bims-moremu Biomed News
on Molecular regulators of muscle mass
Issue of 2022‒01‒09
thirty-nine papers selected by
Anna Vainshtein
Craft Science Inc.
  1. Skeletal muscle phenotyping of Hippo gene-mutated mice reveals that Lats1 deletion increases the percentage of type I muscle fibers.
  2. Costly immunometabolic remodeling in disused muscle buildup through physical exercise.
  3. Altered muscle mitochondrial, inflammatory and trophic markers and reduced exercise training adaptations in type 1 diabetes.
  4. Secreted acid sphingomyelinase as a potential gene therapy for limb girdle muscular dystrophy 2B.
  5. Assessing mitochondrial respiration in permeabilized fibres and biomarkers for mitochondrial content in human skeletal muscle.
  6. CRISPR/Cas9 editing of directly reprogrammed myogenic progenitors restores dystrophin expression in a mouse model of muscular dystrophy.
  7. Time-controlled and muscle-specific CRISPR/Cas9-mediated deletion of CTG-repeat expansion in the DMPK gene.
  8. Recapitulating human myogenesis ex vivo using human pluripotent stem cells.
  9. Reducing sarcolipin expression improves muscle metabolism in mdx mice.
  10. Preliminary evidence of differential expression of myogenic and stress factors in skeletal muscle of older adults with low muscle strength.
  11. Acute normobaric hypoxia blunts contraction-mediated mTORC1- and JNK-signaling in human skeletal muscle.
  12. Skeletal muscle alterations in patients with acute Covid-19 and post-acute sequelae of Covid-19.
  13. Bioinspired electrospun decellularized extracellular matrix scaffolds promote muscle regeneration in a rat skeletal muscle defect model.
  14. Neuromuscular Junction Dysfunction in Amyotrophic Lateral Sclerosis.
  15. Filamin C regulates skeletal muscle atrophy by stabilizing dishevelled-2 to inhibit autophagy and mitophagy.
  16. Factors Mediating Exercise-induced Organ Crosstalk.
  17. Disruption of STIM1-mediated Ca2+ sensing and energy metabolism in adult skeletal muscle compromises exercise tolerance, proteostasis and lean mass.
  18. Muscle-specific functional deficits and lifelong fibrosis in response to paediatric radiotherapy and tumour elimination.
  19. Frequent Manipulation of Resistance Training Variables Promotes Myofibrillar Spacing Changes in Resistance-Trained Individuals.
  20. Spinal Muscular Atrophy Patient iPSC-Derived Motor Neurons Display Altered Proteomes at Early Stages of Differentiation.
  21. A neuromuscular perspective of sarcopenia pathogenesis: deciphering the signaling pathways involved.
  22. Skeletal muscle wasting during neoadjuvant therapy as a prognosticator in patients with esophageal and esophagogastric junction cancer: A systematic review and meta-analysis.
  23. The role of action potential changes in depolarization-induced failure of excitation contraction coupling in mouse skeletal muscle.
  24. Astrocyte-targeting RNA interference against mutated superoxide dismutase 1 induces motoneuron plasticity and protects fast-fatigable motor units in a mouse model of amyotrophic lateral sclerosis.
  25. GAPDH S-nitrosation contributes to age-related sarcopenia through mediating apoptosis.
  26. Skeletal muscle as a treatment target for older adults with diabetes mellitus: The importance of a multimodal intervention based on functional category.
  27. Rbfox1 is required for myofibril development and maintaining fiber type-specific isoform expression in Drosophila muscles.
  28. Distribution of alternative untranslated regions within the mRNA of the CELF1 splicing factor affects its expression.
  29. Cis-regulation of antisense noncoding RNA at the JAZF1 locus in type 2 diabetes.
  30. Dendrimer-2PMPA Delays Muscle Function Loss and Denervation in a Murine Model of Amyotrophic Lateral Sclerosis.
  31. Sestrin2 ablation attenuates the exercise-induced browning of white adipose tissue in C57BL/6J mice.
  32. Spexin ameliorates skeletal muscle insulin resistance through activation of GAL2 receptor.
  33. Effects of multicomponent exercise on the muscle strength, muscle endurance and balance of frail older adults: A meta-analysis of randomised controlled trials.
  34. Caenorhabditis elegans ETR-1/CELF has broad effects on the muscle cell transcriptome, including genes that regulate translation and neuroblast migration.
  35. MicroRNAs in obesity, sarcopenia, and commonalities for sarcopenic obesity: a systematic review.
  36. Therapy development for spinal muscular atrophy: perspectives for muscular dystrophies and neurodegenerative disorders.
  37. Muscle-Specific Tyrosine Kinase-Associated Myasthenia Gravis: A Neuromuscular Surprise.
  38. Depletion of NIMA-related kinase Nek2 induces aberrant self-renewal and apoptosis in stem/progenitor cells of aged muscular tissues.
  39. The Ability of Nutrition to Mitigate Epigenetic Drift: A Novel Look at Regulating Gene Expression.
  1. Transgenic Res. 2022 Jan 05.
    Skeletal muscle phenotyping of Hippo gene-mutated mice reveals that Lats1 deletion increases the percentage of type I muscle fibers.
    Fakhreddin Yaghoob Nezhad, Annett Riermeier, Martin Schönfelder, Lore Becker, Martin Hrabĕ de Angelis, Henning Wackerhage.
      The Hippo signal transduction network regulates transcription through Yap/Taz-Tead1-4 in many tissues including skeletal muscle. Whilst transgenic mice have been generated for many Hippo genes, the resultant skeletal muscle phenotypes were not always characterized. Here, we aimed to phenotype the hindlimb muscles of Hippo gene-mutated Lats1-/-, Mst2-/-, Vgll3-/-, and Vgll4+/- mice. This analysis revealed that Lats1-/- mice have 11% more slow type I fibers than age and sex-matched wild-type controls. Moreover, the mRNA expression of slow Myh7 increased by 50%, and the concentration of type I myosin heavy chain is 80% higher in Lats1-/- mice than in age and sex-matched wild-type controls. Second, to find out whether exercise-related stimuli affect Lats1, we stimulated C2C12 myotubes with the hypertrophy agent clenbuterol or the energy stress agent AICAR. We found that both stimulated Lats1 expression by 1.2 and 1.3 fold respectively. Third, we re-analyzed published datasets and found that Lats1 mRNA in muscle is 63% higher in muscular dystrophy, increases by 17-77% after cardiotoxin-induced muscle injury, by 41-71% in muscles during overload-induced hypertrophy, and by 19-21% after endurance exercise when compared to respective controls. To conclude, Lats1 contributes to the regulation of muscle fiber type proportions, and its expression is regulated by physiological and pathological situations in skeletal muscle.
    Keywords:  Fiber type; Hippo pathway; Lats1; Skeletal muscle; Transgenic mice
    DOI:  https://doi.org/10.1007/s11248-021-00293-4
  2. Acta Physiol (Oxf). 2022 Jan 06. e13782
    Costly immunometabolic remodeling in disused muscle buildup through physical exercise.
    Camila S Padilha, Caique Figueiredo, Rafael Deminice, Karsten Krüger, Marília Seelaender, José Cesar Rosa-Neto, Fabio S Lira.
      The mechanisms underlying the immunometabolic disturbances during skeletal muscle atrophy caused by a plethora of circumstances ranging from hospitalization to spaceflight missions, remain unknown. Here, we outline the possible pathways that might be dysregulated in such conditions and assess the potential of physical exercise to mitigate and promote the recovery of muscle morphology, metabolism, and function after intervals of disuse. Studies applying exercise to attenuate disuse-induced muscle atrophy have shown a pivotal role of circulating myokines in the activation of anabolic signaling pathways. These muscle-derived factors induce accretion of contractile proteins in the myofibers, and at the same time decrease protein breakdown and loss. Regular exercise plays a crucial role in re-establishing adequate immunometabolism and increasing the migration and presence in the muscle of macrophages with an anti-inflammatory phenotype (M2) and T regulatory cells (Tregs) after disease-induced muscle loss. Additionally, the switch in metabolic pathways (glycolysis to oxidative phosphorylation [OXPHOS]) is important for achieving rapid metabolic homeostasis during muscle regeneration. In this review, we discuss the molecular aspects of the immunometabolic response elicited by exercise during skeletal muscle regeneration. There is not, nevertheless, consensus on a single optimal intensity of exercise required to improve muscle strength, mass, and functional capacity owing to the wide range of exercise protocols studied so far. Despite the absence of agreement on the specific strategy, physical exercise appears as a powerful complementary strategy to attenuate the harmful effects of muscle disuse in different scenarios.
    Keywords:  cell metabolism; disuse; exercise; muscle remodeling; unloaded muscle
    DOI:  https://doi.org/10.1111/apha.13782
  3. J Physiol. 2022 Jan 07.
    Altered muscle mitochondrial, inflammatory and trophic markers and reduced exercise training adaptations in type 1 diabetes.
    Dean Minnock, Giosuè Annibalini, Giacomo Valli, Roberta Saltarelli, Mauricio Krause, Elena Barbieri, Giuseppe De Vito.
      KEY POINTS: Type 1 diabetes negatively affects skeletal muscle health; however, the effect of structured exercise training on markers of mitochondrial function, inflammation and regeneration is not known. Even though participants with type 1 diabetes and healthy control were comparable for cardiorespiratory fitness (VO2 max) and muscle strength at baseline, molecular markers related to muscle health were decreased in type 1 diabetes. After training, both groups increased the VO2 max and muscle strength, however, a larger improvement was achieved by the control group. The training intervention decreased glucose fluctuations and occurrence of hypoglycaemic events in type 1 diabetes, while signs of mild myopathy found in the muscle of participants with type 1 diabetes only partially improved after training Improving muscle health by specific exercise protocols is of considerable clinical interest in therapeutic strategies for improving type 1 diabetes management and prevent or delay long-term complications.ABSTRACT: Growing evidence of impaired skeletal muscle health in people with type 1 diabetes points toward the presence of a mild myopathy in this population. However, this myopathic condition is not jet well characterised and often overlooked, even though it might affect the whole-body glucose homeostasis and the development of comorbidities. This study aims to compare skeletal muscle adaptations and changes in glycaemic control after 12 weeks of combined resistance and aerobic (COMB) training between people with type 1 diabetes and healthy controls, and whether the impaired muscle health in type 1 diabetes can affect the exercise-induced adaptations. The COMB training intervention increased aerobic capacity and muscle strength in both healthy and type 1 diabetes sedentary participants, although these improvements were higher in the control group. Better glucose control, reduced glycaemic fluctuations and fewer hypoglycaemic events were recorded at Post- compared to Pre-intervention in type 1 diabetes. Analysis of muscle biopsies showed an alteration of muscle markers of mitochondrial functions, inflammation, aging and growth/atrophy compared to the control group. These muscular molecular differences were only partially modified by the COMB training and might explain the reduced exercise adaptation observed in type 1 diabetes. In brief, type 1 diabetes impairs many aspects of skeletal muscle health and might affect the exercise-induced adaptations. Defining the magnitude of diabetic myopathy and the effect of exercise, including longer duration of the intervention, will drive the development of strategies to maximize muscle health in the type 1 diabetes population. This article is protected by copyright. All rights reserved.
