or those that protect muscle cells from contraction-induced injury. STATEMENT OF SIGNIFICANCE: : Duchenne muscular dystrophy (DMD) is a progressive muscle-wasting disorder that is caused by mutation of the dystrophin gene. The biological basis of DMD pathology is only partially characterized and there is no cure for this fatal disease. Here we report a method to produce 3D human skeletal muscle microtissues (hMMTs) using immortalized human DMD and healthy myoblasts. Morphological and functional assessment revealed DMD-associated pathophysiology including impaired calcium handling and the presence of dystrophin-positive revertant muscle cells, a feature of many DMD patients that has not been recapitulated in culture prior to this report. We further demonstrate that this "DMD in a dish" system can be used as a pre-clinical assay to test a putative DMD therapeutic and study the mechanism of action.
    Keywords:  DMD; Disease modeling; Dystrophin; Human skeletal muscle; Revertant fiber; Tissue Engineering; immortalized human myoblast; therapy
  4. Biochem Biophys Rep. 2021 Jul;26 101019
      Essentially employed for the treatment of airway obstructions in humans, β-agonists are also known to have an anabolic effect in animals' skeletal muscle. In vivo and in vitro studies have attested the increase in animal body mass and the hypertrophy of muscle cells following the administration of specific β-agonists. However, the contribution of β-agonists to C2C12 myoblasts growth remains obscure. We therefore aimed to investigate the impact of β1-and β2-agonist drugs on the proliferation and differentiation of skeletal muscle cells. Direct observations and cytotoxicity assay showed that clenbuterol, salbutamol, cimaterol and ractopamine enhanced muscle cell growth and viability during the proliferation stage. Structural examinations coupled to Western blot analysis indicated that salbutamol and cimaterol triggered a decrease in myotube formation. A better comprehension of the effect of β-agonists on myogenic regulatory genes in the muscle cells is crucial to establish a specific role of β-agonists in muscle development, growth, and regeneration.
    Keywords:  Agonist drugs; C2C12; DM, Differentiation Medium; Differentiation; GM, Growth medium; MyHC, Myosin heavy chain; MyoD, Myoblast determination protein 1; Proliferation
  5. J Physiol. 2021 May 25.
      KEY POINTS: A hallmark trait of aging skeletal muscle health is a reduction in size and function, which is most pronounced in the fast muscle fibers. We studied older men (74±4y) with a history of lifelong (>50y) endurance exercise to examine potential benefits for slow and fast muscle fiber size and contractile function. Lifelong endurance exercisers had slow muscle fibers that were larger, stronger, faster, and more powerful than young exercisers (25±1y) and age-matched non-exercisers (75±2y). Limited benefits with lifelong endurance exercise were noted in the fast muscle fibers. These findings suggest that additional exercise modalities (e.g., resistance exercise) or other therapeutic interventions are needed to target fast muscle fibers with age.ABSTRACT: We investigated single muscle fiber size and contractile function among three groups of men: lifelong exercisers (LLE; n = 21, 74±4y), old healthy non-exercisers (OH; n = 10, 75±2y), and young exercisers (YE; n = 10, 25±1y). On average, LLE exercised ∼5d/wk for ∼7h/wk over the past 53±6y. LLE were subdivided based on lifelong exercise intensity into performance (LLE-P, n = 14) and fitness (LLE-F, n = 7). Muscle biopsies (vastus lateralis) were examined for myosin heavy chain (MHC) slow (MHC I) and fast (MHC IIa) fiber size and function (strength, speed, power). LLE MHC I size (7624±2765 μm2 ) was 25-40% larger (P<0.001) than YE (6106±1710 μm2 ) and OH (5476±2467 μm2 ). LLE MHC I fibers were ∼20% stronger, ∼10% faster and ∼30% more powerful than YE and OH (P<0.05). In contrast, LLE MHC IIa size (6466±2659 μm2 ) was similar to OH (6237±2525 μm2 ; P = 0.854), with both groups ∼20% smaller (P<0.001) than YE (7860±1930 μm2 ). MHC IIa contractile function was variable across groups, with a hierarchical pattern (OH>LLE>YE; P<0.05) in normalized power among OH (16.7±6.4 W•L-1 ), LLE (13.9±4.5 W•L-1 ), and YE (12.4±3.5 W•L-1 ). The LLE-P and LLE-F had similar single fiber profiles with MHC I power driven by speed (LLE-P) or force (LLE-F), suggesting exercise intensity impacted slow muscle fiber mechanics. These data suggest that lifelong endurance exercise benefited slow muscle fiber size and function. Comparable fast fiber characteristics between LLE and OH, regardless of training intensity, suggest other exercise modes (e.g., resistance training) or myotherapeutics may be necessary to preserve fast muscle fiber size and performance with age. This article is protected by copyright. All rights reserved.
    Keywords:  aging; contractile function; masters athletes; myocellular; physical activity
  6. J Biomed Mater Res A. 2021 May 26.
      Skeletal muscles normally have a remarkable ability to repair themselves; however, large muscle injuries and several myopathies diminish this ability leading to permanent loss of function. No clinical therapy yet exists that reliably restores muscle integrity and function following severe injury. Consequently, numerous tissue engineering techniques, both acellular and with cells, are being investigated to enhance muscle regeneration. Biomaterials are an essential part of these techniques as they can present physical and biochemical signals that augment the repair process. Successful tissue engineering strategies require regenerative biomaterials that either actively promote endogenous muscle repair or create an environment supportive of regeneration. This review will discuss several acellular biomaterial strategies for skeletal muscle regeneration with a focus on those under investigation in vivo. This includes materials that release bioactive molecules, biomimetic materials and immunomodulatory materials.
    Keywords:  biomaterials; endogenous repair; immunomodulation; in situ regeneration; skeletal muscle
  7. Front Nutr. 2021 ;8 615849
      Anabolic resistance is defined by a blunted stimulation of muscle protein synthesis rates (MPS) to common anabolic stimuli in skeletal muscle tissue such as dietary protein and exercise. Generally, MPS is the target of most exercise and feeding interventions as muscle protein breakdown rates seem to be less responsive to these stimuli. Ultimately, the blunted responsiveness of MPS to dietary protein and exercise underpins the loss of the amount and quality of skeletal muscle mass leading to decrements in physical performance in these populations. The increase of both habitual physical activity (including structured exercise that targets general fitness characteristics) and protein dense food ingestion are frontline strategies utilized to support muscle mass, performance, and health. In this paper, we discuss anabolic resistance as a common denominator underpinning muscle mass loss with aging, obesity, and other disease states. Namely, we discuss the fact that anabolic resistance exists as a dimmer switch, capable of varying from higher to lower levels of resistance, to the main anabolic stimuli of feeding and exercise depending on the population. Moreover, we review the evidence on whether increased physical activity and targeted exercise can be leveraged to restore the sensitivity of skeletal muscle tissue to dietary amino acids regardless of the population.
