bims-moremu 2024-02-25 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2024‒02‒25
24 papers selected by
Anna Vainshtein, Craft Science Inc.

MFN2 overexpression in skeletal muscles of young and old mice causes a mild hypertrophy without altering mitochondrial respiration and H2 O2 emission.
Skeletal muscle ageing: lessons from teleosts.
Exercise-Induced MYC as an Epigenetic Reprogramming Factor That Combats Skeletal Muscle Aging.
Control of muscle satellite cell function by specific exercise-induced cytokines and their applications in muscle maintenance.
Mitochondrial Quantity and Quality in Age-Related Sarcopenia.
The RNA-binding protein Msi2 regulates autophagy during myogenic differentiation.
Roles of Myokines and Muscle-Derived Extracellular Vesicles in Musculoskeletal Deterioration under Disuse Conditions.
Macrophage-Myofibroblast Transition as a Potential Origin for Skeletal Muscle Fibrosis After Injury via Complement System Activation.
The Effects of Aging on Sarcoplasmic Reticulum-Related Factors in the Skeletal Muscle of Mice.
Assessments of individual fiber glycogen and mitochondrial volume percentages reveal a graded reduction in muscle oxidative power during prolonged exhaustive exercise.
Recent advances in skeletal muscle physiology.
Decoding muscle-resident Schwann cell dynamics during neuromuscular junction remodeling.
Metastasis-associated 1 localizes to the sarcomeric Z-disc and is implicated in skeletal muscle pathology.
Lactate administration induces skeletal muscle synthesis by influencing Akt/mTOR and MuRF1 in non-trained mice but not in trained mice.
5'-Cytimidine Monophosphate Ameliorates H2O2-Induced Muscular Atrophy in C2C12 Myotubes by Activating IRS-1/Akt/S6K Pathway.
Tirasemtiv enhances submaximal muscle tension in an Acta1:p.Asp286Gly mouse model of nemaline myopathy.
Sex differences in neuromuscular and biological determinants of isometric maximal force.
A knock down strategy for rapid, generic, and versatile modelling of muscular dystrophies in 3D-tissue-engineered-skeletal muscle.
Sympathetic innervation in skeletal muscle and its role at the neuromuscular junction.
Celebrating a decade of exercise physiology and metabolism research in physiological reports.
A Pharmacological Investigation of the TMEM16A Currents in Murine Skeletal Myogenic Precursor Cells.
High-dose atorvastatin therapy progressively decreases skeletal muscle mitochondrial respiratory capacity in humans.
Effect of CB1 Receptor Deficiency on Mitochondrial Quality Control Pathways in Gastrocnemius Muscle.
Next Generation Sequencing and Electromyography Reveal the Involvement of the P2RX6 Gene in Myopathy.

Acta Physiol (Oxf). 2024 Feb 23. e14119

MFN2 overexpression in skeletal muscles of young and old mice causes a mild hypertrophy without altering mitochondrial respiration and H2 O2 emission.

Marina Cefis, Manon Dargegen, Vincent Marcangeli, Shima Taherkhani, Maude Dulac, Jean-Philippe Leduc-Gaudet, Dominique Mayaki, Sabah N A Hussain, Gilles Gouspillou.

  AIM: Sarcopenia, the aging-related loss of muscle mass and function, is a debilitating process negatively impacting the quality of life of affected individuals. Although the mechanisms underlying sarcopenia are incompletely understood, impairments in mitochondrial dynamics, including mitochondrial fusion, have been proposed as a contributing factor. However, the potential of upregulating mitochondrial fusion proteins to alleviate the effects of aging on skeletal muscles remains unexplored. We therefore hypothesized that overexpressing Mitofusin 2 (MFN2) in skeletal muscle in vivo would mitigate the effects of aging on muscle mass and improve mitochondrial function.METHODS: MFN2 was overexpressed in young (7 mo) and old (24 mo) male mice for 4 months through intramuscular injections of an adeno-associated viruses. The impacts of MFN2 overexpression on muscle mass and fiber size (histology), mitochondrial respiration, and H2 O2 emission (Oroboros fluororespirometry), and various signaling pathways (qPCR and western blotting) were investigated.
RESULTS: MFN2 overexpression increased muscle mass and fiber size in both young and old mice. No sign of fibrosis, necrosis, or inflammation was found upon MFN2 overexpression, indicating that the hypertrophy triggered by MFN2 overexpression was not pathological. MFN2 overexpression even reduced the proportion of fibers with central nuclei in old muscles. Importantly, MFN2 overexpression had no impact on muscle mitochondrial respiration and H2 O2 emission in both young and old mice. MFN2 overexpression attenuated the increase in markers of impaired autophagy in old muscles.
CONCLUSION: MFN2 overexpression may be a viable approach to mitigate aging-related muscle atrophy and may have applications for other muscle disorders.

Keywords:  autophagy; mitochondria; mitochondrial dynamics; mitochondrial fusion; mitofusin 2; sarcopenia; skeletal muscle aging

DOI:  https://doi.org/10.1111/apha.14119
J Gerontol A Biol Sci Med Sci. 2024 Feb 17. pii: glae052. [Epub ahead of print]

Skeletal muscle ageing: lessons from teleosts.

Tuyen K Quach, Megan F Taylor, Peter D Currie, Nir Eynon, Avnika A Ruparelia.