    Keywords:  exercise; exercise physiology; glucose variability; hypoglycaemia; mitochondria; muscle adaptation; myopathy; type 1 diabetes
    DOI:  https://doi.org/10.1113/JP282433
  4. J Clin Invest. 2022 Jan 04. pii: e141295. [Epub ahead of print]132(1):
    Secreted acid sphingomyelinase as a potential gene therapy for limb girdle muscular dystrophy 2B.
    Daniel C Bittel, Sen Chandra Sreetama, Goutam Chandra, Robin Ziegler, Kanneboyina Nagaraju, Jack H Van der Meulen, Jyoti K Jaiswal.
      Efficient sarcolemmal repair is required for muscle cell survival, with deficits in this process leading to muscle degeneration. Lack of the sarcolemmal protein dysferlin impairs sarcolemmal repair by reducing secretion of the enzyme acid sphingomyelinase (ASM), and causes limb girdle muscular dystrophy 2B (LGMD2B). The large size of the dysferlin gene poses a challenge for LGMD2B gene therapy efforts aimed at restoring dysferlin expression in skeletal muscle fibers. Here, we present an alternative gene therapy approach targeting reduced ASM secretion, the consequence of dysferlin deficit. We showed that the bulk endocytic ability is compromised in LGMD2B patient cells, which was addressed by extracellularly treating cells with ASM. Expression of secreted human ASM (hASM) using a liver-specific adeno-associated virus (AAV) vector restored membrane repair capacity of patient cells to healthy levels. A single in vivo dose of hASM-AAV in the LGMD2B mouse model restored myofiber repair capacity, enabling efficient recovery of myofibers from focal or lengthening contraction-induced injury. hASM-AAV treatment was safe, attenuated fibro-fatty muscle degeneration, increased myofiber size, and restored muscle strength, similar to dysferlin gene therapy. These findings elucidate the role of ASM in dysferlin-mediated plasma membrane repair and to our knowledge offer the first non-muscle-targeted gene therapy for LGMD2B.
    Keywords:  Gene therapy; Muscle Biology
    DOI:  https://doi.org/10.1172/JCI141295
  5. Acta Physiol (Oxf). 2022 Jan 05. e13772
    Assessing mitochondrial respiration in permeabilized fibres and biomarkers for mitochondrial content in human skeletal muscle.
    Jujiao Kuang, Nicholas J Saner, Javier Botella, Matthew J-C Lee, Cesare Granata, Zhenhuan Wang, Xu Yan, Jia Li, Amanda J Genders, David J Bishop.
      AIM: Assessments of mitochondrial respiration and mitochondrial content are common in skeletal muscle research and exercise science. However, many sources of technical and biological variation render these analyses susceptible to error. This study aimed to better quantify the reliability of the experimental design and/or techniques employed, therefore assist researcher in obtaining more reliable data.METHODS: We examined the repeatability of maximal mitochondrial oxidative phosphorylation in permeabilized muscle fibres via high-resolution respirometry, and of citrate synthase activity (a biomarker for mitochondrial content) in a microplate with spectrophotometery.
    RESULTS: For mitochondrial respiration using permeabilised skeletal muscle fibres, the variability was reduced by using three chambers and removing outliers compared to two chambers (CV reduced from 12.7% to 11.0%), and the minimal change that can be detected with 10 participants reduced from 17% to 13% according to modelling. For citrate synthase activity, the within-plate CV (3.5%) increased when the assay was repeated after 4 hours (CV = 10.2%) and 4 weeks (CV = 30.5%). The readings were correlated, but significantly different after 4 hours and 4 weeks.
    CONCLUSION: This research provides evidence for important technical considerations when measuring mitochondrial respiration and content using citrate synthase activity as a biomarker. When assessing mitochondrial respiration in human skeletal muscle, the technical variability of high-resolution respirometry can be reduced by increasing technical repeats and excluding outliers, practices which are not currently common. When analysing citrate synthase activity, our results highlight the importance of analysing all samples from the same study at the same time.
    Keywords:  Exercise; Human skeletal muscle; Mitochondrial content; Mitochondrial respiration
    DOI:  https://doi.org/10.1111/apha.13772
  6. Stem Cell Reports. 2021 Dec 21. pii: S2213-6711(21)00642-1. [Epub ahead of print]
    CRISPR/Cas9 editing of directly reprogrammed myogenic progenitors restores dystrophin expression in a mouse model of muscular dystrophy.
    Seraina A Domenig, Nicola Bundschuh, Ajda Lenardič, Adhideb Ghosh, Inseon Kim, Xhem Qabrati, Gommaar D'Hulst, Ori Bar-Nur.
      Genetic mutations in dystrophin manifest in Duchenne muscular dystrophy (DMD), the most commonly inherited muscle disease. Here, we report on reprogramming of fibroblasts from two DMD mouse models into induced myogenic progenitor cells (iMPCs) by MyoD overexpression in concert with small molecule treatment. DMD iMPCs proliferate extensively, while expressing myogenic stem cell markers including Pax7 and Myf5. Additionally, DMD iMPCs readily give rise to multinucleated myofibers that express mature skeletal muscle markers; however, they lack DYSTROPHIN expression. Utilizing an exon skipping-based approach with CRISPR/Cas9, we report on genetic correction of the dystrophin mutation in DMD iMPCs and restoration of protein expression in vitro. Furthermore, engraftment of corrected DMD iMPCs into the muscles of dystrophic mice restored DYSTROPHIN expression and contributed to the muscle stem cell reservoir. Collectively, our findings report on a novel in vitro cellular model for DMD and utilize it in conjunction with gene editing to restore DYSTROPHIN expression in vivo.
    Keywords:  CRISPR/Cas9 editing of myogenic stem cells; Duchenne muscular dystrophy; direct lineage reprogramming; stem-cell-based therapy
    DOI:  https://doi.org/10.1016/j.stemcr.2021.12.003
  7. Mol Ther Nucleic Acids. 2022 Mar 08. 27 184-199
    Time-controlled and muscle-specific CRISPR/Cas9-mediated deletion of CTG-repeat expansion in the DMPK gene.
    Beatrice Cardinali, Claudia Provenzano, Mariapaola Izzo, Christine Voellenkle, Jonathan Battistini, Georgios Strimpakos, Elisabetta Golini, Silvia Mandillo, Ferdinando Scavizzi, Marcello Raspa, Alessandra Perfetti, Denisa Baci, Dejan Lazarevic, Jose Manuel Garcia-Manteiga, Geneviève Gourdon, Fabio Martelli, Germana Falcone.
      CRISPR/Cas9-mediated therapeutic gene editing is a promising technology for durable treatment of incurable monogenic diseases such as myotonic dystrophies. Gene-editing approaches have been recently applied to in vitro and in vivo models of myotonic dystrophy type 1 (DM1) to delete the pathogenic CTG-repeat expansion located in the 3' untranslated region of the DMPK gene. In DM1-patient-derived cells removal of the expanded repeats induced beneficial effects on major hallmarks of the disease with reduction in DMPK transcript-containing ribonuclear foci and reversal of aberrant splicing patterns. Here, we set out to excise the triplet expansion in a time-restricted and cell-specific fashion to minimize the potential occurrence of unintended events in off-target genomic loci and select for the target cell type. To this aim, we employed either a ubiquitous promoter-driven or a muscle-specific promoter-driven Cas9 nuclease and tetracycline repressor-based guide RNAs. A dual-vector approach was used to deliver the CRISPR/Cas9 components into DM1 patient-derived cells and in skeletal muscle of a DM1 mouse model. In this way, we obtained efficient and inducible gene editing both in proliferating cells and differentiated post-mitotic myocytes in vitro as well as in skeletal muscle tissue in vivo.
    Keywords:  CRISPR/Cas9; CTG repeats; DM1; DMSXL mouse model; gene editing; gene therapy; myotonic dystrophy; skeletal muscle
    DOI:  https://doi.org/10.1016/j.omtn.2021.11.024
  8. Exp Cell Res. 2021 Dec 29. pii: S0014-4827(21)00546-2. [Epub ahead of print] 112990
    Recapitulating human myogenesis ex vivo using human pluripotent stem cells.
    Peggie Chien, Haibin Xi, April D Pyle.
      Human pluripotent stem cells (hPSCs) provide a human model for developmental myogenesis, disease modeling and development of therapeutics. Differentiation of hPSCs into muscle stem cells has the potential to provide a cell-based therapy for many skeletal muscle wasting diseases. This review describes the current state of hPSCs towards recapitulating human myogenesis ex vivo, considerations of stem cell and progenitor cell state as well as function for future use of hPSC-derived muscle cells in regenerative medicine.
    Keywords:  cell differentiation; development; human myogenesis; human pluripotent stem cells; muscle stem and progenitor cells
    DOI:  https://doi.org/10.1016/j.yexcr.2021.112990
  9. Am J Physiol Cell Physiol. 2022 Jan 05.
    Reducing sarcolipin expression improves muscle metabolism in mdx mice.
    Rekha Balakrishnan, Satvik Mareedu, Gopal J Babu.