    Keywords:  chronic kidney disease; dietary protein; exercise; obesity; sarcopenia
  8. Redox Biol. 2021 May 20. pii: S2213-2317(21)00174-9. [Epub ahead of print]44 102016
      Histidine-containing dipeptides (HCDs) are abundantly expressed in striated muscles. Although important properties have been ascribed to HCDs, including H+ buffering, regulation of Ca2+ transients and protection against oxidative stress, it remains unknown whether they play relevant functions in vivo. To investigate the in vivo roles of HCDs, we developed the first carnosine synthase knockout (CARNS1-/-) rat strain to investigate the impact of an absence of HCDs on skeletal and cardiac muscle function. Male wild-type (WT) and knockout rats (4 months-old) were used. Skeletal muscle function was assessed by an exercise tolerance test, contractile function in situ and muscle buffering capacity in vitro. Cardiac function was assessed in vivo by echocardiography and cardiac electrical activity by electrocardiography. Cardiomyocyte contractile function was assessed in isolated cardiomyocytes by measuring sarcomere contractility, along with the determination of Ca2+ transient. Markers of oxidative stress, mitochondrial function and expression of proteins were also evaluated in cardiac muscle. Animals were supplemented with carnosine (1.8% in drinking water for 12 weeks) in an attempt to rescue tissue HCDs levels and function. CARNS1-/- resulted in the complete absence of carnosine and anserine, but it did not affect exercise capacity, skeletal muscle force production, fatigability or buffering capacity in vitro, indicating that these are not essential for pH regulation and function in skeletal muscle. In cardiac muscle, however, CARNS1-/- resulted in a significant impairment of contractile function, which was confirmed both in vivo and ex vivo in isolated sarcomeres. Impaired systolic and diastolic dysfunction were accompanied by reduced intracellular Ca2+ peaks and slowed Ca2+ removal, but not by increased markers of oxidative stress or impaired mitochondrial respiration. No relevant increases in muscle carnosine content were observed after carnosine supplementation. Results show that a primary function of HCDs in cardiac muscle is the regulation of Ca2+ handling and excitation-contraction coupling.
    Keywords:  Calcium transient; Cardiac dysfunction; Cardiac muscle; Carnosine; Carnosine synthase; Skeletal muscle
  9. Am J Physiol Cell Physiol. 2021 05 26.
      Skeletal muscle protein turnover plays a crucial role in controlling muscle mass and protein quality control, including sarcomeric (structural and contractile) proteins. Protein turnover is a dynamic and continual process of protein synthesis and degradation. The ubiquitin proteasome system (UPS) is a key degradative system for protein degradation and protein quality control in skeletal muscle. UPS-mediated protein quality control is known to be impaired in ageing and diseases. Exercise is a well-recognized non-pharmacological approach to promote muscle protein turnover rates. Over the past decades, we have acquired substantial knowledge of molecular mechanisms of muscle protein synthesis after exercise. However, there has been considerable gaps in the mechanisms of how muscle protein degradation is regulated at the molecular level. The main challenge to understand muscle protein degradation is due in part to the lack of solid stable isotope tracer methodology to measure muscle protein degradation rate. Understanding the mechanisms of UPS with the concomitant measurement of protein degradation rate in skeletal muscle will help identify novel therapeutic strategies to ameliorate impaired protein turnover and protein quality control in ageing and diseases. Thus, the goal of this present review is to highlight how recent advances in the field may help improve our understanding of exercise-mediated protein degradation. We discuss 1) the emerging roles of protein phosphorylation and ubiquitylation modifications in regulating proteasome-mediated protein degradation after exercise and 2) methodological advances to measure in vivo myofibrillar protein degradation rate using stable isotope tracer methods.
    Keywords:  Phosphorylation; Protein turnover; Stable isotope tracer; The ubiquitin proteasome system; Ubiquitylation
  10. Geroscience. 2021 May 27.
      Optimising approaches for measuring skeletal muscle mass and turnover that are widely applicable, minimally invasive and cost effective is crucial in furthering research into sarcopenia and cachexia. Traditional approaches for measurement of muscle protein turnover require infusion of expensive, sterile, isotopically labelled tracers which limits the applicability of these approaches in certain populations (e.g. clinical, frail elderly). To concurrently quantify skeletal muscle mass and muscle protein turnover i.e. muscle protein synthesis (MPS) and muscle protein breakdown (MPB), in elderly human volunteers using stable-isotope labelled tracers i.e. Methyl-[D3]-creatine (D3-Cr), deuterium oxide (D2O), and Methyl-[D3]-3-methylhistidine (D3-3MH), to measure muscle mass, MPS and MPB, respectively. We recruited 10 older males (71 ± 4 y, BMI: 25 ± 4 kg.m2, mean ± SD) into a 4-day study, with DXA and consumption of D2O and D3-Cr tracers on day 1. D3-3MH was consumed on day 3, 24 h prior to returning to the lab. From urine, saliva and blood samples, and a single muscle biopsy (vastus lateralis), we determined muscle mass, MPS and MPB. D3-Cr derived muscle mass was positively correlated to appendicular fat-free mass (AFFM) estimated by DXA (r = 0.69, P = 0.027). Rates of cumulative myofibrillar MPS over 3 days were 0.072%/h (95% CI, 0.064 to 0.081%/h). Whole-body MPB over 6 h was 0.052 (95% CI, 0.038 to 0.067). These rates were similar to previous literature. We demonstrate the potential for D3-Cr to be used alongside D2O and D3-3MH for concurrent measurement of muscle mass, MPS, and MPB using a minimally invasive design, applicable for clinical and frail populations.
    Keywords:  Protein synthesis; Skeletal muscle; Stable isotope tracer
  11. Appl Physiol Nutr Metab. 2021 May 26.
      SESN2 and JNK are emerging powerful stress-inducible proteins in regulating lipid metabolism. The aim of this study was to determine the underlying mechanism of SESN2/JNK signaling in exercise improving lipid disorder induced by high-fat diet (HFD). Our data showed that HFD and SESN2 knockout resulted in abnormalities including elevated body weight, increased fat mass, serum total cholesterol (TC), lipid biosynthesis related proteins, and a concomitant increase of pJNK-Thr183/Tyr185. The above changes were reversed by exercise training. SESN2 silencing or JNK inhibition in palmitate-treated C2C12 further confirmed that SESN2 and JNK play a vital role in lipid biosynthesis. Rescue experiment further demonstrated that SESN2 reduced lipid biosynthesis through inhibition of JNK. SESN2/JNK signaling axis regulates lipid biosynthesis in both animal and cell models with abnormalities of lipid metabolism induced by HFD or palmitate treatment. This study provided evidence that exercise ameliorated lipid metabolic disorder induced by HFD feeding or by SESN2 knockout. SESN2 may improve lipid metabolism through inhibition JNK expression in skeletal muscle cells, providing a molecular mechanism that may represent an attractive target for the treatment of lipid disorder. Novelty: ● Exercise improved lipid disorder induced by HFD feeding and SESN2 knockout. ● SESN2 and JNK play a vital role in lipid biosynthesis in vivo and in vitro. ● SESN2 suppressed JNK to improve lipid metabolism in skeletal muscle cells.