Ageing is the greatest risk factor for a multitude of age-related diseases including sarcopenia -the loss of skeletal muscle mass and strength - which occurs at remarkable rates each year. There is an unmet need not only to understand the mechanisms that drive sarcopenia, but also to identify novel therapeutic strategies. Given the ease and affordability of husbandry, along with advances in genomics, genome editing technologies and imaging capabilities, teleost models are increasingly used for ageing and sarcopenia research. Here, we explain how teleost species such as zebrafish, African turquoise killifish and medaka recapitulate many of the classical hallmarks of sarcopenia, and discuss the various dietary, pharmacological and genetic approaches that have been used in teleosts to understand the mechanistic basis of sarcopenia.

DOI: https://doi.org/10.1093/gerona/glae052
Exerc Sport Sci Rev. 2024 Feb 23.

Exercise-Induced MYC as an Epigenetic Reprogramming Factor That Combats Skeletal Muscle Aging.

Ronald G Jones, Ferdinand von Walden, Kevin A Murach.

ABSTRACT: Of the "Yamanaka factors" Oct3/4, Sox2, Klf4, and c-Myc (OSKM), the transcription factor c-Myc (Myc) is the most responsive to exercise in skeletal muscle and is enriched within the muscle fiber. We hypothesize that the pulsatile induction of MYC protein after bouts of exercise can serve to epigenetically reprogram skeletal muscle toward a more resilient and functional state.

DOI: https://doi.org/10.1249/JES.0000000000000333
J Cachexia Sarcopenia Muscle. 2024 Feb 20.

Control of muscle satellite cell function by specific exercise-induced cytokines and their applications in muscle maintenance.

Qian Guo, Qing Luo, Guanbin Song.

  Exercise is recognized to play an observable role in improving human health, especially in promoting muscle hypertrophy and intervening in muscle mass loss-related diseases, including sarcopenia. Recent rapid advances have demonstrated that exercise induces the release of abundant cytokines from several tissues (e.g., liver, muscle, and adipose tissue), and multiple cytokines improve the functions or expand the numbers of adult stem cells, providing candidate cytokines for alleviating a wide range of diseases. Muscle satellite cells (SCs) are a population of muscle stem cells that are mitotically quiescent but exit from the dormancy state to become activated in response to physical stimuli, after which SCs undergo asymmetric divisions to generate new SCs (stem cell pool maintenance) and commit to later differentiation into myocytes (skeletal muscle replenishment). SCs are essential for the postnatal growth, maintenance, and regeneration of skeletal muscle. Emerging evidence reveals that exercise regulates muscle function largely via the exercise-induced cytokines that govern SC potential, but this phenomenon is complicated and confusing. This review provides a comprehensive integrative overview of the identified exercise-induced cytokines and the roles of these cytokines in SC function, providing a more complete picture regarding the mechanism of SC homeostasis and rejuvenation therapies for skeletal muscle.

Keywords:  Cytokines; Exercise; Homeostasis; Muscle satellite cells; Skeletal muscle

DOI:  https://doi.org/10.1002/jcsm.13440
Int J Mol Sci. 2024 Feb 08. pii: 2052. [Epub ahead of print]25(4):

Mitochondrial Quantity and Quality in Age-Related Sarcopenia.

Emanuele Marzetti, Riccardo Calvani, Hélio José Coelho-Júnior, Francesco Landi, Anna Picca.

  Sarcopenia, the age-associated decline in skeletal muscle mass and strength, is a condition with a complex pathophysiology. Among the factors underlying the development of sarcopenia are the progressive demise of motor neurons, the transition from fast to slow myosin isoform (type II to type I fiber switch), and the decrease in satellite cell number and function. Mitochondrial dysfunction has been indicated as a key contributor to skeletal myocyte decline and loss of physical performance with aging. Several systems have been implicated in the regulation of muscle plasticity and trophism such as the fine-tuned and complex regulation between the stimulator of protein synthesis, mechanistic target of rapamycin (mTOR), and the inhibitor of mTOR, AMP-activated protein kinase (AMPK), that promotes muscle catabolism. Here, we provide an overview of the molecular mechanisms linking mitochondrial signaling and quality with muscle homeostasis and performance and discuss the main pathways elicited by their imbalance during age-related muscle wasting. We also discuss lifestyle interventions (i.e., physical exercise and nutrition) that may be exploited to preserve mitochondrial function in the aged muscle. Finally, we illustrate the emerging possibility of rescuing muscle tissue homeostasis through mitochondrial transplantation.

Keywords:  DAMPs; extracellular vesicles; inflammaging; metabolism; mitochondrial DNA; mitochondrial biogenesis; mitochondrial transplantation; mitophagy; muscle aging; muscle plasticity

DOI:  https://doi.org/10.3390/ijms25042052
Life Sci Alliance. 2024 May;pii: e202302016. [Epub ahead of print]7(5):

The RNA-binding protein Msi2 regulates autophagy during myogenic differentiation.

Ruochong Wang, Futaba Kato, Rio Yasui Watson, Aaron M Beedle, Jarrod A Call, Yugo Tsunoda, Takeshi Noda, Takaho Tsuchiya, Makoto Kashima, Ayuna Hattori, Takahiro Ito.