      Duchenne muscular dystrophy (DMD) is an inherited muscle wasting disease. Metabolic impairments and oxidative stress are major secondary mechanisms that severely worsen muscle function in DMD. Here, we sought to determine whether germline reduction or ablation of sarcolipin (SLN), an inhibitor of sarco/endoplasmic reticulum (SR) Ca2+ ATPase (SERCA) improves muscle metabolism and ameliorates muscle pathology in the mdx mouse model of DMD. Glucose and insulin tolerance tests show that glucose clearance rate and insulin sensitivity were improved in the SLN haploinsufficient mdx (mdx:sln+/-) and SLN deficient mdx (mdx:sln-/-) mice. The histopathological analysis shows that fibrosis and necrosis were significantly reduced in muscles of mdx:sln+/- and mdx:sln-/-mice. SR Ca2+ uptake, mitochondrial complex protein levels, complex activities, mitochondrial Ca2+ uptake and release, and mitochondrial metabolism were significantly improved and, lipid peroxidation and protein carbonylation were reduced in the muscles of mdx:sln+/- and mdx:sln-/-mice. These data demonstrate that reduction or ablation of SLN expression can improve muscle metabolism, reduce oxidative stress, decrease muscle pathology, and protects the mdx mice from glucose intolerance.
    Keywords:  Duchenne muscular dystrophy; SERCA; mdx; metabolism; sarcolipin
    DOI:  https://doi.org/10.1152/ajpcell.00125.2021
  10. J Gerontol A Biol Sci Med Sci. 2022 Jan 04. pii: glac002. [Epub ahead of print]
    Preliminary evidence of differential expression of myogenic and stress factors in skeletal muscle of older adults with low muscle strength.
    Sebastiaan Dalle, Jolan Dupont, Lenore Dedeyne, Sabine Verschueren, Jos Tournoy, Evelien Gielen, Katrien Koppo.
      The age-related loss of muscle strength and mass, or sarcopenia, is a growing concern in the ageing population. Yet, it is not fully understood which molecular mechanisms underlie sarcopenia. Therefore, the present study compared the protein expression profile, such as catabolic, oxidative, stress-related and myogenic pathways, between older adults with preserved (8 ♀ and 5 ♂; 71.5 ±2.6 years) and low muscle strength (6 ♀ and 5 ♂; 78.0±5.0 years). Low muscle strength was defined as chair stand test time >15 seconds and/or handgrip strength <16kg (women) or <27kg (men) according the EWGSOP2 criteria. Catabolic signaling (i.e. FOXO1/3a, MuRF1, MAFbx, LC3b, Atg5, p62) was not differentially expressed between both groups, whereas the mitochondrial marker COX-IV, but not PGC1α and citrate synthase, was lower in the low muscle strength group. Stress factors CHOP and p-ERK1/2 were higher (~1.5-fold) in older adults with low muscle strength. Surprisingly, the inflammatory marker p-p65NF-κB was ~7-fold higher in older adults with preserved muscle strength. Finally, expression of myogenic factors (i.e. Pax7, MyoD, desmin; ~2-fold) was higher in adults with low muscle strength. To conclude, whereas the increased stress factors might reflect the age-related deterioration of tissue homeostasis, e.g. due to misfolded proteins (CHOP), upregulation of myogenic markers in the low strength group might be an attempt to compensate for the gradual loss in muscle quantity and quality. These data might provide valuable insights in the processes that underlie sarcopenia.
    Keywords:  Sarcopenia; muscle aging; muscle molecular signaling; muscle strength
    DOI:  https://doi.org/10.1093/gerona/glac002
  11. Acta Physiol (Oxf). 2022 Jan 05. e13771
    Acute normobaric hypoxia blunts contraction-mediated mTORC1- and JNK-signaling in human skeletal muscle.
    Marcus Moberg, William Apró, Oscar Horwath, Gerrit van Hall, Sarah Joan Blackwood, Abram Katz.
      AIM: Hypoxia has been shown to reduce resistance exercise-induced stimulation of protein synthesis and long-term gains in muscle mass. However, the mechanism whereby hypoxia exerts its effect is not clear. Here we examine the effect of acute hypoxia on the activity of several signaling pathways involved in regulation of muscle growth following a bout of resistance exercise.METHODS: Eight men performed two sessions of leg resistance exercise in Normoxia or Hypoxia (12% O2 ) in a randomized crossover fashion. Muscle biopsies were obtained at rest and at 0, 90,180 min after exercise. Muscle analyses included levels of signaling proteins and metabolites associated with energy turnover.
    RESULTS: Exercise during Normoxia induced a 5-10-fold increase of S6K1Thr389 phosphorylation throughout the recovery period, but Hypoxia blunted the increases by ~50%. Phosphorylation of JNKThr183/Tyr185 and the JNK target SMAD2Ser245/250/255 was increased by 30-40-fold immediately after exercise in Normoxia, but Hypoxia blocked almost 70% of the activation. Throughout recovery, phosphorylation of JNK and SMAD2 remained elevated following exercise in Normoxia, but the effect of Hypoxia was lost at 90-180 min post-exercise. Hypoxia had no effect on exercise induced Hippo- or autophagy-signaling and ubiquitin-proteasome related protein levels. Nor did Hypoxia alter the changes induced by exercise in high energy phosphates, glucose 6-P, lactate, or phosphorylation of AMPK or ACC.
    CONCLUSION: We conclude that acute severe hypoxia inhibits resistance exercise induced mTORC1- and JNK signaling in human skeletal muscle, effects that do not appear to be mediated by changes in the degree of metabolic stress in the muscle.
    Keywords:  FSR; Hippo-pathway; Muscle metabolites; deuterium oxide; oxygen
    DOI:  https://doi.org/10.1111/apha.13771
  12. J Cachexia Sarcopenia Muscle. 2022 Jan 07.
    Skeletal muscle alterations in patients with acute Covid-19 and post-acute sequelae of Covid-19.
    Madu N Soares, Moritz Eggelbusch, Elie Naddaf, Karin H L Gerrits, Marike van der Schaaf, Bram van den Borst, W Joost Wiersinga, Michele van Vugt, Peter J M Weijs, Andrew J Murray, Rob C I Wüst.
      Skeletal muscle-related symptoms are common in both acute coronavirus disease (Covid)-19 and post-acute sequelae of Covid-19 (PASC). In this narrative review, we discuss cellular and molecular pathways that are affected and consider these in regard to skeletal muscle involvement in other conditions, such as acute respiratory distress syndrome, critical illness myopathy, and post-viral fatigue syndrome. Patients with severe Covid-19 and PASC suffer from skeletal muscle weakness and exercise intolerance. Histological sections present muscle fibre atrophy, metabolic alterations, and immune cell infiltration. Contributing factors to weakness and fatigue in patients with severe Covid-19 include systemic inflammation, disuse, hypoxaemia, and malnutrition. These factors also contribute to post-intensive care unit (ICU) syndrome and ICU-acquired weakness and likely explain a substantial part of Covid-19-acquired weakness. The skeletal muscle weakness and exercise intolerance associated with PASC are more obscure. Direct severe acute respiratory syndrome coronavirus (SARS-CoV)-2 viral infiltration into skeletal muscle or an aberrant immune system likely contribute. Similarities between skeletal muscle alterations in PASC and chronic fatigue syndrome deserve further study. Both SARS-CoV-2-specific factors and generic consequences of acute disease likely underlie the observed skeletal muscle alterations in both acute Covid-19 and PASC.
    Keywords:  Covid-19; Inflammation; Metabolism; Muscle wasting; Skeletal muscle
    DOI:  https://doi.org/10.1002/jcsm.12896
  13. J Biomed Mater Res A. 2022 Jan 06.
    Bioinspired electrospun decellularized extracellular matrix scaffolds promote muscle regeneration in a rat skeletal muscle defect model.
    Katie J Hogan, Mollie M Smoak, Gerry L Koons, Marissa R Perez, Matthew L Bedell, Emily Y Jiang, Simon Young, Antonios G Mikos.
      Volumetric muscle loss is a debilitating injury that can leave patients with long-lasting or permanent structural and functional deficits. With clinical treatments failing to address these shortcomings, there is a great need for tissue-engineered therapies to promote skeletal muscle regeneration. In this study, we aim to assess the potential for electrospun decellularized skeletal muscle extracellular matrix (dECM) to promote skeletal muscle regeneration in a rat partial thickness tibialis anterior defect model. Aligned electrospun scaffolds with varying degrees of crosslinking density were implanted into the defect site and compared to an empty defect control. After 8 weeks, muscles were harvested, weighed, and cellular and morphological analyses were performed via histology and immunohistochemistry. Cell infiltration, angiogenesis, and myogenesis were observed in the defect site in both dECM groups. However, favorable mechanical properties and slower degradation kinetics resulted in greater support of tissue remodeling in the more crosslinked scaffolds and preservation of existing myofiber area in both dECM groups compared to the empty defect control. More sustained release of pro-regenerative degradation products also promoted greater myofiber formation in the defect site. This study allowed for a greater understanding of how electrospun skeletal muscle scaffolds interact with existing skeletal muscle and can inform their potential as a therapy in a wide variety of soft tissue applications.
    Keywords:  decellularized extracellular matrix; electrospun scaffold; skeletal muscle; volumetric muscle loss
    DOI:  https://doi.org/10.1002/jbm.a.37355
  14. Mol Neurobiol. 2022 Jan 08.
    Neuromuscular Junction Dysfunction in Amyotrophic Lateral Sclerosis.
    Sagar Verma, Shiffali Khurana, Abhishek Vats, Bandana Sahu, Nirmal Kumar Ganguly, Pradip Chakraborti, Mandaville Gourie-Devi, Vibha Taneja.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder characterized by progressive degeneration of motor neurons leading to skeletal muscle denervation. Earlier studies have shown that motor neuron degeneration begins in motor cortex and descends to the neuromuscular junction (NMJ) in a dying forward fashion. However, accumulating evidences support that ALS is a distal axonopathy where early pathological changes occur at the NMJ, prior to onset of clinical symptoms and propagates towards the motor neuron cell body supporting "dying back" hypothesis. Despite several evidences, series of events triggering NMJ disassembly in ALS are still obscure. Neuromuscular junction is a specialized tripartite chemical synapse which involves a well-coordinated communication among the presynaptic motor neuron, postsynaptic skeletal muscle, and terminal Schwann cells. This review provides comprehensive insight into the role of NMJ in ALS pathogenesis. We have emphasized the molecular alterations in cellular components of NMJ leading to loss of effective neuromuscular transmission in ALS. Further, we provide a preview into research involved in exploring NMJ as potential target for designing effective therapies for ALS.