  12. FASEB J. 2021 Jun;35(6): e21644
      How regular physical activity is able to improve health remains poorly understood. The release of factors from skeletal muscle following exercise has been proposed as a possible mechanism mediating such systemic benefits. We describe a mechanism wherein skeletal muscle, in response to a hypertrophic stimulus induced by mechanical overload (MOV), released extracellular vesicles (EVs) containing muscle-specific miR-1 that were preferentially taken up by epidydimal white adipose tissue (eWAT). In eWAT, miR-1 promoted adrenergic signaling and lipolysis by targeting Tfap2α, a known repressor of Adrβ3 expression. Inhibiting EV release prevented the MOV-induced increase in eWAT miR-1 abundance and expression of lipolytic genes. Resistance exercise decreased skeletal muscle miR-1 expression with a concomitant increase in plasma EV miR-1 abundance, suggesting a similar mechanism may be operative in humans. Altogether, these findings demonstrate that skeletal muscle promotes metabolic adaptations in adipose tissue in response to MOV via EV-mediated delivery of miR-1.
    Keywords:  adipose tissue; extracellular vesicles; lipolysis; microRNAs; skeletal muscle
  13. Nat Commun. 2021 May 25. 12(1): 3094
      Short-term, systemic expression of the Yamanaka reprogramming factors (Oct-3/4, Sox2, Klf4 and c-Myc [OSKM]) has been shown to rejuvenate aging cells and promote tissue regeneration in vivo. However, the mechanisms by which OSKM promotes tissue regeneration are unknown. In this work, we focus on a specific tissue and demonstrate that local expression of OSKM, specifically in myofibers, induces the activation of muscle stem cells or satellite cells (SCs), which accelerates muscle regeneration in young mice. In contrast, expressing OSKM directly in SCs does not improve muscle regeneration. Mechanistically, expressing OSKM in myofibers regulates the expression of genes important for the SC microenvironment, including upregulation of p21, which in turn downregulates Wnt4. This is critical because Wnt4 is secreted by myofibers to maintain SC quiescence. Thus, short-term induction of the Yamanaka factors in myofibers may promote tissue regeneration by modifying the stem cell niche.
  14. Life Sci. 2021 May 24. pii: S0024-3205(21)00625-1. [Epub ahead of print] 119639
      AIMS: Strength training (ST) improves insulin resistance and glucose tolerance by yet unknown mechanisms. The aims of this study were to investigate the effects of ST on mitochondrial adaptation in skeletal muscle and adipose tissue, on heat shock protein 72 (Hsp72) in skeletal muscle, and on visceral adipocyte size in mice with high-fat diet (HFD)-induced insulin resistance.MATERIALS AND METHODS: Male Balb/c mice were divided into sedentary control-chow (C-chow), strength trained-chow (ST-chow), sedentary control-HFD (C-HFD) and strength trained-HFD (ST-HFD). Diet was provided for 12 weeks, while ladder climbing ST was performed for the final six weeks of the study at a frequency of three days per week.
    KEY FINDINGS: Strength training led to increased strength, muscular endurance, and skeletal muscle hypertrophy. Compared to the C-HFD group, mice in the ST-HFD group decreased their whole-body insulin resistance, improved their glucose tolerance, and had higher activation of the insulin pathway in skeletal muscle. ST increased citrate synthase (CS) activity in skeletal muscle, but this increase was blunted in ST-HFD. Conversely, HFD reduced adipose tissue CS activity regardless of training status. Hsp72 content was reduced in C-HFD, but returned to control levels in ST-HFD. Finally, reduced epididymal adipocyte size was observed in ST-HFD.
    SIGNIFICANCE: These results suggest that the improvement in insulin resistance induced by ST is related to mitochondrial adaptation in skeletal muscle, but not in adipose tissue. Moreover, this improvement might be related to increased skeletal muscle Hsp72 and reduced epididymal adipocyte size.
    Keywords:  Glucose metabolism; Glucose tolerance; Heat shock protein 72; Mitochondria; Obesity; Resistance training
  15. Sci Rep. 2021 May 26. 11(1): 11005
      Fibroblast growth factor 2 (FGF2) is important in musculoskeletal homeostasis, therefore the impact of reduction or Fgf2 knockout on skeletal muscle function and phenotype was determined. Gait analysis as well as muscle strength testing in young and old WT and Fgf2KO demonstrated age-related gait disturbances and reduction in muscle strength that were exacerbated in the KO condition. Fgf2 mRNA and protein were significantly decreased in skeletal muscle of old WT compared with young WT. Muscle fiber cross-sectional area was significantly reduced with increased fibrosis and inflammatory infiltrates in old WT and Fgf2KO vs. young WT. Inflammatory cells were further significantly increased in old Fgf2KO compared with old WT. Lipid-related genes and intramuscular fat was increased in old WT and old Fgf2KO with a further increase in fibro-adipocytes in old Fgf2KO compared with old WT. Impaired FGF signaling including Increased β-Klotho, Fgf21 mRNA, FGF21 protein, phosphorylated FGF receptors 1 and 3, was observed in old WT and old Fgf2KO. MAPK/ ERK1/2 was significantly increased in young and old Fgf2KO. We conclude that Fgf2KO, age-related decreased FGF2 in WT mice, and increased FGF21 in the setting of impaired Fgf2 expression likely contribute to impaired skeletal muscle function and sarcopenia in mice.
  16. Front Physiol. 2021 ;12 666964
      Skeletal muscle function deficits associated with advancing age are due to several physiological and morphological changes including loss of muscle size and quality (conceptualized as a reduction in the intrinsic force-generating capacity of a muscle when adjusted for muscle size). Several factors can contribute to loss of muscle quality, including denervation, excitation-contraction uncoupling, increased fibrosis, and myosteatosis (excessive levels of inter- and intramuscular adipose tissue and intramyocellular lipids). These factors also adversely affect metabolic function. There is a major unmet need for tools to rapidly and easily assess muscle mass and quality in clinical settings with minimal patient and provider burden. Herein, we discuss the potential for electrical impedance myography (EIM) as a tool to evaluate muscle mass and quality in older adults. EIM applies weak, non-detectible (e.g., 400 μA), mutifrequency (e.g., 1 kHz-1 MHz) electrical currents to a muscle (or muscle group) through two excitation electrodes, and resulting voltages are measured via two sense electrodes. Measurements are fast (~5 s/muscle), simple to perform, and unaffected by factors such as hydration that may affect other simple measures of muscle status. After nearly 2 decades of study, EIM has been shown to reflect muscle health status, including the presence of atrophy, fibrosis, and fatty infiltration, in a variety of conditions (e.g., developmental growth and maturation, conditioning/deconditioning, and obesity) and neuromuscular diseases states [e.g., amyotrophic lateral sclerosis (ALS) and muscular dystrophies]. In this article, we describe prior work and current evidence of EIM's potential utility as a measure of muscle health in aging and geriatric medicine.