Skeletal muscle development is a highly ordered process orchestrated transcriptionally by the myogenic regulatory factors. However, the downstream molecular mechanisms of myogenic regulatory factor functions in myogenesis are not fully understood. Here, we identified the RNA-binding protein Musashi2 (Msi2) as a myogenin target gene and a post-transcriptional regulator of myoblast differentiation. Msi2 knockdown in murine myoblasts blocked differentiation without affecting the expression of MyoD or myogenin. Msi2 overexpression was also sufficient to promote myoblast differentiation and myocyte fusion. Msi2 loss attenuated autophagosome formation via down-regulation of the autophagic protein MAPL1LC3/ATG8 (LC3) at the early phase of myoblast differentiation. Moreover, forced activation of autophagy effectively suppressed the differentiation defects incurred by Msi2 loss. Consistent with its functions in myoblasts in vitro, mice deficient for Msi2 exhibited smaller limb skeletal muscles, poorer exercise performance, and muscle fiber-type switching in vivo. Collectively, our study demonstrates that Msi2 is a novel regulator of mammalian myogenesis and establishes a new functional link between muscular development and autophagy regulation.

DOI: https://doi.org/10.26508/lsa.202302016
Metabolites. 2024 Jan 26. pii: 88. [Epub ahead of print]14(2):

Roles of Myokines and Muscle-Derived Extracellular Vesicles in Musculoskeletal Deterioration under Disuse Conditions.

Jie Zhang, Yunfang Gao, Jiangwei Yan.

  Prolonged inactivity and disuse conditions, such as those experienced during spaceflight and prolonged bedrest, are frequently accompanied by detrimental effects on the motor system, including skeletal muscle atrophy and bone loss, which greatly increase the risk of osteoporosis and fractures. Moreover, the decrease in glucose and lipid utilization in skeletal muscles, a consequence of muscle atrophy, also contributes to the development of metabolic syndrome. Clarifying the mechanisms involved in disuse-induced musculoskeletal deterioration is important, providing therapeutic targets and a scientific foundation for the treatment of musculoskeletal disorders under disuse conditions. Skeletal muscle, as a powerful endocrine organ, participates in the regulation of physiological and biochemical functions of local or distal tissues and organs, including itself, in endocrine, autocrine, or paracrine manners. As a motor organ adjacent to muscle, bone tissue exhibits a relative lag in degenerative changes compared to skeletal muscle under disuse conditions. Based on this phenomenon, roles and mechanisms involved in the communication between skeletal muscle and bone, especially from muscle to bone, under disuse conditions have attracted widespread attention. In this review, we summarize the roles and regulatory mechanisms of muscle-derived myokines and extracellular vesicles (EVs) in the occurrence of muscle atrophy and bone loss under disuse conditions, as well as discuss future perspectives based on existing research.

Keywords:  disuse; extracellular vesicles; muscle–bone communication; musculoskeletal deterioration; myokines

DOI:  https://doi.org/10.3390/metabo14020088
J Inflamm Res. 2024 ;17 1083-1094

Macrophage-Myofibroblast Transition as a Potential Origin for Skeletal Muscle Fibrosis After Injury via Complement System Activation.

Beijie Qi, Yuqi Li, Zhen Peng, Zhiwen Luo, Xingyu Zhang, Jiwu Chen, Guoqi Li, Yaying Sun.

  Background: Acute skeletal muscle injury is common in sports. The injured muscle cannot fully recover due to fibrosis resulting from myofibroblasts. Understanding the origin of fibroblasts is, therefore, important for the development of anti-fibrotic therapies. Accumulating evidence shows that a mechanism called macrophage-myofibroblast transition (MMT) can lead to tissue or organ fibrosis, yet it is still unclear whether MMT exists in skeletal muscle and the exact mechanisms.Methods: Single-cell transcriptome of mice skeletal muscle after acute injury was analyzed with a specific attention on the process of MMT. Cell-cell interaction network, pseudotime trajectory analysis, Gene Ontology (GO), and Kyoto Genome Encyclopedia (KEGG) were conducted. A series of experiments in vivo and in vitro were launched for verification.
Results: Single cell transcriptomic analysis indicated that, following acute injury, there were much interactions between macrophages and myofibroblasts. A detailed analysis on macrophages indicated that, CD68+α-SMA+ cells, which represented the status of MMT, mainly appeared at five days post-injury. KEGG/GO analysis underlined the involvement of complement system, within which C3ar1, C1qa, C1qb, and C1qc were up-regulated. Trajectory analysis also confirmed a potential shift from macrophages to myofibroblasts. These findings were verified by histological study in mice skeletal muscle, that there were much MMT cells at five days, declined gradually, and vanished 14 days after trauma, when there was remarkable fibrosis formation within the injured muscle. Moreover, C3a stimulation could directly induce MMT in BMDMs.
Conclusion: Fibrosis following acute injury is disastrous to skeletal muscle, but the origin of myofibroblasts remains unclear. We proved that, following acute injury, macrophage-myofibroblast transition happened in skeletal muscle, which may contribute to fibrosis formation. This phenomenon mainly occurred at five days post-injury. The complement system can activate MMT. More evidence is needed to directly support the pro-fibrotic role of MMT in skeletal muscle fibrosis after acute injury.