    Keywords:  Amyotrophic lateral sclerosis; Dying back; Motor neuron; Neuromuscular junction; Skeletal muscle; Terminal Schwann cells
    DOI:  https://doi.org/10.1007/s12035-021-02658-6
  15. Mol Ther Nucleic Acids. 2022 Mar 08. 27 147-164
    Filamin C regulates skeletal muscle atrophy by stabilizing dishevelled-2 to inhibit autophagy and mitophagy.
    Shunshun Han, Can Cui, Xiyu Zhao, Yao Zhang, Yun Zhang, Jing Zhao, Xiaoxu Shen, Haorong He, Jianping Wang, Menggen Ma, Diyan Li, Qing Zhu, Huadong Yin.
      FilaminC (Flnc) is a member of the actin binding protein family, which is preferentially expressed in the cardiac and skeletal muscle tissues. Although it is known to interact with proteins associated with myofibrillar myopathy, its unique role in skeletal muscle remains largely unknown. In this study, we identify the biological functions of Flnc in vitro and in vivo using chicken primary myoblast cells and animal models, respectively. From the results, we observe that the growth rate and mass of the skeletal muscle of fast-growing chickens (broilers) were significantly higher than those in slow-growing chickens (layers). Furthermore, we find that the expression of Flnc in the skeletal muscle of broilers was higher than that in the layers. Our results indicated that Flnc was highly expressed in the skeletal muscle, especially in the skeletal muscle of broilers than in layers. This suggests that Flnc plays a positive regulatory role in myoblast development. Flnc knockdown resulted in muscle atrophy, whereas the overexpression of Flnc promotes muscle hypertrophy in vivo in an animal model. We also found that Flnc interacted with dishevelled-2 (Dvl2), activated the wnt/β-catenin signaling pathway, and controlled skeletal muscle development. Flnc also antagonized the LC3-mediated autophagy system by decreasing Dvl2 ubiquitination. Moreover, Flnc knockdown activated and significantly increased mitophagy. In summary, these results indicate that the absence of Flnc induces autophagy or mitophagy and regulates muscle atrophy.
    Keywords:  atrophy; autophagy; dishevelled-2; filamin C; mitophagy; skeletal muscle
    DOI:  https://doi.org/10.1016/j.omtn.2021.11.022
  16. Acta Physiol (Oxf). 2022 Jan 04. e13766
    Factors Mediating Exercise-induced Organ Crosstalk.
    Rugivan Sabaratnam, Jørgen F P Wojtaszewski, Kurt Højlund.
      Exercise activates a plethora of metabolic and signalling pathways in skeletal muscle and other organs causing numerous systemic beneficial metabolic effects. Thus, regular exercise may ameliorate and prevent the development of several chronic metabolic diseases. Skeletal muscle is recognized as an important endocrine organ regulating systemic adaptations to exercise. Skeletal muscle may mediate crosstalk with other organs through the release of exercise-induced cytokines, peptides and proteins, termed myokines, into the circulation. Importantly, other tissues such as the liver and adipose tissue may also release cytokines and peptides in response to exercise. Hence, exercise-released molecules are collectively called exerkines. Moreover, extracellular vesicles (EVs), in the form of exosomes or microvesicles, may carry some of the signals involved in tissue crosstalk. This review focuses on the role of factors potentially mediating crosstalk between muscle and other tissues in response to exercise.
    Keywords:  Exercise; crosstalk; exerkines; exosomes; hepatokines; myokines; skeletal muscle
    DOI:  https://doi.org/10.1111/apha.13766
  17. Mol Metab. 2021 Dec 31. pii: S2212-8778(21)00287-8. [Epub ahead of print] 101429
    Disruption of STIM1-mediated Ca2+ sensing and energy metabolism in adult skeletal muscle compromises exercise tolerance, proteostasis and lean mass.
    Rebecca J Wilson, Scott P Lyons, Tim R Koves, Victoria G Bryson, Hengtao Zhang, TianYu Li, Scott B Crown, Jin-Dong Ding, Paul A Grimsrud, Paul B Rosenberg, Deborah M Muoio.
      STIM1 is a single-pass transmembrane endoplasmic/sarcoplasmic reticulum (E/SR) protein recognized for its role in store operated Ca2+ entry (SOCE), an ancient and ubiquitous signaling pathway. Whereas STIM1 is indispensable during development, its biological and metabolic functions in mature muscle were unclear. Shown here, STIM1 is abundant in adult skeletal muscle, upregulated by exercise, and present at SR-mitochondria interfaces. Among its multifaceted roles, STIM1 regulates Ca2+ signaling, mitochondrial Ca2+ loading, energy metabolism and protein homeostasis. Thus, inducible tissue-specific deletion of STIM1 (iSTIM1 KO) in adult muscle leads to diminished lean mass, reduced exercise capacity, and perturbed fuel selection in settings of energetic stress, without affecting whole-body glucose tolerance. Proteomics and phospho-proteomics analyses of iSTIM1 KO muscles revealed molecular signatures of low-grade E/SR stress and broad activation of processes and signaling networks involved in proteostasis. The findings provide insight into the pathophysiology of muscle diseases linked to disturbances in STIM1-dependent calcium handling.
    DOI:  https://doi.org/10.1016/j.molmet.2021.101429
  18. J Cachexia Sarcopenia Muscle. 2022 Jan 08.
    Muscle-specific functional deficits and lifelong fibrosis in response to paediatric radiotherapy and tumour elimination.
    Jacob G Kallenbach, John F Bachman, Nicole D Paris, Roméo S Blanc, Thomas O'Connor, Esraa Furati, Jacqueline P Williams, Joe V Chakkalakal.
      BACKGROUND: As paediatric cancer survivors are living into adulthood, they suffer from the age-related, accelerated decline of functional skeletal muscle tissue, termed sarcopenia. With ionizing radiation (radiotherapy) at the core of paediatric cancer therapies, its direct and indirect effects can have lifelong negative impacts on paediatric growth and maintenance of skeletal muscle. Utilizing our recently developed preclinical rhabdomyosarcoma mouse model, we investigated the late effects of paediatric radiation treatment on skeletal muscles from late adolescent (8 weeks old) and middle-aged (16 months old) mice.METHODS: Paediatric C57BL/6J male mice (3 weeks old) were injected with rhabdomyosarcoma cells into their right hindlimbs, and then fractionated irradiation (3 × 8.2 Gy) was administered to those limbs at 4 weeks old to eliminate the tumours. Radiation-alone and tumour-irradiated mice were assessed at either 8 weeks (3 weeks post-irradiation) or 16 months (14 months post-irradiation) of age for muscle physiology, myofibre characteristics, cell loss, histopathology, fibrosis, inflammatory gene expression, and fibrotic gene expression.
    RESULTS: Mice that received only paediatric radiation demonstrated reduced muscle mass (-17%, P < 0.001), muscle physiological function (-25%, P < 0.01), muscle contractile kinetics (-25%, P < 0.05), satellite cell number (-45%, P < 0.05), myofibre cross-sectional area (-30%, P < 0.0001), and myonuclear number (-17%, P < 0.001). Paediatric radiation increased inflammatory gene expression, increased fibrotic gene expression, and induced extracellular matrix protein deposition (fibrosis) with tumour elimination exacerbating some phenotypes. Paediatric tumour-eliminated mice demonstrated exacerbated deficits to function (-20%, P < 0.05) and myofibre size (-17%, P < 0.001) in some muscles as well as further increases to inflammatory and fibrotic gene expression. Examining the age-related effects of paediatric radiotherapy in middle-aged mice, we found persistent myofibre atrophy (-20%, P < 0.01), myonuclear loss (-18%, P < 0.001), up-regulated inflammatory and fibrotic signalling, and lifelong fibrosis.
    CONCLUSIONS: The results from this paediatric radiotherapy model are consistent and recapitulate the clinical and molecular features of accelerated sarcopenia, musculoskeletal frailty, and radiation-induced fibrosis experienced by paediatric cancer survivors. We believe that this preclinical mouse model is well poised for future mechanistic insights and therapeutic interventions that improve the quality of life for paediatric cancer survivors.
    Keywords:  Ageing; Cancer survivorship; DNA damage; Development; Frailty; Musculoskeletal; Physiology; Radiation; Regeneration; Rhabdomyosarcoma; Sarcopenia; Stem cell
    DOI:  https://doi.org/10.1002/jcsm.12902
  19. Front Physiol. 2021 ;12 773995
    Frequent Manipulation of Resistance Training Variables Promotes Myofibrillar Spacing Changes in Resistance-Trained Individuals.
    Carlton D Fox, Paulo H C Mesquita, Joshua S Godwin, Vitor Angleri, Felipe Damas, Bradley A Ruple, Casey L Sexton, Michael D Brown, Andreas N Kavazis, Kaelin C Young, Carlos Ugrinowitsch, Cleiton A Libardi, Michael D Roberts.