    Keywords:  aging; diagnosis; dynapenia; sarcopenia; skeletal muscle
  17. Clin Interv Aging. 2021 ;16 811-821
      Background: Sarcopenia is a syndrome characterized by the loss of skeletal muscle mass and strength. Most studies have focused on dynamic resistance exercises for preventing muscular decline and maintaining the muscle strength of older individuals. However, this training mode is impractical for older people with osteoarthritis and a limited range of motion. The static strength training mode is more suitable for older people. Therefore, a determination of the effect and mechanism of static strength training on sarcopenia is critical.Methods: In this study, we developed a training device designed to collect training data and evaluate the effects of static training on the upper limbs of rats. The expression of PGC-1α was locally blocked by injecting a siRNA at the midpoint of the biceps to determine whether PGC-1α signal transduction participates in the effects of high-intensity interval static training on muscle strength. Then, the rat's motor capacity was measured after static strength training. Immunohistochemistry and Western blotting were applied to determine PGC-1α/FNDC5/UCP1 expression levels in the muscle and adipose tissue. The serum irisin level was also detected using an enzyme-linked immunosorbent assay (ELISA).
    Results: Increased levels of serum irisin and local expression of FNDC5, PGC-1α, and UCP1 were observed in the biceps brachii and surrounding fatty tissue after static strength training. Static strength training showed an advantage in reducing body weight and white fat accumulation while increasing the muscle fiber volume, which resulted in a longer training time and shorter rest time.
    Conclusion: Overall, these results indicated that high-intensity interval static training prevents skeletal muscle atrophy and improves the motor function of aged rats through the PGC-1α/FNDC5/UCP1 signaling pathway.
    Keywords:  FNDC5; PGC-1α; muscle function; sarcopenia; static strength training
  18. Physiol Rep. 2021 May;9(10): e14850
      Exercise training improves peripheral insulin sensitivity and leads to molecular adaptations in the skeletal muscle. We investigated changes in the expression of key muscle proteins in the glucose metabolic pathway following active commuting by bike or leisure-time exercise at two different intensities. In addition, potential associations between insulin sensitivity and muscle protein expression were examined. This per-protocol analysis included 72 out of 130 physically inactive, healthy women and men (20-45 years) with overweight/obesity (BMI: 25-35 kg/m2 ) who completed 6 months of no intervention (CON, n = 12), active commuting by bike (BIKE, n = 14), or leisure-time exercise of moderate (MOD, n = 28) or vigorous (VIG, n = 18) intensity. Exercise was prescribed 5 days/week with a weekly exercise energy expenditure of 1,600 kcal for women and 2,100 kcal for men. Insulin sensitivity was determined by a hyperinsulinemic euglycemic clamp and skeletal muscle biopsies were obtained from m. vastus lateralis and analyzed for protein expression at baseline and after 3 and 6 months of intervention. We found an increased expression of pyruvate dehydrogenase (PDH) in the exercise groups compared with the control group following 6 months of training. No differential effects were observed on the protein expression following moderate versus vigorous intensity exercise. In addition, we found a positive association between insulin sensitivity and the expression of glucose transporter type 4 as well as PDH. The positive association and the increase in expression of PDH after exercise training points toward a role for PDH in the training-induced enhancement of insulin sensitivity.
    Keywords:  PDH; exercise intensity; exercise training; insulin sensitivity
  19. Arch Med Sci. 2021 ;17(3): 752-763
      Introduction: Replicative senescence results in dysregulation of cell proliferation and differentiation, which plays a role in the regenerative defects observed during age-related muscle atrophy. Vitamin E is a well-known antioxidant, which potentially ameliorates a wide range of age-related manifestations. The aim of this study was to determine the effects of tocotrienol-rich fraction (TRF) in modulating the expression of proliferation- and differentiation-associated proteins in senescent human myoblasts during the differentiation phase.Material and methods: Human skeletal muscle myoblasts were cultured until senescence. Young and senescent cells were treated with TRF for 24 h before and after differentiation induction, followed by evaluation of cellular morphology and efficiency of differentiation. Expression of cell proliferation marker Ki67 protein and myogenic regulatory factors MyoD and myogenin were determined.
    Results: Our findings showed that treatment with TRF significantly improved the morphology of senescent myoblasts. Promotion of differentiation was observed in young and senescent myoblasts with TRF treatment as shown by the increased fusion index and larger size of myotubes. Increased Ki67 and myogenin expression with TRF treatment was also observed in senescent myoblasts, suggesting amelioration of the myogenic program by TRF during replicative senescence.
    Conclusions: TRF modulates the expression of regulatory factors related to proliferation and differentiation in senescent human myoblasts and could be beneficial for ameliorating the regenerative defects during aging.
    Keywords:  differentiation; myoblasts; myotubes; replicative senescence; tocotrienols
  20. Sci Rep. 2021 May 24. 11(1): 10753
      Disruption of iron metabolism is closely related to metabolic diseases. Iron deficiency is frequently associated with obesity and hepatic steatosis. However, the effects of iron supplementation on obesity and energy metabolism remain unclear. Here we show that a high-fat diet supplemented with iron reduces body weight gain and hepatic lipid accumulation in mice. Iron supplementation was found to reduce mitochondrial morphological abnormalities and upregulate gene transcription involved in mitochondrial function and beta oxidation in the liver and skeletal muscle. In both these tissues, iron supplementation increased the expression of genes involved in heme or iron-sulfur (Fe-S) cluster synthesis. Heme and Fe-S cluster, which are iron prosthetic groups contained in electron transport chain complex subunits, are essential for mitochondrial respiration. The findings of this study demonstrated that iron regulates mitochondrial signaling pathways-gene transcription of mitochondrial component molecules synthesis and their energy metabolism. Overall, the study elucidates the molecular basis underlying the relationship between iron supplementation and obesity and hepatic steatosis progression, and the role of iron as a signaling molecule.
  21. Arch Biochem Biophys. 2021 May 24. pii: S0003-9861(21)00183-1. [Epub ahead of print] 108934
      H2O2 is endogenously generated and its removal in the matrix of skeletal muscle mitochondria (SMM) is dependent on NADPH likely provided by NAD(P)+ transhydrogenase (NNT) and isocitrate dehydrogenase (IDH2). Importantly, NNT activity is linked to mitochondrial protonmotive force. Here, we demonstrate the presence of NNT function in detergent-solubilized and intact functional SMM isolated from rats and wild type (Nnt+/+) mice, but not in SMM from congenic mice carrying a mutated NNT gene (Nnt-/-). Further comparisons between SMM from both Nnt mouse genotypes revealed that the NADPH supplied by NNT supports up to 600 pmol/mg/min of H2O2 removal under selected conditions. Surprisingly, SMM from Nnt-/- mice removed exogenous H2O2 at wild-type levels and exhibited a maintained or even decreased net emission of endogenous H2O2 when substrates that support Krebs cycle reactions were present (e.g., pyruvate plus malate or palmitoylcarnitine plus malate). These results may be explained by a compensation for the lack of NNT, since the total activities of concurrent NADP+-reducing enzymes (IDH2, malic enzymes and glutamate dehydrogenase) were ∼70% elevated in Nnt-/- mice. Importantly, respiratory rates were similar between SMM from both Nnt genotypes despite differing NNT contributions to H2O2 removal and their implications for an evolving concept in the literature are discussed. We concluded that NNT is capable of meaningfully sustaining NADPH-dependent H2O2 removal in intact SMM. Nonetheless, if the available substrates favor non-NNT sources of NADPH, the H2O2 removal by SMM is maintained in Nnt-/- mice SMM.