Keywords:  complement system; fibrosis; macrophage-myofibroblast transition; single-cell transcriptomic analysis; skeletal muscle

DOI:  https://doi.org/10.2147/JIR.S450599
Int J Mol Sci. 2024 Feb 10. pii: 2148. [Epub ahead of print]25(4):

The Effects of Aging on Sarcoplasmic Reticulum-Related Factors in the Skeletal Muscle of Mice.

Yuji Kanazawa, Tatsuo Takahashi, Mamoru Nagano, Satoshi Koinuma, Yasufumi Shigeyoshi.

  The pathogenesis of sarcopenia includes the dysfunction of calcium homeostasis associated with the sarcoplasmic reticulum; however, the localization in sarcoplasmic reticulum-related factors and differences by myofiber type remain unclear. Here, we investigated the effects of aging on sarcoplasmic reticulum-related factors in the soleus (slow-twitch) and gastrocnemius (fast-twitch) muscles of 3- and 24-month-old male C57BL/6J mice. There were no notable differences in the skeletal muscle weight of these 3- and 24-month-old mice. The expression of Atp2a1, Atp2a2, Sln, and Pln increased with age in the gastrocnemius muscles, but not in the soleus muscles. Subsequently, immunohistochemical analysis revealed ectopic sarcoplasmic reticulum calcium ion ATPase (SERCA) 1 and SERCA2a immunoreactivity only in the gastrocnemius muscles of old mice. Histochemical and transmission electron microscope analysis identified tubular aggregate (TA), an aggregation of the sarcoplasmic reticulum, in the gastrocnemius muscles of old mice. Dihydropyridine receptor α1, ryanodine receptor 1, junctophilin (JPH) 1, and JPH2, which contribute to sarcoplasmic reticulum function, were also localized in or around the TA. Furthermore, JPH1 and JPH2 co-localized with matrix metalloproteinase (MMP) 2 around the TA. These results suggest that sarcoplasmic reticulum-related factors are localized in or around TAs that occur in fast-twitch muscle with aging, but some of them might be degraded by MMP2.

Keywords:  aging; fast-twitch muscle; sarcoplasmic reticulum; skeletal muscle; slow-twitch muscle; tubular aggregate

DOI:  https://doi.org/10.3390/ijms25042148
Scand J Med Sci Sports. 2024 Feb;34(2): e14571

Assessments of individual fiber glycogen and mitochondrial volume percentages reveal a graded reduction in muscle oxidative power during prolonged exhaustive exercise.

Joachim Nielsen, Rasmus Jensen, Niels Ørtenblad.

  During submaximal exercise, there is a heterogeneous recruitment of skeletal muscle fibers, with an ensuing heterogeneous depletion of muscle glycogen both within and between fiber types. Here, we show that the mean (95% CI) mitochondrial volume as a percentage of fiber volume of non-glycogen-depleted fibers was 2 (-10:6), 5 (-21:11), and 12 (-21:-2)% lower than all the sampled fibers after continuing exercise for 1, 2 h, and until task failure, respectively. Therefore, a glycogen-dependent fatigue of individual fibers during submaximal exercise may reduce the muscular oxidative power. These findings suggest a relationship between glycogen and mitochondrial content in individual muscle fibers, which is important for understanding fatigue during prolonged exercise.

Keywords:  exercise; fatigue; glycogen; mitochondria; muscle fiber; transmission electron microscopy

DOI:  https://doi.org/10.1111/sms.14571
BJA Educ. 2024 Mar;24(3): 84-90

Recent advances in skeletal muscle physiology.

V Kaura, P M Hopkins.



Keywords:  excitation–contraction coupling; malignant hyperthermia; muscle fatigue; sarcopenia; skeletal muscle

DOI:  https://doi.org/10.1016/j.bjae.2023.12.003
bioRxiv. 2023 Oct 07. pii: 2023.10.06.561193. [Epub ahead of print]

Decoding muscle-resident Schwann cell dynamics during neuromuscular junction remodeling.

Steve D Guzman, Ahmad Abu-Mahfouz, Carol S Davis, Lloyd P Ruiz, Peter C Macpherson, Susan V Brooks.

Understanding neuromuscular junction (NMJ) repair mechanisms is essential for addressing degenerative neuromuscular conditions. Here, we focus on the role of muscle-resident Schwann cells in NMJ reinnervation. In young Sod1 -/- mice, a model of progressive NMJ degeneration, we identified a clear NMJ 'regenerative window' that allowed us to define regulators of reinnervation and crossing Sod1 -/- mice with S100GFP -tg mice permitted visualization and analysis of Schwann cells. High-resolution imaging and single-cell RNA sequencing provide a detailed analysis of Schwann cell number, morphology, and transcriptome revealing multiple subtypes, including a previously unrecognized terminal Schwann cell (tSC) population expressing a synapse promoting signature. We also discovered a novel SPP1-driven cellular interaction between myelin Schwann cells and tSCs and show that it promotes tSC proliferation and reinnervation following nerve injury in wild type mice. Our findings offer important insights into molecular regulators critical in NMJ reinnervation that are mediated through tSCs to maintain NMJ function.

DOI: https://doi.org/10.1101/2023.10.06.561193
Cytoskeleton (Hoboken). 2024 Feb 23.

Metastasis-associated 1 localizes to the sarcomeric Z-disc and is implicated in skeletal muscle pathology.

Hongsheng Xue, Li Han, Haidi Sun, Zhe Piao, Wenjun Cao, Haili Qian, Zhilong Zhao, Ming-Fei Lang, Chundong Gu.