      We sought to determine if manipulating resistance training (RT) variables differentially altered the expression of select sarcoplasmic and myofibril proteins as well as myofibrillar spacing in myofibers. Resistance-trained men (n = 20; 26 ± 3 years old) trained for 8 weeks where a randomized leg performed either a standard (CON) or variable RT protocol (VAR: manipulation of load, volume, muscle action, and rest intervals at each RT session). A pre-training (PRE) vastus lateralis biopsy was obtained from a randomized single leg, and biopsies were obtained from both legs 96 h following the last training bout. The sarcoplasmic protein pool was assayed for proteins involved in energy metabolism, and the myofibril protein pool was assayed for relative myosin heavy chain (MHC) and actin protein abundances. Sections were also histologically analyzed to obtain myofibril spacing characteristics. VAR resulted in ~12% greater volume load (VL) compared to CON (p < 0.001). The mean fiber cross-sectional area increased following both RT protocols [CON: 14.6% (775.5 μm2), p = 0.006; VAR: 13.9% (743.2 μm2), p = 0.01 vs. PRE for both], but without significant differences between protocols (p = 0.79). Neither RT protocol affected a majority of assayed proteins related to energy metabolism, but both training protocols increased hexokinase 2 protein levels and decreased a mitochondrial beta-oxidation marker (VLCAD protein; p < 0.05). Citrate synthase activity levels increased with CON RT (p < 0.05), but not VAR RT. The relative abundance of MHC (summed isoforms) decreased with both training protocols (p < 0.05). However, the relative abundance of actin protein (summed isoforms) decreased with VAR only (13.5 and 9.0%, respectively; p < 0.05). A decrease in percent area occupied by myofibrils was observed from PRE to VAR (-4.87%; p = 0.048), but not for the CON (4.53%; p = 0.979). In contrast, there was an increase in percent area occupied by non-contractile space from PRE to VAR (10.14%; p = 0.048), but not PRE to CON (0.72%; p = 0.979). In conclusion, while both RT protocols increased muscle fiber hypertrophy, a higher volume-load where RT variables were frequently manipulated increased non-contractile spacing in resistance-trained individuals.
    Keywords:  actin; muscle fiber; myofibrils; myosin; sarcoplasm
    DOI:  https://doi.org/10.3389/fphys.2021.773995
  20. ACS Omega. 2021 Dec 28. 6(51): 35375-35388
    Spinal Muscular Atrophy Patient iPSC-Derived Motor Neurons Display Altered Proteomes at Early Stages of Differentiation.
    Suzy Varderidou-Minasian, Bert M Verheijen, Oliver Harschnitz, Sandra Kling, Henk Karst, W Ludo van der Pol, R Jeroen Pasterkamp, Maarten Altelaar.
      Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder characterized by loss of motor neurons (MN) in the spinal cord leading to progressive muscle atrophy and weakness. SMA is caused by mutations in the survival motor neuron 1 (SMN1) gene, resulting in reduced levels of survival motor neuron (SMN) protein. The mechanisms that link SMN deficiency to selective motor neuron dysfunction in SMA remain largely unknown. We present here, for the first time, a comprehensive quantitative TMT-10plex proteomics analysis that covers the development of induced pluripotent stem cell-derived MNs from both healthy individuals and SMA patients. We show that the proteomes of SMA samples segregate from controls already at early stages of neuronal differentiation. The altered proteomic signature in SMA MNs is associated with mRNA splicing, ribonucleoprotein biogenesis, organelle organization, cellular biogenesis, and metabolic processes. We highlight several known SMN-binding partners and evaluate their expression changes during MN differentiation. In addition, we compared our study to human and mouse in vivo proteomic studies revealing distinct and similar signatures. Altogether, our work provides a comprehensive resource of molecular events during early stages of MN differentiation, containing potentially therapeutically interesting protein expression profiles for SMA.
    DOI:  https://doi.org/10.1021/acsomega.1c04688
  21. Geroscience. 2022 Jan 04.
    A neuromuscular perspective of sarcopenia pathogenesis: deciphering the signaling pathways involved.
    Alexandra Moreira-Pais, Rita Ferreira, Paula A Oliveira, José A Duarte.
      The escalation of life expectancy is accompanied by an increase in the prevalence of age-related conditions, such as sarcopenia. Sarcopenia, a muscle condition defined by low muscle strength, muscle quality or quantity, and physical performance, has a high prevalence among the elderly and is associated to increased mortality. The neuromuscular system has been emerging as a key contributor to sarcopenia pathogenesis. Indeed, the age-related degeneration of the neuromuscular junction (NMJ) function and structure may contribute to the loss of muscle strength and ultimately to the loss of muscle mass that characterize sarcopenia. The present mini-review discusses important signaling pathways involved in the function and maintenance of the NMJ, giving emphasis to the ones that might contribute to sarcopenia pathogenesis. Some conceivable biomarkers, such as C-terminal agrin fragment (CAF) and brain-derived neurotrophic factor (BDNF), and therapeutic targets, namely acetylcholine and calcitonin gene-related peptide (CGRP), can be retrieved, making way to future studies to validate their clinical use.
    Keywords:  BDNF; CAF; Denervation; Muscle wasting; Neuromuscular junction; Neurotrophins
    DOI:  https://doi.org/10.1007/s11357-021-00510-2
  22. Int J Surg. 2022 Jan 04. pii: S1743-9191(21)00369-1. [Epub ahead of print]97 106206
    Skeletal muscle wasting during neoadjuvant therapy as a prognosticator in patients with esophageal and esophagogastric junction cancer: A systematic review and meta-analysis.
    Peiyu Wang, Shaodong Wang, Xiao Li, Guihu Lin, Yi Ma, Rongxin Xiao, Haoran Li, Mantang Qiu, Fan Yang.
      BACKGROUND: Considerable controversies exist regarding the severity of skeletal muscle wasting (SMW) during neoadjuvant therapy (NAT) and its impact on therapeutic outcomes in patients with esophageal or esophagogastric junction cancer (EC/EGJC). This systematic review and meta-analysis aimed to resolve these issues. Particularly, the prognostic value of SMW during NAT was compared to pre-NAT and pre-surgery sarcopenia status.METHODS: We searched PubMed, Embase, and Cochrane Library databases through October 13th, 2021 to identify cohort studies focusing on SMW during NAT and therapeutic outcomes in EC/EGJC patients. Both neoadjuvant chemotherapy and neoadjuvant chemoradiotherapy were studied. A meta-analysis was conducted to quantify SMW and increased sarcopenia during NAT. Therapeutic outcomes include perioperative morbidities and survival profiles. A separate meta-analysis investigating the impacts of pre-NAT/pre-surgery sarcopenia on therapeutic outcomes was synchronously performed.
    RESULTS: Twenty-five studies with 2706 participants were included in this review. The pooled SMW during NAT were -2.47 cm2/m2 in skeletal muscle index and -0.23 cm2/m2 in psoas muscle index, with wasting proportion reaching 4.44%. The pooled prevalence rate of sarcopenia increased from 53.1% before NAT to 65.8% before surgery. Neoadjuvant chemoradiotherapy, advanced age, and being male were identified as risk factors for severe SMW during NAT. Notably, severe SMW during NAT showed a greater hazard ratio (HR) than pre-NAT and pre-surgery sarcopenia in predicting overall survival (HR 1.92, P < 0.001; HR 1.17, P = 0.036; and HR 1.28, P = 0.011, respectively) and recurrence-free survival (HR 1.51, P = 0.002; HR 1.27, P = 0.008; and HR 1.38, P = 0.006, respectively). However, severe SMW during NAT was not significantly associated with perioperative morbidities.
    CONCLUSIONS: SMW during NAT is a novel prognosticator that is different from sarcopenia for poor survival in EC/EGJC patients. Interventions aiming at maintaining skeletal muscle during NAT are anticipated to promote therapeutic outcomes.
    Keywords:  Esophageal cancer; Esophagogastric junction cancer; Neoadjuvant therapy; Sarcopenia; Skeletal muscle wasting
    DOI:  https://doi.org/10.1016/j.ijsu.2021.106206
  23. Elife. 2022 Jan 05. pii: e71588. [Epub ahead of print]11
    The role of action potential changes in depolarization-induced failure of excitation contraction coupling in mouse skeletal muscle.
    Xueyong Wang, Murad Nawaz, Chris DuPont, Jessica H Myers, Steve Ra Burke, Roger A Bannister, Brent D Foy, Andrew A Voss, Mark M Rich.
      Excitation-contraction coupling (ECC) is the process by which electrical excitation of muscle is converted into force generation. Depolarization of skeletal muscle resting potential contributes to failure of ECC in diseases such as periodic paralysis, intensive care unit acquired weakness and possibly fatigue of muscle during vigorous exercise. When extracellular K+ is raised to depolarize the resting potential, failure of ECC occurs suddenly, over a narrow range of resting potentials. Simultaneous imaging of Ca2+ transients and recording of action potentials (APs) demonstrated failure to generate Ca2+ transients when APs peaked at potentials more negative than -30mV. An AP property that closely correlated with failure of the Ca2+ transient was the integral of AP voltage with respect to time. Simultaneous recording of Ca2+ transients and APs with electrodes separated by 1.6mm revealed AP conduction fails when APs peak below -21mV. We hypothesize propagation of APs and generation of Ca2+ transients are governed by distinct AP properties: AP conduction is governed by AP peak, whereas Ca2+ release from the sarcoplasmic reticulum is governed by AP integral. The reason distinct AP properties may govern distinct steps of ECC is the kinetics of the ion channels involved. Na channels, which govern propagation, have rapid kinetics and are insensitive to AP width (and thus AP integral) whereas Ca2+ release is governed by gating charge movement of Cav1.1 channels, which have slower kinetics such that Ca2+ release is sensitive to AP integral. The quantitative relationships established between resting potential, AP properties, AP conduction and Ca2+ transients provide the foundation for future studies of failure of ECC induced by depolarization of the resting potential.
    Keywords:  action potential; calcium release; depolarization; excitation contraction coupling; medicine; mouse; neuroscience; skeletal muscle
    DOI:  https://doi.org/10.7554/eLife.71588
  24. Glia. 2022 Jan 03.
    Astrocyte-targeting RNA interference against mutated superoxide dismutase 1 induces motoneuron plasticity and protects fast-fatigable motor units in a mouse model of amyotrophic lateral sclerosis.
    Cylia Rochat, Nathalie Bernard-Marissal, Emma Källstig, Sylvain Pradervand, Florence E Perrin, Patrick Aebischer, Cédric Raoul, Bernard L Schneider.