    Keywords:  Antioxidant; C57BL/6J; Krebs cycle; Oxidative stress; Redox balance
  22. Aging Clin Exp Res. 2021 May 28.
      Persons suffering with systemic neuromuscular disorders or chronic organ failures, spend less time for daily physical activity, aggravating their mobility impairments. From 2020, patients at risk are also older adults, who, though negative for the SARS-Cov-2 infection, suffer with a fatigue syndrome due to home restriction/quarantine. Besides eventual psycological managements, it could be useful to offer to these patients a rehabilitation workouts easy to learn and to independently repeat at home (Full-Body In-Bed Gym). Inspired by the proven capability to recover skeletal muscle contractility and strength by home-based volitional exercises and functional electrical stimulation (FES), we suggest for this fatigue syndrome a 10-20 min long daily routine of easy and safe physical exercises that may recover from muscle weakness the main 400 skeletal muscles used for every-day activities. Leg muscles could be trained also by an adjunctive neuro-muscular electrical stimulation (NMES) in frail old persons. Many of the exercises could be performed in bed (Full-Body in-Bed Gym), thus hospitalized patients can learn this light training before leaving the hospital. Full-Body in-Bed Gym is, indeed, an extension of well-established cardiovascular-ventilation rehabilitation training performed by patients after heavy surgery. Blood pressure readings, monitored before and after daily routine of Full-Body in-Bed Gym, demonstrate a transient decrease in peripheral resistance due to increased blood flow to major body muscles. Continued regularly, Full-Body in-Bed Gym may help maintaining independence of frail people, including those suffering with the fatigue syndrome related to the restrictions/quarantine imposed to the general population during the COVID-19 pandemic.
    Keywords:  Borderline mobility impaired persons; COVID-19 fatigue syndrome; Home-based Full-Body in-Bed Gym; Neuro-muscular electrical stimulation; Skeletal muscle weakness
  23. J Physiol. 2021 May 25.
      KEY POINTS: Healthy older adults exhibit lower cardiorespiratory fitness (VO2 peak) than young in the absence of any age-related difference in skeletal muscle mitochondrial capacity, suggesting central hemodynamics plays a larger role in age-related declines in VO2 peak. Total physical activity did not differ by age, but moderate-to-vigorous physical activity was lower in older compared to young adults. Moderate-to-vigorous physical activity is associated with VO2 peak and muscle oxidative capacity, but physical inactivity cannot entirely explain the age-related reduction in VO2 peak.ABSTRACT: Declining fitness (VO2 peak) is a hallmark of aging and believed to arise from decreased oxygen delivery and reduced muscle oxidative capacity. Physical activity is a modifiable lifestyle factor that is critical when evaluating the effects of age on parameters of fitness and energy metabolism. The objective was to evaluate the effects of age and sex on VO2 peak, muscle mitochondrial physiology, and physical activity in young and older adults. An additional objective was to assess the contribution of skeletal muscle oxidative capacity to age-related reductions in VO2 peak and determine if age-related variation in VO2 peak and muscle oxidative capacity could be explained on the basis of physical activity levels. 23 young and 52 older men and women completed measurements of VO2 peak, mitochondrial physiology in permeabilized muscle fibers, and free-living physical activity by accelerometry. Regression analyses were used to evaluate associations between age and VO2 peak, mitochondrial function, and physical activity. Significant age-related reductions were observed for VO2 peak (P<0.001), but not muscle mitochondrial capacity. Total daily step counts did not decrease with age, but older adults showed lower moderate-to-vigorous physical activity, which was associated with VO2 peak (R2 = 0.323, P<0.001) and muscle oxidative capacity (R2 = 0.086, P = 0.011). After adjusting for sex and physical activity, age was negatively associated with VO2 peak but not muscle oxidative capacity. Healthy older adults exhibit lower VO2 peak but preserved mitochondrial capacity compared to young. Physical activity, particularly moderate-to-vigorous, is a key factor in observed age-related changes in fitness and muscle oxidative capacity, but cannot entirely explain the age-related reduction in VO2 peak. This article is protected by copyright. All rights reserved.
    Keywords:  ageing; mitochondria; physical activity; skeletal muscle
  24. Cell Rep. 2021 May 25. pii: S2211-1247(21)00525-8. [Epub ahead of print]35(8): 109180
      Mitochondrial respiratory complex subunits assemble in supercomplexes. Studies of supercomplexes have typically relied upon antibody-based quantification, often limited to a single subunit per respiratory complex. To provide a deeper insight into mitochondrial and supercomplex plasticity, we combine native electrophoresis and mass spectrometry to determine the supercomplexome of skeletal muscle from sedentary and exercise-trained mice. We quantify 422 mitochondrial proteins within 10 supercomplex bands in which we show the debated presence of complexes II and V. Exercise-induced mitochondrial biogenesis results in non-stoichiometric changes in subunits and incorporation into supercomplexes. We uncover the dynamics of supercomplex-related assembly proteins and mtDNA-encoded subunits after exercise. Furthermore, exercise affects the complexing of Lactb, an obesity-associated mitochondrial protein, and ubiquinone biosynthesis proteins. Knockdown of ubiquinone biosynthesis proteins leads to alterations in mitochondrial respiration. Our approach can be applied to broad biological systems. In this instance, comprehensively analyzing respiratory supercomplexes illuminates previously undetectable complexity in mitochondrial plasticity.
    Keywords:  complexome; exercise; mitochondrial respiratory complexes; mitochondrial supercomplexes; oxidative phosphorylation; protein complexes
  25. J Physiol. 2021 May 25.
      KEY POINTS: During exercise, bradykinin (BK), a muscle metabolite in ischemic muscles exaggerates autonomic responses to activation of muscle afferent nerves in peripheral artery disease (PAD). We examined if BK inhibits activity of KV 4 channels in muscle afferent neurons of PAD rats induced by femoral artery occlusion. We demonstrated that 1) femoral occlusion attenuates KV 4 currents in dorsal root ganglion (DRG) neurons innervating the hindlimb muscles and decreases threshold of action potential firing; 2) BK has a greater inhibitory effect on KV 4 currents in muscle DRG neurons of PAD rats; and 3) expression of KV 4.3 is downregulated in DRGs of PAD rats and inhibition of KV 4.3 significantly decreases activity of KV 4 currents in muscle DRG neurons. Femoral artery occlusion induced-limb ischemia and/or ischemia induced-metabolites (i.e., BK) inhibit activity of KV 4 channels in muscle afferent neurons and this is likely involved in the exaggerated exercise pressor reflex in PAD.ABSTRACT: Muscle afferent nerve-activated reflex sympathetic nervous and blood pressure responses are exaggerated during exercise in patients with peripheral artery diseases (PAD) and in PAD rats induced by femoral artery occlusion. However, the precise signaling pathways and molecular mediators responsible for these abnormal autonomic responses in PAD are poorly understood. A-type voltage-gated K+ (KV ) channels are quintessential regulators of cellular excitability in the various tissues. Among KV channels, KV 4 (i.e., KV 4.1 and KV 4.3) in primary sensory neurons mainly participate in physiological functions in regulation of mechanical and chemical sensation. However, little is known about the role of KV 4 in regulating neuronal activity in muscle afferent neurons of PAD. In addition, bradykinin (BK) is considered as a muscle metabolite contributing to the exaggerated exercise pressor reflex in PAD rats with femoral artery occlusion. Our data demonstrated that 1) KV 4 currents are attenuated in dorsal root ganglion (DRG) neurons innervating the hindlimb muscles of PAD rats, along with decreasing threshold of action potential firing; 2) KV 4 currents are inhibited by application of BK onto muscle DRG neurons of PAD rats to a greater degree; and 3) expression of KV 4.3 is downregulated in DRGs of PAD rats and KV 4.3 channel is a major contributor to the activity of KV 4 currents in muscle DRG neurons. In conclusion, data suggest that femoral artery occlusion induced-limb ischemia and/or ischemia induced-metabolites (i.e., BK) inhibit the activity of KV 4 channels in muscle afferent neurons likely leading to the exaggerated exercise pressor reflex observed in PAD. This article is protected by copyright. All rights reserved.