  Metastasis-associated 1 (MTA1), a subunit of the nucleosome remodeling and histone deacetylation (NuRD) corepressor complex, was reported to be expressed in the cytoplasm of skeletal muscles. However, the exact subcellular localization and the functional implications of MTA1 in skeletal muscles have not been examined. This study aims to demonstrate the subcellular localization of MTA1 in skeletal muscles and reveal its possible roles in skeletal muscle pathogenesis. Striated muscles (skeletal and cardiac) from C57BL/6 mice of 4-5 weeks were collected to examine the expression of MTA1 by Western blotting and immunohistochemistry. Immunofluorescence and immunoelectron microscopy were performed for MTA1, α-actinin (a Z-disc marker protein), and SMN (survival of motor neuron) proteins. Gene Expression Omnibus (GEO) data sets were analyzed using the GEO2R online tool to explore the functional implications of MTA1 in skeletal muscles. MTA1 expression was detected by Western blotting and immunohistochemistry in skeletal and cardiac muscles. Subcellular localization of MTA1 was found in the Z-disc of sarcomeres, where α-actinin and SMN were expressed. Data mining of GEO profiles suggested that MTA1 dysregulation is associated with multiple skeletal muscle defects, such as Duchenne muscular dystrophy, Emery-Dreifuss muscular dystrophy, nemaline myopathy, and dermatomyositis. The GEO analysis also showed that MTA1 expression gradually decreased with age in mouse skeletal muscle precursor cells. The subcellular localization of MTA1 in sarcomeres of skeletal muscles implies its biological roles in sarcomere structures and its possible contribution to skeletal muscle pathology.

Keywords:  metastasis-associated 1; pathogenesis; sarcomere; skeletal muscle

DOI:  https://doi.org/10.1002/cm.21841
Physiol Rep. 2024 Feb;12(4): e15952

Lactate administration induces skeletal muscle synthesis by influencing Akt/mTOR and MuRF1 in non-trained mice but not in trained mice.

Sunghwan Kyun, Jisu Kim, Deunsol Hwang, Inkwon Jang, Hun-Young Park, Kiwon Lim.

  The perception regarding lactate has changed over the past decades, and some of its physiological roles have gradually been revealed. However, the effects of exogenous lactate on skeletal muscle synthesis remain unclear. This study aimed to confirm the effects of a 5-week lactate administration and post-exercise lactate administration on skeletal muscle synthesis. Thirty-two Institute of Cancer Research mice were randomly assigned to non-trained + placebo, non-trained + lactate, trained + placebo, and trained + lactate groups. Furthermore, 3 g/kg of lactate or an equivalent volume of saline was immediately administered after exercise training (maximum oxygen uptake: 70%). Lactate administration and/or exercise training was performed 5 days/week for 5 weeks. After the experimental period, it was observed that lactate administration tended to elevate skeletal muscle weight, increased protein kinase B (p < 0.05) and mammalian target of rapamycin (p < 0.05) mRNA levels, and decreased muscle ring-finger protein-1 expression (p < 0.05). Lactate administration after exercise training significantly enhanced plantaris muscle weight; however, it had no additional effects on most signaling factors. This study demonstrated that a 5-week lactate administration could stimulate skeletal muscle synthesis, and lactate administration after exercise training may provide additional effects, such as increasing skeletal muscle.

Keywords:  MuRF1; exercise; lactate; mTOR pathway; oral administration; protein synthesis

DOI:  https://doi.org/10.14814/phy2.15952
Antioxidants (Basel). 2024 Feb 19. pii: 249. [Epub ahead of print]13(2):

5'-Cytimidine Monophosphate Ameliorates H2O2-Induced Muscular Atrophy in C2C12 Myotubes by Activating IRS-1/Akt/S6K Pathway.

Xin Wu, Na Zhu, Lixia He, Meihong Xu, Yong Li.

  Age-related muscle atrophy (sarcopenia), characterized by reduced skeletal muscle mass and muscle strength, is becoming increasingly prevalent worldwide, which is especially true for older people, and can seriously damage health and quality of life in older adults. This study aims to investigate the beneficial effects of 5'-cytimidine monophosphate (CMP) on H2O2-induced muscular atrophy in C2C12 myotubes. C2C12 myotubes were treated with H2O2 in the presence and absence of CMP and the changes in the anti-oxidation, mitochondrial functions, and expression of sarcopenia-related proteins were observed. Immunofluorescence analysis showed that CMP significantly increased the diameter of myotubes. We found that CMP could increase the activity of antioxidant enzymes and improve mitochondrial dysfunction, as well as reduce inflammatory cytokine levels associated with sarcopenia. RNA-seq analysis showed that CMP could relieve insulin resistance and promote protein digestion and absorption. Western blot analysis further confirmed that CMP could promote the activation of the IRS-1/Akt/S6K signaling pathway and decrease the expression of MuRF1 and Atrogin-1, which are important markers of muscle atrophy. The above results suggest that CMP protects myotubes from H2O2-induced atrophy and that its potential mechanism is associated with activating the IRS-1/Akt/S6K pathway to promote protein synthesis by improving mitochondrial dysfunction and insulin resistance. These results indicate that CMP can improve aging-related sarcopenia.