      In amyotrophic lateral sclerosis (ALS) caused by SOD1 gene mutations, both cell-autonomous and noncell-autonomous mechanisms lead to the selective degeneration of motoneurons (MN). Here, we evaluate the therapeutic potential of gene therapy targeting mutated SOD1 in mature astrocytes using mice expressing the mutated SOD1G93A protein. An AAV-gfaABC1 D vector encoding an artificial microRNA is used to deliver RNA interference against mutated SOD1 selectively in astrocytes. The treatment leads to the progressive rescue of neuromuscular junction occupancy, to the recovery of the compound muscle action potential in the gastrocnemius muscle, and significantly improves neuromuscular function. In the spinal cord, gene therapy targeting astrocytes protects a small pool of the most vulnerable fast-fatigable MN until disease end stage. In the gastrocnemius muscle of the treated SOD1G93A mice, the fast-twitch type IIB muscle fibers are preserved from atrophy. Axon collateral sprouting is observed together with muscle fiber type grouping indicative of denervation/reinnervation events. The transcriptome profiling of spinal cord MN shows changes in the expression levels of factors regulating the dynamics of microtubules. Gene therapy delivering RNA interference against mutated SOD1 in astrocytes protects fast-fatigable motor units and thereby improves neuromuscular function in ALS mice.
    Keywords:  RNA interference; amyotrophic lateral sclerosis; astrocyte; gene therapy; neuromuscular function; neuronal plasticity; superoxide dismutase 1
    DOI:  https://doi.org/10.1002/glia.24140
  25. Nitric Oxide. 2021 Dec 29. pii: S1089-8603(21)00134-8. [Epub ahead of print]120 1-8
    GAPDH S-nitrosation contributes to age-related sarcopenia through mediating apoptosis.
    Ting Xie, Xinhua Qiao, Chuanxin Sun, Boyu Chu, Jiao Meng, Chang Chen.
      The age-related loss of muscle mass and muscle function known as sarcopenia is a major public health problem among older people. Recent research suggests that activation of apoptotic signaling is a critical aspect of the pathogenesis of age-related sarcopenia. However, little information exists in the literature about the apoptotic mechanism of sarcopenia in aging. Herein, we report that elevated glyceraldehyde-3-phosphate dehydrogenase (GAPDH) S-nitrosation and apoptosis occur in sarcopenia during natural aging and that translocation of S-nitrosated GAPDH to the nucleus and S-nitrosated GAPDH-mediated apoptosis contributed to sarcopenia. The levels and sites of GAPDH S-nitrosation in muscle tissues of young, adult and old mice were studied with a quantitative S-nitrosation proteomic analysis approach. GAPDH S-nitrosation increased with aging, and the GAPDH modification sites Cys150, Cys154 and Cys245 were identified. The upregulated S-nitrosation of GAPDH relies on inducible nitric oxide synthase (iNOS) rather than enzymes involved in denitrosylation. Treatment with the iNOS inhibitor 1400W or mutation of GAPDH S-nitrosation sites alleviated apoptosis of C2C12 cells, further demonstrating that GAPDH S-nitrosation in aging contributes to sarcopenia. Taken together, these findings reveal a new cellular mechanism underlying age-related sarcopenia, and the demonstration of muscle loss mediated by iNOS-induced GAPDH S-nitrosation suggests a potential therapeutic strategy for sarcopenia.
    Keywords:  Aging; Apoptosis; GAPDH; S-nitrosation/S-nitrosylation; Sarcopenia; iNOS
    DOI:  https://doi.org/10.1016/j.niox.2021.12.006
  26. Geriatr Gerontol Int. 2022 Jan 05.
    Skeletal muscle as a treatment target for older adults with diabetes mellitus: The importance of a multimodal intervention based on functional category.
    Takuya Omura, Atsushi Araki.
      Although the lifespan of people with diabetes has increased in many countries, the age-related increase in comorbidities (sarcopenia, frailty and disabilities) and diabetic complications has become a major issue. Diabetes accelerates the aging of skeletal muscles and blood vessels through mechanisms, such as increased oxidative stress, chronic inflammation, insulin resistance, mitochondrial dysfunction, genetic polymorphism (fat mass and obesity-associated genes) and accumulation of advanced glycation end-products. Diabetes is associated with early onset, and progression of muscle weakness and sarcopenia, thus resulting in diminished daily life function. The type and duration of diabetes, insulin section/resistance, hyperglycemia, diabetic neuropathy, malnutrition and low physical activity might affect muscular loss and weakness. To prevent the decline in daily activities in older adults with diabetes, resistance training or multicomponent exercise should be recommended. To maintain muscle function, optimal energy and sufficient protein intake are necessary. Although no specific drug enhances muscle mass and function, antidiabetic drugs that increase insulin sensitivity or secretion could be candidates for improvement of sarcopenia. The goals of glycemic control for older patients are determined based on three functional categories through an assessment of cognitive function and activities of daily living, and the presence or absence of medications that pose a hypoglycemic risk. As these functional categories are associated with muscle weakness, frailty and mortality risk, providing multimodal interventions (exercise, nutrition, social network or support and optimal medical treatment) is important, starting at the category II stage for maintenance or improvement in daily life functions. Geriatr Gerontol Int 2022; ••: ••-••.
    Keywords:  exercise therapy; frailty; functional category; older diabetes; sarcopenia
    DOI:  https://doi.org/10.1111/ggi.14339
  27. Life Sci Alliance. 2022 Apr;pii: e202101342. [Epub ahead of print]5(4):
    Rbfox1 is required for myofibril development and maintaining fiber type-specific isoform expression in Drosophila muscles.
    Elena Nikonova, Amartya Mukherjee, Ketaki Kamble, Christiane Barz, Upendra Nongthomba, Maria L Spletter.
      Protein isoform transitions confer muscle fibers with distinct properties and are regulated by differential transcription and alternative splicing. RNA-binding Fox protein 1 (Rbfox1) can affect both transcript levels and splicing, and is known to contribute to normal muscle development and physiology in vertebrates, although the detailed mechanisms remain obscure. In this study, we report that Rbfox1 contributes to the generation of adult muscle diversity in Drosophila Rbfox1 is differentially expressed among muscle fiber types, and RNAi knockdown causes a hypercontraction phenotype that leads to behavioral and eclosion defects. Misregulation of fiber type-specific gene and splice isoform expression, notably loss of an indirect flight muscle-specific isoform of Troponin-I that is critical for regulating myosin activity, leads to structural defects. We further show that Rbfox1 directly binds the 3'-UTR of target transcripts, regulates the expression level of myogenic transcription factors myocyte enhancer factor 2 and Salm, and both modulates expression of and genetically interacts with the CELF family RNA-binding protein Bruno1 (Bru1). Rbfox1 and Bru1 co-regulate fiber type-specific alternative splicing of structural genes, indicating that regulatory interactions between FOX and CELF family RNA-binding proteins are conserved in fly muscle. Rbfox1 thus affects muscle development by regulating fiber type-specific splicing and expression dynamics of identity genes and structural proteins.
    DOI:  https://doi.org/10.26508/lsa.202101342
  28. Sci Rep. 2022 Jan 07. 12(1): 190
    Distribution of alternative untranslated regions within the mRNA of the CELF1 splicing factor affects its expression.
    Arkadiusz Kajdasz, Daria Niewiadomska, Michal Sekrecki, Krzysztof Sobczak.
      CUG-binding protein, ELAV-like Family Member 1 (CELF1) plays an important role during the development of different tissues, such as striated muscle and brain tissue. CELF1 is an RNA-binding protein that regulates RNA metabolism processes, e.g., alternative splicing, and antagonizes other RNA-binding proteins, such as Muscleblind-like proteins (MBNLs). Abnormal activity of both classes of proteins plays a crucial role in the pathogenesis of myotonic dystrophy type 1 (DM1), the most common form of muscular dystrophy in adults. In this work, we show that alternative splicing of exons forming both the 5' and 3' untranslated regions (UTRs) of CELF1 mRNA is efficiently regulated during development and tissue differentiation and is disrupted in skeletal muscles in the context of DM1. Alternative splicing of the CELF1 5'UTR leads to translation of two potential protein isoforms that differ in the lengths of their N-terminal domains. We also show that the MBNL and CELF proteins regulate the distribution of mRNA splicing isoforms with different 5'UTRs and 3'UTRs and affect the CELF1 expression by changing its sensitivity to specific microRNAs or RNA-binding proteins. Together, our findings show the existence of different mechanisms of regulation of CELF1 expression through the distribution of various 5' and 3' UTR isoforms within CELF1 mRNA.
    DOI:  https://doi.org/10.1038/s41598-021-03901-9
  29. J Gene Med. 2022 Jan 02. e3407
    Cis-regulation of antisense noncoding RNA at the JAZF1 locus in type 2 diabetes.
    Qiuju Ding, Weiwei Zhao, Jirong Long, Habiba Alsafar, Qing Zhou, Huimei Chen.
      BACKGROUND: Several genomic loci of type 2 diabetes (T2D) nominated in genome-wide association studies (GWASs) have been suggested to regulate metabolism in muscle. However, a large portion of the genetic risk and the underlying regulation remain unexplained. This study aimed to localize the potentially functional regions or genes at juxtaposed with another zinc finger protein 1 (JAZF1) locus and interpret their possible biological mechanisms in the muscle of T2D.METHODS AND RESULTS: With a cross-population meta-analysis of 7 GWASs, we identified a linkage disequilibrium (LD) block within intron 1 of JAZF1 that was significantly associated with T2D (FDR < 0.05). The colocalization analysis showed a significant association between genetically determined expression of JAZF1 in skeletal muscle and T2D with a strong probability of colocalization (PP4=75.09%). This region also encodes the upstream regulatory region (URR) of the antisense noncoding RNA JAZF1-AS1. Expression-QTL (e-QTL) analysis detected a regulatory SNP within this LD block, rs864745, that is associated with the expression of JAZF1-AS1 and JAZF1. With in vitro cloning, we further reported the role of JAZF1-AS1 in cis-regulating JAZF1 by directly forming RNA double strands. Downregulation of JAZF1, caused by JAZF1-AS1 depletion, inhibited the glucose uptake and lipid oxidation in skeletal muscle.
    CONCLUSIONS: This study proposes a strategy to identify a novel T2D gene at the reported locus and generated a model in which polymorphisms at JAZF1 influence T2D risk through antisense-mediated gene regulation.
    Keywords:  Antisense transcription; Genome-wide association study; JAZF1-AS1; Skeletal muscle; Type 2 diabetes
    DOI:  https://doi.org/10.1002/jgm.3407
  30. Neurotherapeutics. 2022 Jan 04.
    Dendrimer-2PMPA Delays Muscle Function Loss and Denervation in a Murine Model of Amyotrophic Lateral Sclerosis.