    Keywords:  A-type voltage-gated K+ channels; bradykinin; dorsal root ganglion; peripheral artery disease
  26. Sci Rep. 2021 May 24. 11(1): 10790
      The regenerative effect of Epimedium and its major bioactive flavonoid icariin (ICA) have been documented in traditional medicine, but their effect on sarcopenia has not been evaluated. The aim of this study was to investigate the effects of Epimedium extract (EE) on skeletal muscle as represented by differentiated C2C12 cells. Here we demonstrated that EE and ICA stimulated C2C12 myotube hypertrophy by activating several, including IGF-1 signal pathways. C2C12 myotube hypertrophy was demonstrated by enlarged myotube and increased myosin heavy chains (MyHCs). In similar to IGF-1, EE/ICA activated key components of the IGF-1 signal pathway, including IGF-1 receptor. Pre-treatment with IGF-1 signal pathway specific inhibitors such as picropodophyllin, LY294002, and rapamycin attenuated EE induced myotube hypertrophy and MyHC isoform overexpression. In a different way, EE induced MHyC-S overexpression can be blocked by AMPK, but not by mTOR inhibitor. On the level of transcription, EE suppressed myostatin and MRF4 expression, but did not suppress atrogenes MAFbx and MuRF1 like IGF-1 did. Differential regulation of MyHC isoform and atrogenes is probably due to inequivalent AKT and AMPK phosphorylation induced by EE and IGF-1. These findings suggest that EE/ICA stimulates pathways partially overlapping with IGF-1 signaling pathway to promote myotube hypertrophy.
  27. J Clin Biochem Nutr. 2021 May;68(3): 228-234
      We previously found that a single dose of theaflavins induced skeletal muscle metabolic changes. In this study, we examined the effect of theaflavins on disuse muscle atrophy model mice by hindlimb suspension. Mice were assigned to 4 groups; ground-vehicle, ground-theaflavins, suspension-vehicle, and suspension-theaflavins, dosed with theaflavins (250 mg/kg/day) for 2 weeks. The peak of myotube size of cross sectional area was significantly moved to the smaller side in the suspension-vehicle group compared with the ground-vehicle group, and these shifts were significantly reduced by the treatment with theaflavins in both soleus and extensor digitorum longus. The level of phosphorylated eukaryotic translation initiation factor 4E-binding protein (4EBP)-1, located downstream of the Akt/mTOR pathway, was significantly different between suspension-vehicle and suspension-theaflavins in soleus. The ratio of forkhead box O (FoxO) 3a to phosphorylated FoxO3a significantly increased in soleus or tended to rise in extensor digitorum longus of suspension-vehicle group compared with ground-vehicle. In contrast, these changes were not observed in suspension-theaflavins group. These results suggested that theaflavins inhibited the progress of disuse muscle atrophy through modulation of protein metabolism.
    Keywords:  FoxO3a; hindlimb suspension; skeletal muscle atrophy; theaflavins
  28. J Nutr Biochem. 2021 Apr 29. pii: S0955-2863(21)00170-4. [Epub ahead of print]94 108750
      Lycopene has a wide range of biological functions, especially its antioxidant capacity. However, effects of lycopene on muscle fatigue resistant and muscle fiber type conversion are unknown. In this study, we found that lycopene significantly prolonged the swimming time to exhaustion in mice. We also showed that lycopene increased the proportion of slow-twitch muscle fiber by promoting muscle fiber type conversion from fast-twitch to slow-twitch in mice and in C2C12 myotubes. The AMP-activated protein kinase (AMPK) signaling was activated by lycopene. AMPK upstream and downstream regulators including nuclear respiratory factor 1, calcium calmodulin-dependent protein kinase kinase-β, sirtuin 1 and peroxisome proliferator activated receptor-γ coactivator-1ɑ were also increased by lycopene. AMPK inhibitor compound C markedly attenuated the lycopene-induced skeletal muscle fiber type conversion in C2C12 myotubes. Taken together, we provided the first evidence that lycopene increases the proportion of slow-twitch muscle fiber through AMPK signaling pathway to improve fatigue resistant of skeletal muscle.
    Keywords:  AMPK signaling pathway; C2C12 myotubes; Lycopene; Mice; Slow-twitch muscle fiber
  29. Nat Commun. 2021 May 28. 12(1): 3210
      Diseases caused by heteroplasmic mitochondrial DNA mutations have no effective treatment or cure. In recent years, DNA editing enzymes were tested as tools to eliminate mutant mtDNA in heteroplasmic cells and tissues. Mitochondrial-targeted restriction endonucleases, ZFNs, and TALENs have been successful in shifting mtDNA heteroplasmy, but they all have drawbacks as gene therapy reagents, including: large size, heterodimeric nature, inability to distinguish single base changes, or low flexibility and effectiveness. Here we report the adaptation of a gene editing platform based on the I-CreI meganuclease known as ARCUS®. These mitochondrial-targeted meganucleases (mitoARCUS) have a relatively small size, are monomeric, and can recognize sequences differing by as little as one base pair. We show the development of a mitoARCUS specific for the mouse m.5024C>T mutation in the mt-tRNAAla gene and its delivery to mice intravenously using AAV9 as a vector. Liver and skeletal muscle show robust elimination of mutant mtDNA with concomitant restoration of mt-tRNAAla levels. We conclude that mitoARCUS is a potential powerful tool for the elimination of mutant mtDNA.
  30. Muscle Nerve. 2021 May 25.
      INTRODUCTION: Clinically, the chemotherapeutic agent oxaliplatin can cause peripheral neuropathy, impaired balance, and muscle wastage. Using a preclinical model, we investigated whether exercise intervention improved these adverse conditions.METHODS: Mice were chronically treated with oxaliplatin alone or in conjunction with exercise. Behavioural studies including mechanical allodynia, rotarod, open field and grip strength tests were performed. Following euthanasia, multiple organs and four different muscle types were dissected and weighed. The cross-sectional area (CSA) of muscle fibres in the gastrocnemius muscle was assessed and gene expression analysis performed on forelimb triceps muscle.