Keywords:  5′-cytimidine monophosphate; aging; muscular atrophy; sarcopenia

DOI:  https://doi.org/10.3390/antiox13020249
J Gen Physiol. 2024 Apr 01. pii: e202313471. [Epub ahead of print]156(4):

Tirasemtiv enhances submaximal muscle tension in an Acta1:p.Asp286Gly mouse model of nemaline myopathy.

Ricardo A Galli, Tamara C Borsboom, Charlotte Gineste, Lorenza Brocca, Maira Rossi, Darren T Hwee, Fady I Malik, Roberto Bottinelli, Julien Gondin, Maria-Antonietta Pellegrino, Josine M de Winter, Coen A C Ottenheijm.

Nemaline myopathies are the most common form of congenital myopathies. Variants in ACTA1 (NEM3) comprise 15-25% of all nemaline myopathy cases. Patients harboring variants in ACTA1 present with a heterogeneous disease course characterized by stable or progressive muscle weakness and, in severe cases, respiratory failure and death. To date, no specific treatments are available. Since NEM3 is an actin-based thin filament disease, we tested the ability of tirasemtiv, a fast skeletal muscle troponin activator, to improve skeletal muscle function in a mouse model of NEM3, harboring the patient-based p.Asp286Gly variant in Acta1. Acute and long-term tirasemtiv treatment significantly increased muscle contractile capacity at submaximal stimulation frequencies in both fast-twitch extensor digitorum longus and gastrocnemius muscle, and intermediate-twitch diaphragm muscle in vitro and in vivo. Additionally, long-term tirasemtiv treatment in NEM3 mice resulted in a decreased respiratory rate with preserved minute volume, suggesting more efficient respiration. Altogether, our data support the therapeutic potential of fast skeletal muscle troponin activators in alleviating skeletal muscle weakness in a mouse model of NEM3 caused by the Acta1:p.Asp286Gly variant.

DOI: https://doi.org/10.1085/jgp.202313471
Acta Physiol (Oxf). 2024 Feb 22. e14118

Sex differences in neuromuscular and biological determinants of isometric maximal force.

Gaia Giuriato, Maria Grazia Romanelli, Desirée Bartolini, Gianluca Vernillo, Anna Pedrinolla, Tatiana Moro, Martino Franchi, Elena Locatelli, Mehran Emadi Andani, Fabio Giuseppe Laginestra, Chiara Barbi, Gloria Fiorini Aloisi, Valentia Cavedon, Chiara Milanese, Elisa Orlandi, Tonia De Simone, Stefania Fochi, Cristina Patuzzo, Giovanni Malerba, Paolo Fabene, Massimo Donadelli, Anna Maria Stabile, Alessandra Pistilli, Mario Rende, Francesco Galli, Federico Schena, Massimo Venturelli.

  AIM: Force expression is characterized by an interplay of biological and molecular determinants that are expected to differentiate males and females in terms of maximal performance. These include muscle characteristics (muscle size, fiber type, contractility), neuromuscular regulation (central and peripheral factors of force expression), and individual genetic factors (miRNAs and gene/protein expression). This research aims to comprehensively assess these physiological variables and their role as determinants of maximal force difference between sexes.METHODS: Experimental evaluations include neuromuscular components of isometric contraction, intrinsic muscle characteristics (proteins and fiber type), and some biomarkers associated with muscle function (circulating miRNAs and gut microbiome) in 12 young and healthy males and 12 females.
RESULTS: Male strength superiority appears to stem primarily from muscle size while muscle fiber-type distribution plays a crucial role in contractile properties. Moderate-to-strong pooled correlations between these muscle parameters were established with specific circulating miRNAs, as well as muscle and plasma proteins.
CONCLUSION: Muscle size is crucial in explaining the differences in maximal voluntary isometric force generation between males and females with similar fiber type distribution. Potential physiological mechanisms are seen from associations between maximal force, skeletal muscle contractile properties, and biological markers.

Keywords:  gut microbiota; miRNA; muscle force; muscle proteins; neuromuscular determinants; sex differences

DOI:  https://doi.org/10.1111/apha.14118
Skelet Muscle. 2024 Feb 22. 14(1): 3

A knock down strategy for rapid, generic, and versatile modelling of muscular dystrophies in 3D-tissue-engineered-skeletal muscle.

Stijn L M In 't Groen, Marnix Franken, Theresa Bock, Marcus Krüger, Jessica C de Greef, W W M Pim Pijnappel.

  BACKGROUND: Human iPSC-derived 3D-tissue-engineered-skeletal muscles (3D-TESMs) offer advanced technology for disease modelling. However, due to the inherent genetic heterogeneity among human individuals, it is often difficult to distinguish disease-related readouts from random variability. The generation of genetically matched isogenic controls using gene editing can reduce variability, but the generation of isogenic hiPSC-derived 3D-TESMs can take up to 6 months, thereby reducing throughput.METHODS: Here, by combining 3D-TESM and shRNA technologies, we developed a disease modelling strategy to induce distinct genetic deficiencies in a single hiPSC-derived myogenic progenitor cell line within 1 week.
RESULTS: As proof of principle, we recapitulated disease-associated pathology of Duchenne muscular dystrophy and limb-girdle muscular dystrophy type 2A caused by loss of function of DMD and CAPN3, respectively. shRNA-mediated knock down of DMD or CAPN3 induced a loss of contractile function, disruption of tissue architecture, and disease-specific proteomes. Pathology in DMD-deficient 3D-TESMs was partially rescued by a candidate gene therapy treatment using micro-dystrophin, with similar efficacy compared to animal models.
CONCLUSIONS: These results show that isogenic shRNA-based humanized 3D-TESM models provide a fast, cheap, and efficient tool to model muscular dystrophies and are useful for the preclinical evaluation of novel therapies.