    Carolyn Tallon, Anjali Sharma, Zhi Zhang, Ajit G Thomas, Justin Ng, Xiaolei Zhu, Amanda Donoghue, Michael Schulte, Tawnjerae R Joe, Siva P Kambhampati, Rishi Sharma, Kevin Liaw, Sujatha Kannan, Rangaramanujam M Kannan, Barbara S Slusher.
      Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease where muscle weakness and neuromuscular junction (NMJ) denervation precede motor neuron cell death. Although acetylcholine is the canonical neurotransmitter at the mammalian NMJ synapse, glutamate has recently been identified as a critical neurotransmitter for NMJ development and maintenance. One source of glutamate is through the catabolism of N-acetyl-aspartyl-glutamate (NAAG), which is found in mM concentrations in mammalian motoneurons, where it is released upon stimulation and hydrolyzed to glutamate by the glial enzyme glutamate carboxypeptidase II (GCPII). Using the SOD1G93A model of ALS, we found an almost fourfold elevation of GCPII enzymatic activity in SOD1G93A versus WT muscle and a robust increase in GCPII expression which was specifically associated with activated macrophages infiltrating the muscle. 2-(Phosphonomethyl)pentanedioic acid (2PMPA) is a potent GCPII inhibitor which robustly blocks glutamate release from NAAG but is highly polar with limited tissue penetration. To improve this, we covalently attached 2PMPA to a hydroxyl polyamidoamine (PAMAM-G4-OH) dendrimer delivery system (D-2PMPA) which is known to target activated macrophages in affected tissues. Systemic D-2PMPA therapy (20 mg/kg 2PMPA equivalent; IP 2 × /week) was found to localize in muscle macrophages in SOD1G93A mice and completely normalize the enhanced GCPII activity. Although no changes in body weight or survival were observed, D-2PMPA significantly improved grip strength and inhibited the loss of NMJ innervation in the gastrocnemius muscles. Our finding that inhibiting elevated GCPII activity in SOD1G93A muscle can prolong muscle function and delay NMJ denervation may have early therapeutic implications for ALS patients.
    Keywords:  Amyotrophic lateral sclerosis; Dendrimer; Glutamate; Glutamate carboxypeptidase II (GCPII); N-acetyl-aspartyl-glutamate (NAAG); NMDA; Neuroinflammation; Neuromuscular junction (NJM); mGluR3
    DOI:  https://doi.org/10.1007/s13311-021-01159-7
  31. Acta Physiol (Oxf). 2022 Jan 07. e13785
    Sestrin2 ablation attenuates the exercise-induced browning of white adipose tissue in C57BL/6J mice.
    Lu Wang, Xinmeng Liu, Sujuan Liu, Yanmei Niu, Li Fu.
      AIM: With exercise, white adipose tissues (WAT) are readily convertible to a "brown-like" state, altering from lipid-storing to energy-catabolizing function, which counteracts obesity and increases insulin sensitivity. Sestrin2 (SESN2) is a stress-inducible protein that can regulate the cold-induced increase of Uncoupling Protein 1 (UCP1), which is paramount for the thermogenic capacity of brown-like WAT. This study aimed to elucidate the necessity of SESN2 in mediating exercise-induced browning of WAT.METHODS: We used 8-week, male wild-type and SESN2 knockout C57BL/6J mice to explore the potential role of SESN2 in the exercise-induced WAT browning process. Over a 3-week intervention (sedentary versus treadmill exercise, normal chow versus 60% high-fat diet), we examined the exercise-induced alterations of the browning phenotype in different depots of white fat. In vitro, 3T3-L1 pre-adipocytes and primary adipocytes were used to determine the potential mechanism.
    RESULTS: Our data revealed that SESN2 was required for the exercise-induced subcutaneous WAT (scWAT) browning. This may be mediated by higher fibronectin type III domain containing 5 (FNDC5) contents in scWAT locally, rather than skeletal muscle FNDC5 expression and circulating serum irisin levels. SESN2 ablation significantly impaired the exercise-improved glucose metabolism, where browning of scWAT may serve as an essential pathway. Moreover, SESN2 ablation significantly attenuated the exercise-promoted respiratory exchange ratio and indexes of energy metabolism (oxygen uptake and energy expenditure).
    CONCLUSION: Taken together, our results provided evidence that SESN2 is a key integrating factor in driving the diverse metabolic benefits conferred by aerobic exercise.
    Keywords:  Sestrins; UCP1; beige adipocyte; energy metabolism; exercise training; glucose homeostasis
    DOI:  https://doi.org/10.1111/apha.13785
  32. Eur J Pharmacol. 2021 Dec 30. pii: S0014-2999(21)00887-6. [Epub ahead of print] 174731
    Spexin ameliorates skeletal muscle insulin resistance through activation of GAL2 receptor.
    Mei Yu, Mengyuan Wang, Shiyu Han, Long Han, Yue Kan, Juan Zhao, Xizhong Yu, Jing Yan, Yu Jin, Zhenwen Zhang, Wenbing Shang, Penghua Fang.
      Skeletal muscle is a principal tissue involved in energy expenditure and glucose metabolism. Although the results of our and other studies show that spexin could decrease food intake and obesity, the specific metabolic effect of spexin on glucose metabolism of skeletal muscle is still unclear. The aim of this study is to investigate whether spexin might mitigate obesity-induced insulin resistance in skeletal muscles and to explore its underlying mechanisms. The high fat diet-fed mice were treated with 50 μg/kg/d spexin for 21 consecutive days, and the differentiated myotubes of L6 were treated with spexin (200, 400, 800 nM) in the absence or presence of M871 (800 nM) for 12 h respectively. Besides, the galanin type 2 (GAL2) receptor knockdown myotubes were treated with 800 nM spexin for 12 h in this study. The present findings showed that spexin reversed hyperglycemia and glucose intolerance as well as insulin intolerance and insulin resistance in the mice fed with high fat diet. Furthermore, spexin markedly augmented the peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) expression and deacetylation, and further triggered glucose transporter 4 (GLUT4) expression and trafficking in myotubes through p38 mitogen-activated protein kinase (P38MAPK) and protein kinase B (AKT) activation. More importantly, the elevation of glucose consumption related genes by spexin were abolished by GAL2 receptor antagonist or silencing of GAL2 receptor in myotubes. In conclusion, our findings provide a novel insight that spexin can protect against insulin resistance and increase glucose consumption in skeletal muscles mainly through activation of GAL2/GLUT4 signal pathway. Spexin might therefore be a novel therapeutic target for hyperglycemia and insulin resistance in clinic.
    Keywords:  GAL2; Insulin resistance; Obesity; Spexin
    DOI:  https://doi.org/10.1016/j.ejphar.2021.174731
  33. J Clin Nurs. 2022 Jan 05.
    Effects of multicomponent exercise on the muscle strength, muscle endurance and balance of frail older adults: A meta-analysis of randomised controlled trials.
    Yao Li, Yan Gao, Shuang Hu, Hongyu Chen, Minyi Zhang, Yi Yang, Yan Liu.
      OBJECTIVES: This study aims to evaluate the effects of multicomponent exercise on the muscle strength, muscle endurance and balance of frail older adults living in the community and provide the latest evidence from published randomised controlled trials (RCTs).BACKGROUND: The number of frail older adults is rapidly increasing. Previous studies have reported that multicomponent exercise is one of the best types of intervention for increasing muscle strength, muscle endurance and balance for frail older adults. However, due to the small sample size and lack of evidential support, a meta-analysis of RCTs remains necessary.
    METHODS: RCTs reporting the effects of multicomponent exercise on the muscle strength, muscle endurance and balance of frail older adults, published in English, were retrieved from five electronic databases: PubMed, CINAHL, Web of Science, Embase and Cochrane Library available from their inception up to January 2021. RevMan5.3 software was adopted for statistical analysis. This study followed the PRSIMA checklist.
    RESULTS: A total of 10 articles and 667 patients were included in this study. Meta-analysis showed that multicomponent exercise could improve the muscle strength [MD = 2.46, p = .007], muscle endurance [MD = 2.16, p = .03] and balance [MD = .39, p = .03] of frail older adults, and subgroup analysis showed the muscle endurance of frail older adults was significantly improved as the intervention lasted for >12 weeks.
    CONCLUSIONS: RCTs provided in this study show the latest evidence that multicomponent exercise can improve the muscle strength, endurance and balance of frail older adults and that long-duration (>12weeks) multicomponent exercise is more effective for improving muscle endurance.
    RELEVANCE TO CLINICAL PRACTICE: Multicomponent exercise contributes to improving the muscle strength, muscle endurance and balance of frail older adults, so it can be considered as a complement to the physical function management programme for frail older adults.
    Keywords:  balance; frail older adults; meta-analysis; multicomponent exercise; muscle endurance; muscle strength
    DOI:  https://doi.org/10.1111/jocn.16196
  34. BMC Genomics. 2022 Jan 06. 23(1): 13
    Caenorhabditis elegans ETR-1/CELF has broad effects on the muscle cell transcriptome, including genes that regulate translation and neuroblast migration.
    Matthew E Ochs, Rebecca M McWhirter, Robert L Unckless, David M Miller, Erik A Lundquist.