    RESULTS: Oxaliplatin treated mice displayed reduced weight gain, mechanical allodynia, and exploratory behaviour deficits that were not significantly improved by exercise. Oxaliplatin treated exercised mice showed modest evidence of reduced muscle wastage compared to mice treated with oxaliplatin alone, and exercised mice demonstrated evidence of a mild increase in CSA of muscle fibres.
    DISCUSSION: Exercise intervention did not improve signs of peripheral neuropathy but moderately reduced the negative impact of oxaliplatin chemotherapy related to muscle morphology suggesting the potential for exploring the impact of exercise on reducing oxaliplatin-induced neuromuscular toxicity in cancer patients.
    Keywords:  Exercise; Muscle wasting; Neuromuscular; Oxaliplatin; Peripheral neuropathy
  31. J Appl Physiol (1985). 2021 05 27.
      Dietary nitrate supplementation improves exercise performance by reducing the oxygen cost of exercise and enhancing skeletal muscle function. However, the mechanisms underlying these effects are not well understood. The purpose of this study was to assess changes in skeletal muscle energy metabolism associated with exercise performance in a zebrafish model. Fish were exposed to sodium nitrate (60.7 mg/L, 303.5 mg/L, 606.9 mg/L), or control water, for 21 days and analyzed at intervals (5, 10, 20, 30, 40 cm/sec) during a two-hour strenuous exercise test. We measured oxygen consumption during an exercise test and assessed muscle nitrate concentrations, gene expression and the muscle metabolome before, during and after exercise. Nitrate exposure reduced the oxygen cost of exercise and increased muscle nitrate concentrations at rest, which were reduced with increasing exercise duration. In skeletal muscle, nitrate treatment upregulated expression of genes central to nutrient sensing (mtor), redox signaling (nrf2a) and muscle differentiation (sox6). In rested muscle, nitrate treatment increased phosphocreatine (P = 0.002), creatine (P =0.0005), ATP (P = 0.0008), ADP (P = 0.002), and AMP (P =0.004) compared to rested-control muscle. Following the highest swimming speed, concentration of phosphocreatine (P = 8.0 x 10-5), creatine (P =6.0 x 10-7), ATP (P = 2.0 x 10-6), ADP (P = 0.0002), and AMP (P =0.004) decreased compared to rested nitrate muscle. Our data suggests nitrate exposure in zebrafish lowers the oxygen cost of exercise by changing the metabolic programming of muscle prior to exercise and increasing availability of energy-rich metabolites required for exercise.
    Keywords:  energy metabolism; exercise performance; metabolomics; nitrate; skeletal muscle
  32. Cell Death Dis. 2021 May 25. 12(6): 535
      Tet dioxygenases are responsible for the active DNA demethylation. The functions of Tet proteins in muscle regeneration have not been well characterized. Here we find that Tet2, but not Tet1 and Tet3, is specifically required for muscle regeneration in vivo. Loss of Tet2 leads to severe muscle regeneration defects. Further analysis indicates that Tet2 regulates myoblast differentiation and fusion. Tet2 activates transcription of the key differentiation modulator Myogenin (MyoG) by actively demethylating its enhancer region. Re-expressing of MyoG in Tet2 KO myoblasts rescues the differentiation and fusion defects. Further mechanistic analysis reveals that Tet2 enhances MyoD binding by demethylating the flanking CpG sites of E boxes to facilitate the recruitment of active histone modifications and increase chromatin accessibility and activate its transcription. These findings shed new lights on DNA methylation and pioneer transcription factor activity regulation.
  33. Exp Gerontol. 2021 May 21. pii: S0531-5565(21)00202-3. [Epub ahead of print] 111420
      BACKGROUND: In 2018, the European Working Group on Sarcopenia in Older People (EWGSOP) updated the definition and the diagnosis criteria of sarcopenia. Previous systematic reviews have shown the effect of exercise on sarcopenia including people with different sarcopenia diagnostic criteria.OBJECTIVE: This systematic review and meta-analysis aims to summarise and synthesise the evidence about the effect of exercise on muscle mass, strength and physical performance in older adults with sarcopenia according to the EWGSOP criteria.
    METHODS: Major electronic databases were searched for articles published until September 2020. Randomised controlled trials (RCTs) and non-randomised interventional studies examining the effect of exercise on muscle mass, strength or physical performance in adults older than 60 years with sarcopenia according to the EWGSOP criteria were included.
    RESULTS: Four RCTs and three non-randomised interventional studies with a total of 235 patients with sarcopenia were included. Five of the seven included studies reported a low risk of bias. Exercise showed a large effect on physical performance (d = 1.21, 95%CI [0.79 to 1.62]; P < 0.001), a medium effect on muscle strength (d = 0.51, 95%CI [0.25 to 0.76]; P < 0.001), and no effect on muscle mass (d = 0.27, 95%CI [-0.05 to 0.58]; P = 0.10).
    CONCLUSION: The present systematic review showed an effect of exercise on physical performance and muscle strength but an inconsistent effect on muscle mass. The grading of recommendations assessment, development and evaluation criteria showed a low level of evidence in muscle mass, a low or moderate level of evidence in muscle strength and a high level of evidence in physical performance.
    Keywords:  Exercise; Muscle mass; Physical performance; Sarcopenia; Strength
  34. Sci Rep. 2021 May 27. 11(1): 11261
      Thoroughbreds have high maximal oxygen consumption and show hypoxemia and hypercapnia during intense exercise, suggesting that the peripheral environment in skeletal muscle may be severe. Changes in metabolites following extreme alterations in the muscle environment in horses after exercise may provide useful evidence. We compared the muscle metabolites before and after supramaximal exercise to fatigue in horses. Six well-trained horses ran until exhaustion in incremental exercise tests. Biopsy samples were obtained from the gluteus medius muscle before and immediately after exercise for capillary electrophoresis-mass spectrometry analysis. In the incremental exercise test, the total running time and speed of the last step were 10.4 ± 1.3 (mean ± standard deviation) min and 12.7 ± 0.5 m/s, respectively. Of 73 metabolites, 18 and 11 were significantly increased and decreased after exercise, respectively. The heat map of the hierarchical cluster analysis of muscle metabolites showed that changes in metabolites were clearly distinguishable before and after exercise. Strenuous exercise increased many metabolites in the glycolytic pathway and the tricarboxylic acid cycle in skeletal muscle. Targeted metabolomic analysis of skeletal muscle may clarify the intramuscular environment caused by exercise and explain the response of working muscles to strenuous exercise that induces hypoxemia and hypercapnia in Thoroughbred horses.
  35. Arch Physiother. 2021 May 27. 11(1): 14
      BACKGROUND: Inflammatory myopathies (IMs) are a group of rare conditions characterized by proximal and often symmetrical muscle weakness and reduced muscle endurance. The recommended medical treatment is based on corticosteroids in combination with immunosuppressants. This anti-inflammatory therapy serves to inhibit and prevent inflammation but does not influence impaired muscle strength. Exercise, particularly progressive resistance training, plays therefore an important role in IMs management. Blended therapy, a combination of face-to-face treatment and telerehabilitation, may be a powerful therapy option in improving exercise program adherence in these patients.METHODS: The feasibility of a 12-week interactive tablet-based home exercise program combined with face-to-face therapy sessions - a 'blended therapy' approach - was evaluated using a quasi-experimental one-group pre-post comparison design. Primary outcomes were recruitment, attrition and adherence rates, plus measures of acceptance (Technology Acceptance Model Questionnaire (TAM)) and satisfaction (satisfaction questionnaire). Secondary outcomes comprised potential effects of the intervention on muscle strength and function, activity limitation, disability and health-related quality of life.