Keywords:  3D-organ-on-a chip; Calpain-3; Disease modelling; Duchenne muscular dystrophy; Dystrophin; Gene knockdown; LGMD2A; Skeletal muscle-on-a-chip; Tissue engineering

DOI:  https://doi.org/10.1186/s13395-024-00335-5
J Muscle Res Cell Motil. 2024 Feb 17.

Sympathetic innervation in skeletal muscle and its role at the neuromuscular junction.

Rüdiger Rudolf, Isis C Kettelhut, Luiz Carlos C Navegantes.

  Neuromuscular junctions are the synapses between motor neurons and skeletal muscle fibers, which mediate voluntary muscle movement. Since neuromuscular junctions are also tightly associated with the capping function of terminal Schwann cells, these synapses have been classically regarded as tripartite chemical synapses. Although evidences from sympathetic innervation of neuromuscular junctions was described approximately a century ago, the essential presence and functional relevance of sympathetic contribution to the maintenance and modulation of neuromuscular junctions was demonstrated only recently. These findings shed light on the pathophysiology of different clinical conditions and can optimize surgical and clinical treatment modalities for skeletal muscle disorders.

Keywords:  Acetylcholine receptor; Adrenoceptor; Neuromuscular junction; Sympathetic

DOI:  https://doi.org/10.1007/s10974-024-09665-9
Physiol Rep. 2024 Feb;12(4): e15960

Celebrating a decade of exercise physiology and metabolism research in physiological reports.

David C Wright, Arthur J Cheng, Rebecca E K MacPherson.

  During its first decade of life, Physiological Reports has become a home for well-conceived and rigorously performed exercise physiology and metabolism studies. The breadth of research within this area is impressive, covering exercise-induced increases in skeletal muscle gene expression to the effects of exercise on the gut microbiome. The purpose of the current review is to highlight some of the impactful exercise physiology and metabolism papers published in the journal and to look ahead to what areas exercise physiology publications might address in the next 10 years.

Keywords:  adipose tissue; exercise; metabolism; microbiome; muscle

DOI:  https://doi.org/10.14814/phy2.15960
Int J Mol Sci. 2024 Feb 13. pii: 2225. [Epub ahead of print]25(4):

A Pharmacological Investigation of the TMEM16A Currents in Murine Skeletal Myogenic Precursor Cells.

Marina Sciancalepore, Asja Ragnini, Paola Zacchi, Violetta Borelli, Paola D'Andrea, Paola Lorenzon, Annalisa Bernareggi.

  TMEM16A is a Ca2+-activated Cl- channel expressed in various species and tissues. In mammalian skeletal muscle precursors, the activity of these channels is still poorly investigated. Here, we characterized TMEM16A channels and investigated if the pharmacological activation of Piezo1 channels could modulate the TMEM16A currents in mouse myogenic precursors. Whole-cell patch-clamp recordings combined with the pharmacological agents Ani9, T16inh-A01 and Yoda1 were used to characterize TMEM16A-mediated currents and the possible modulatory effect of Piezo1 activity on TMEM16A channels. Western blot analysis was also carried out to confirm the expression of TMEM16A and Piezo1 channel proteins. We found that TMEM16A channels were functionally expressed in fusion-competent mouse myogenic precursors. The pharmacological blockage of TMEM16A inhibited myocyte fusion into myotubes. Moreover, the specific Piezo1 agonist Yoda1 positively regulated TMEM16A currents. The findings demonstrate, for the first time, a sarcolemmal TMEM16A channel activity and its involvement at the early stage of mammalian skeletal muscle differentiation. In addition, the results suggest a possible role of mechanosensitive Piezo1 channels in the modulation of TMEM16A currents.

Keywords:  Ani9; Piezo1; TMEM16A; TMEM16inh-A01; Yoda1; myogenesis; skeletal muscle

DOI:  https://doi.org/10.3390/ijms25042225
JCI Insight. 2024 Feb 22. pii: e174125. [Epub ahead of print]9(4):

High-dose atorvastatin therapy progressively decreases skeletal muscle mitochondrial respiratory capacity in humans.

Terence E Ryan, Maria J Torres, Chien-Te Lin, Angela H Clark, Patricia M Brophy, Cheryl A Smith, Cody D Smith, E Matthew Morris, John P Thyfault, P Darrell Neufer.