      Migration of neuroblasts and neurons from their birthplace is central to the formation of neural circuits and networks. ETR-1 is the Caenorhabditis elegans homolog of the CELF1 (CUGBP, ELAV-like family 1) RNA-processing factor involved in neuromuscular disorders. etr-1 regulates body wall muscle differentiation. Our previous work showed that etr-1 in muscle has a non-autonomous role in neuronal migration, suggesting that ETR-1 is involved in the production of a signal emanating from body wall muscle that controls neuroblast migration and that interacts with Wnt signaling. etr-1 is extensively alternatively-spliced, and we identified the viable etr-1(lq61) mutant, caused by a stop codon in alternatively-spliced exon 8 and only affecting etr-1 isoforms containing exon 8. We took advantage of viable etr-1(lq61) to identify potential RNA targets of ETR-1 in body wall muscle using a combination of fluorescence activated cell sorting (FACS) of body wall muscles from wild-type and etr-1(lq61) and subsequent RNA-seq. This analysis revealed genes whose splicing and transcript levels were controlled by ETR-1 exon 8 isoforms, and represented a broad spectrum of genes involved in muscle differentiation, myofilament lattice structure, and physiology. Genes with transcripts underrepresented in etr-1(lq61) included those involved in ribosome function and translation, similar to potential CELF1 targets identified in chick cardiomyocytes. This suggests that at least some targets of ETR-1 might be conserved in vertebrates, and that ETR-1 might generally stimulate translation in muscles. As proof-of-principle, a functional analysis of a subset of ETR-1 targets revealed genes involved in AQR and PQR neuronal migration. One such gene, lev-11/tropomyosin, requires ETR-1 for alternative splicing, and another, unc-52/perlecan, requires ETR-1 for the production of long isoforms containing 3' exons. In sum, these studies identified gene targets of ETR-1/CELF1 in muscles, which included genes involved in muscle development and physiology, and genes with novel roles in neuronal migration.
    DOI:  https://doi.org/10.1186/s12864-021-08217-6
  35. J Cachexia Sarcopenia Muscle. 2022 Jan 04.
    MicroRNAs in obesity, sarcopenia, and commonalities for sarcopenic obesity: a systematic review.
    Lisa Dowling, Ankita Duseja, Tatiane Vilaca, Jennifer S Walsh, Katarzyna Goljanek-Whysall.
      Sarcopenic obesity is a distinct condition of sarcopenia in the context of obesity, with the cumulative health risks of both phenotypes. Differential expression of microRNAs (miRNAs) has been reported separately in people with obesity and sarcopenia and may play a role in the pathogenesis of sarcopenic obesity. However, this has not been explored to date. This study aimed to identify differentially expressed miRNAs reported in serum, plasma, and skeletal muscle of people with obesity and sarcopenia and whether there are any commonalities between these conditions. We performed a systematic review on Embase and MEDLINE (PROSPERO, CRD42020224486) for differentially expressed miRNAs (fold change >1.5 or P-value <0.05) in (i) sarcopenia or frailty and (ii) obesity or metabolic syndrome. The functions and targets of miRNAs commonly changed in both conditions, in the same direction, were searched using PubMed. Following deduplication, 247 obesity and 42 sarcopenia studies were identified for full-text screening. Screening identified 36 obesity and 6 sarcopenia studies for final inclusion. A total of 351 miRNAs were identified in obesity and 157 in sarcopenia. Fifty-five miRNAs were identified in both obesity and sarcopenia-by sample type, 48 were found in plasma and one each in serum and skeletal muscle. Twenty-four miRNAs were identified from 10 of the included studies as commonly changed in the same direction (22 in plasma and one each in serum and skeletal muscle) in obesity and sarcopenia. The majority of miRNA-validated targets identified in the literature search were members of the phosphoinositide 3-kinase/protein kinase B and transforming growth factor-β signalling pathways. The most common targets identified were insulin-like growth factor 1 (miR-424-5p, miR-483-3p, and miR-18b-5p) and members of the SMAD family (miR-483-3p, miR-92a-3p, and miR-424-5p). The majority of commonly changed miRNAs were involved in protein homeostasis, mitochondrial dynamics, determination of muscle fibre type, insulin resistance, and adipogenesis. Twenty-four miRNAs were identified as commonly dysregulated in obesity and sarcopenia with functions and targets implicated in the pathogenesis of sarcopenic obesity. Given the adverse health outcomes associated with sarcopenic obesity, understanding the pathogenesis underlying this phenotype has the potential to lead to effective screening, monitoring, or treatment strategies. Further research is now required to confirm whether these miRNAs are differentially expressed in older adults with sarcopenic obesity.
    Keywords:  Frailty; Metabolic syndrome; MicroRNA; Obesity; Sarcopenia
    DOI:  https://doi.org/10.1002/jcsm.12878
  36. Neurol Res Pract. 2022 Jan 04. 4(1): 2
    Therapy development for spinal muscular atrophy: perspectives for muscular dystrophies and neurodegenerative disorders.
    Sibylle Jablonka, Luisa Hennlein, Michael Sendtner.
      BACKGROUND: Major efforts have been made in the last decade to develop and improve therapies for proximal spinal muscular atrophy (SMA). The introduction of Nusinersen/Spinraza™ as an antisense oligonucleotide therapy, Onasemnogene abeparvovec/Zolgensma™ as an AAV9-based gene therapy and Risdiplam/Evrysdi™ as a small molecule modifier of pre-mRNA splicing have set new standards for interference with neurodegeneration.MAIN BODY: Therapies for SMA are designed to interfere with the cellular basis of the disease by modifying pre-mRNA splicing and enhancing expression of the Survival Motor Neuron (SMN) protein, which is only expressed at low levels in this disorder. The corresponding strategies also can be applied to other disease mechanisms caused by loss of function or toxic gain of function mutations. The development of therapies for SMA was based on the use of cell culture systems and mouse models, as well as innovative clinical trials that included readouts that had originally been introduced and optimized in preclinical studies. This is summarized in the first part of this review. The second part discusses current developments and perspectives for amyotrophic lateral sclerosis, muscular dystrophies, Parkinson's and Alzheimer's disease, as well as the obstacles that need to be overcome to introduce RNA-based therapies and gene therapies for these disorders.
    CONCLUSION: RNA-based therapies offer chances for therapy development of complex neurodegenerative disorders such as amyotrophic lateral sclerosis, muscular dystrophies, Parkinson's and Alzheimer's disease. The experiences made with these new drugs for SMA, and also the experiences in AAV gene therapies could help to broaden the spectrum of current approaches to interfere with pathophysiological mechanisms in neurodegeneration.
    Keywords:  Alzheimer disease; Amyotrophic lateral sclerosis; Clinical trial; Gene therapy; Motoneuron disease; Muscular disease; Muscular dystrophy; Neurodegenerative disease; Parkinson disease; Spinal muscular atrophy
    DOI:  https://doi.org/10.1186/s42466-021-00162-9
  37. Case Rep Neurol Med. 2021 ;2021 1326442
    Muscle-Specific Tyrosine Kinase-Associated Myasthenia Gravis: A Neuromuscular Surprise.
    Hassam Ali, Rahul Pamarthy, Nayab Ahsan, WashmaAwan, Shiza Sarfraz.
      Myasthenia gravis is a neuromuscular autoimmune disease that results in skeletal muscle weakness that worsens after periods of activity and improves after rest. Myasthenia gravis means "grave (serious), muscle weakness." Although not completely curable, it can be managed well with a relatively high quality of life and expectancy. In myasthenia gravis, antibodies against the acetylcholine receptors at the neuromuscular junction interfere with regular muscular contraction. Although most commonly caused by antibodies to the acetylcholine receptor, antibodies against MuSK (muscle-specific kinase) protein can also weaken transmission at the neuromuscular junction. Muscle-specific tyrosine kinase myasthenia gravis (MuSK-Ab MG) is a rare subtype of myasthenia gravis with distinct pathogenesis and unique clinical features. Diagnosis can be challenging due to its atypical presentation as compared to seropositive myasthenia gravis. It responds inconsistently to steroids, but plasma exchange and immunosuppressive therapies have shown promising results. We report a case of a 49-year-old female who presented with acute hypoxic respiratory failure. Our patient experienced progressive, undiagnosed MuSK-Ab MG for years without a diagnosis.
    DOI:  https://doi.org/10.1155/2021/1326442
  38. Mech Ageing Dev. 2022 Jan 04. pii: S0047-6374(22)00001-X. [Epub ahead of print] 111619
    Depletion of NIMA-related kinase Nek2 induces aberrant self-renewal and apoptosis in stem/progenitor cells of aged muscular tissues.
    Tatsufumi Mori, Yuta Onodera, Maki Itokazu, Toshiyuki Takehara, Kanae Shigi, Natsumi Iwawaki, Masao Akagi, Takeshi Teramura.
      Frailty of the locomotory organs has become a widespread problem in the geriatric population. The major factor leading to frailty is an age-associated decrease in muscular mass and a reduced number of muscular cells and myofibers. In aged muscular tissues, muscular satellite cells (MuSCs) are reduced due to abnormalities in their self-renewal and the induction of apoptosis. However, the molecular mechanisms connecting aging-associated physiological changes and the reduction of MuSCs are largely unknown. NIMA-related kinase 2 (Nek2), a member of the Nek family of serine/threonine kinases, was found to be downregulated in aged MuSCs/progenitors. Further, Nek2 downregulation was found to inhibit self-renewal and apoptotic cell death by activating the p53-dependent checkpoint. Attenuated NEK2 expression was also observed in the muscular tissues of elderly donors, and its function was confirmed to be conserved in humans. Overall, this study proposes a novel mechanism for inducing muscular atrophy to understand aging-associated muscular diseases.
    Keywords:  Aging-associated muscular degeneration; Cell cycle; Muscular stem cells; Sarcopenia
    DOI:  https://doi.org/10.1016/j.mad.2022.111619
  39. J Nutr Sci Vitaminol (Tokyo). 2021 ;67(6): 359-365
    The Ability of Nutrition to Mitigate Epigenetic Drift: A Novel Look at Regulating Gene Expression.
    Raymond D Palmer, Veronica Papa, Mauro Vaccarezza.
      Epigenetic drift causes modification in gene expression during aging and a myriad of physiological changes that are mostly undesirable, remove youthful phenotype and are related to biological decay and disease onset. The epigenome is considered a stable regulator of genetic expression. Moreover, evidence is now accumulating that commonly available compounds found in foods can influence the epigenome to embrace a more youthful and therefore, more disease resistant state. Here we explore the correlation between nutriment and the epigenetic regulation through various types of alimentation. The aim is not to discuss specific chemicals involved in disease onset. Instead, we offer a brief glance at pathogens and offer a practical pathway into epigenetic regulation, hypothesizing that epigenetic drift might be attenuated by several foods able to drive a more youthful and disease resistant phenotype.
    Keywords:  epigenetic diet; epigenetic drift; gene expression; genomic diet; histones; methylation; nutraceutical; nutrigenomics
    DOI:  https://doi.org/10.3177/jnsv.67.359
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