    RESULTS: Thirteen of the included 14 participants completed the study without any related adverse events. Mean adherence to exercise program was 84% (range: 25-100%) and participants indicated high acceptance of the intervention with mean TAM scores between 6.1 and 6.5 points. Overall satisfaction with the therapy sessions, the home program, and the technology was good. Approximately half the participants wished for longer training periods and more training sessions per week. There were inconsistent effects on muscle strength, muscle function, activity limitation, disability, and health-related quality of life.
    CONCLUSION: Blended therapy combining the use of an interactive tablet-based resistance training program with face-to-face therapy sessions is feasible and safe and participants` acceptance with this approach was high. Furthermore, results were obtained that might be useful in selecting appropriate assessments and sample sizes in future trials.
    Keywords:  Blended therapy; Exercise; Inflammatory myopathy; Progressive resistance training; Tele-rehabilitation
  36. Ageing Res Rev. 2021 May 19. pii: S1568-1637(21)00115-X. [Epub ahead of print]69 101368
      BACKGROUND: We aimed to summarize evidence on the safety, adherence and effectiveness of home-based resistance training (UHBRT) for improving health-related endpoints in community-dwelling older adults.METHODS: Randomized controlled trials of UHBRT in older adults (≥60yrs) were included after a systematic search (PubMed, CINAHL, PsycInfo, SPORTDiscus, Web of Science, MEDLINE, Cochrane Central Register of Controlled Trials) until 02/19/2021. Adverse events and adherence rates were assessed as indicators of feasibility. Other endpoints included physical (muscle strength, muscle power, balance, physical performance) and mental-related measures (cognition, quality of life [QoL]) as well as other health-related variables (body composition, physical activity levels, falls).
    RESULTS: 21 studies (N = 4,053) were included. No major adverse events were reported, with adherence averaging 67 % (range 47-97 %). UHBRT significantly improved lower-limb muscle strength (Hedges' g = 0.33; 95 % confidence interval [CI] = 0.11-0.57), muscle power measured through the sit-to-stand test (g = 0.44; 95 %CI = 0.06-0.84), and balance (assessed with the postural sway, g = 0.32; 95 %CI = 0.16-0.49). No benefits were found for other strength indices (handgrip strength), balance (single leg stance and functional reach test), physical performance (walking speed, TUG and SPPB), QoL, nor for the risk or rate of falls (all p > 0.05, g<0.61). No meta-analysis could be performed for the remaining endpoints.
    CONCLUSIONS: Although efforts are needed to increase adherence, preliminary evidence suggests that UHBRT can be safe and modestly effective for improving some measures of lower-limb muscle strength, balance, and muscle power in community-dwelling older adults. However, no benefits were found for other physical fitness measures, QoL or falls. More evidence is therefore needed to draw definite conclusions.
    Keywords:  Cognition; Elderly; Exercise; Performance; Safety; Strength
  37. Redox Biol. 2021 Jul;pii: S2213-2317(21)00166-X. [Epub ahead of print]43 102008
      Muscles of patients with facioscapulohumeral dystrophy (FSHD) are characterized by sporadic DUX4 expression and oxidative stress which is at least partially induced by DUX4 protein. Nevertheless, targeting oxidative stress with antioxidants has a limited impact on FSHD patients, and the exact role of oxidative stress in the pathology of FSHD, as well as its interplay with the DUX4 expression, remain unclear. Here we set up a screen for genes that are upregulated by DUX4 via oxidative stress with the aim to target these genes rather than the oxidative stress itself. Immortalized human myoblasts expressing DUX4 (MB135-DUX4) have an increased level of reactive oxygen species (ROS) and exhibit differentiation defects which can be reduced by treating the cells with classic (Tempol) or mitochondria-targeted antioxidants (SkQ1). The transcriptome analysis of antioxidant-treated MB135 and MB135-DUX4 myoblasts allowed us to identify 200 genes with expression deregulated by DUX4 but normalized upon antioxidant treatment. Several of these genes, including PITX1, have been already associated with FSHD and/or muscle differentiation. We confirmed that PITX1 was indeed deregulated in MB135-DUX4 cells and primary FSHD myoblasts and revealed a redox component in PITX1 regulation. PITX1 silencing partially reversed the differentiation defects of MB135-DUX4 myoblasts. Our approach can be used to identify and target redox-dependent genes involved in human diseases.
    Keywords:  DUX4; FSHD; Mitochondrial ROS; Muscle differentiation; Oxidative stress; PITX1
  38. J Int Soc Sports Nutr. 2021 May 26. 18(1): 39
      BACKGROUND: Taurine has become a popular supplement among athletes attempting to improve performance. While the effectiveness of taurine as an ergogenic aid remains controversial, this paper summarizes the current evidence regarding the efficacy of taurine in aerobic and anaerobic performance, metabolic stress, muscle soreness, and recovery.METHODS: Google Scholar, Web of Science, and MedLine (PubMed) searches were conducted through September 2020. Peer-reviewed studies that investigated taurine as a single ingredient at dosages of < 1 g - 6 g, ranging from 10 to 15 min-to-2 h prior to exercise bout or chronic dose (7 days- 8 weeks) of consumption were included. Articles were excluded if taurine was not the primary or only ingredient in a supplement or food source, not published in peer-reviewed journals, if participants were older than 50 years, articles published before 1999, animal studies, or included participants with health issues. A total of 19 studies met the inclusion criteria for the review.
    RESULTS: Key results include improvements in the following: VO2max, time to exhaustion (TTE; n = 5 articles), 3 or 4 km time-trial (n = 2 articles), anaerobic performance (n = 7 articles), muscle damage (n = 3 articles), peak power (n = 2 articles), recovery (n = 1 article). Taurine also caused a change in metabolites: decrease in lactate, creatine kinase, phosphorus, inflammatory markers, and improved glycolytic/fat oxidation markers (n = 5 articles). Taurine dosing appears to be effective at ~ 1-3 g/day acutely across a span of 6-15 days (1-3 h before an activity) which may improve aerobic performance (TTE), anaerobic performance (strength, power), recovery (DOMS), and a decrease in metabolic markers (creatine kinase, lactate, inorganic phosphate).
    CONCLUSIONS: Limited and varied findings prohibit definitive conclusions regarding the efficacy of taurine on aerobic and anaerobic performance and metabolic outcomes. There are mixed findings for the effect of taurine consumption on improving recovery from training bouts and/or mitigating muscle damage. The timing of taurine ingestion as well as the type of exercise protocol performed may contribute to the effectiveness of taurine as an ergogenic aid. More investigations are needed to better understand the potential effects of taurine supplementation on aerobic and anaerobic performance, muscle damage, metabolic stress, and recovery.