  BACKGROUNDWhile the benefits of statin therapy on atherosclerotic cardiovascular disease are clear, patients often experience mild to moderate skeletal myopathic symptoms, the mechanism for which is unknown. This study investigated the potential effect of high-dose atorvastatin therapy on skeletal muscle mitochondrial function and whole-body aerobic capacity in humans.METHODSEight overweight (BMI, 31.9 ± 2.0) but otherwise healthy sedentary adults (4 females, 4 males) were studied before (day 0) and 14, 28, and 56 days after initiating atorvastatin (80 mg/d) therapy.RESULTSMaximal ADP-stimulated respiration, measured in permeabilized fiber bundles from muscle biopsies taken at each time point, declined gradually over the course of atorvastatin treatment, resulting in > 30% loss of skeletal muscle mitochondrial oxidative phosphorylation capacity by day 56. Indices of in vivo muscle oxidative capacity (via near-infrared spectroscopy) decreased by 23% to 45%. In whole muscle homogenates from day 0 biopsies, atorvastatin inhibited complex III activity at midmicromolar concentrations, whereas complex IV activity was inhibited at low nanomolar concentrations.CONCLUSIONThese findings demonstrate that high-dose atorvastatin treatment elicits a striking progressive decline in skeletal muscle mitochondrial respiratory capacity, highlighting the need for longer-term dose-response studies in different patient populations to thoroughly define the effect of statin therapy on skeletal muscle health.FUNDINGNIH R01 AR071263.

Keywords:  Bioenergetics; Mitochondria; Muscle biology; Skeletal muscle

DOI:  https://doi.org/10.1172/jci.insight.174125
Biology (Basel). 2024 Feb 11. pii: 116. [Epub ahead of print]13(2):

Effect of CB1 Receptor Deficiency on Mitochondrial Quality Control Pathways in Gastrocnemius Muscle.

Rosalba Senese, Giuseppe Petito, Elena Silvestri, Maria Ventriglia, Nicola Mosca, Nicoletta Potenza, Aniello Russo, Francesco Manfrevola, Gilda Cobellis, Teresa Chioccarelli, Veronica Porreca, Vincenza Grazia Mele, Rosanna Chianese, Pieter de Lange, Giulia Ricci, Federica Cioffi, Antonia Lanni.

  This study aims to explore the complex role of cannabinoid type 1 receptor (CB1) signaling in the gastrocnemius muscle, assessing physiological processes in both CB1+/+ and CB1-/- mice. The primary focus is to enhance our understanding of how CB1 contributes to mitochondrial homeostasis. At the tissue level, CB1-/- mice exhibit a substantial miRNA-related alteration in muscle fiber composition, characterized by an enrichment of oxidative fibers. CB1 absence induces a significant increase in the oxidative capacity of muscle, supported by elevated in-gel activity of Complex I and Complex IV of the mitochondrial respiratory chain. The increased oxidative capacity is associated with elevated oxidative stress and impaired antioxidant defense systems. Analysis of mitochondrial biogenesis markers indicates an enhanced capacity for new mitochondria production in CB1-/- mice, possibly adapting to altered muscle fiber composition. Changes in mitochondrial dynamics, mitophagy response, and unfolded protein response (UPR) pathways reveal a dynamic interplay in response to CB1 absence. The interconnected mitochondrial network, influenced by increased fusion and mitochondrial UPR components, underlines the dual role of CB1 in regulating both protein quality control and the generation of new mitochondria. These findings deepen our comprehension of the CB1 impact on muscle physiology, oxidative stress, and MQC processes, highlighting cellular adaptability to CB1-/-. This study paves the way for further exploration of intricate signaling cascades and cross-talk between cellular compartments in the context of CB1 and mitochondrial homeostasis.

Keywords:  cannabinoid type 1 receptor (CB1); miRNA; mitochondria; mitochondrial quality control (MQC); mitochondrial unfolded protein response (UPRmt); skeletal muscle

DOI:  https://doi.org/10.3390/biology13020116
Curr Issues Mol Biol. 2024 Jan 29. 46(2): 1150-1163

Next Generation Sequencing and Electromyography Reveal the Involvement of the P2RX6 Gene in Myopathy.

Mirella Vinci, Girolamo Aurelio Vitello, Donatella Greco, Simone Treccarichi, Alda Ragalmuto, Antonino Musumeci, Antonio Fallea, Concetta Federico, Francesco Calì, Salvatore Saccone, Maurizio Elia.

  Ion channelopathies result from impaired ion channel protein function, due to mutations affecting ion transport across cell membranes. Over 40 diseases, including neuropathy, pain, migraine, epilepsy, and ataxia, are associated with ion channelopathies, impacting electrically excitable tissues and significantly affecting skeletal muscle. Gene mutations affecting transmembrane ionic flow are strongly linked to skeletal muscle disorders, particularly myopathies, disrupting muscle excitability and contraction. Electromyography (EMG) analysis performed on a patient who complained of weakness and fatigue revealed the presence of primary muscular damage, suggesting an early-stage myopathy. Whole exome sequencing (WES) did not detect potentially causative variants in known myopathy-associated genes but revealed a novel homozygous deletion of the P2RX6 gene likely disrupting protein function. The P2RX6 gene, predominantly expressed in skeletal muscle, is an ATP-gated ion channel receptor belonging to the purinergic receptors (P2RX) family. In addition, STRING pathways suggested a correlation with more proteins having a plausible role in myopathy. No previous studies have reported the implication of this gene in myopathy. Further studies are needed on patients with a defective ion channel pathway, and the use of in vitro functional assays in suppressing P2RX6 gene expression will be required to validate its functional role.

Keywords:  P2RX6 gene; P2X receptors; early-onset myopathy; electromyography; genetic diseases; ion channelopathy; skeletal muscle; whole exome sequencing

DOI:  https://doi.org/10.3390/cimb46020073