bims-moremu 2024-11-17 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2024‒11‒17
39 papers selected by
Anna Vainshtein, Craft Science Inc.

The mitochondrial mRNA-stabilizing protein SLIRP regulates skeletal muscle mitochondrial structure and respiration by exercise-recoverable mechanisms.
Role of myofiber-specific FoxP1 in pancreatic cancer-induced muscle wasting.
Mitochondrial Dynamics Drive Muscle Stem Cell Progression from Quiescence to Myogenic Differentiation.
Acute resistance exercise and training reduce desmin phosphorylation at serine 31 in human skeletal muscle, making the protein less prone to cleavage.
Time-series transcriptomics reveals distinctive mRNA expression dynamics associated with gene ontology specificity and protein expression in skeletal muscle after electrical stimulation-induced resistance exercise.
Tetrandrine induces muscle atrophy involving ROS-mediated inhibition of Akt and FoxO3.
Nicotinamide and pyridoxine stimulate muscle stem cell expansion and enhance regenerative capacity during aging.
Tanshinone IIA alleviates inflammation-induced skeletal muscle atrophy by regulating mitochondrial dysfunction.
Downregulation of Genes for Skeletal Muscle Extracellular Matrix Components by Cisplatin.
Reactive oxygen species in age-related musculoskeletal decline: implications for nutritional intervention.
Endurance exercise attenuates Gαq-RNAi induced hereditary obesity and skeletal muscle dysfunction via improving skeletal muscle Srl/MRCC-I pathway in Drosophila.
Myokine BDNF highly expressed in Type I fibers inhibits the differentiation of myotubes into Type II fibers.
Estrogen Regulates Mitochondrial Activity Through Inducing Brain-Derived Neurotrophic Factor Expression in Skeletal Muscle.
Optimisation of cell fate determination for cultivated muscle differentiation.
The immune landscape of murine skeletal muscle regeneration and aging.
3D-environment and muscle contraction regulate the heterogeneity of myonuclei.
No detectable loss of myonuclei from human muscle fibers after six weeks of immobilization following an Achilles tendon rupture.
In vivo intracellular Ca2+ profiles after eccentric rat muscle contractions: Addressing the mechanistic bases for repeated bout protection.
The unique functions of Runx1 in skeletal muscle maintenance and regeneration are facilitated by an ETS interaction domain.
AEBP1 is a negative regulator of skeletal muscle cell differentiation in oral squamous cell carcinoma.
Metformin restores autophagic flux and mitochondrial function in late passage myoblast to impede age-related muscle loss.
Muscle déjà vu: are myonuclei the blueprint for muscle regrowth?
The whole-body and skeletal muscle metabolic response to 14 days of highly controlled low energy availability in endurance-trained females.
Angiopoietin 1 Attenuates Dysregulated Angiogenesis in the Gastrocnemius of DMD Mice.
Protein phosphatase-1 regulates the binding of filamin C to FILIP1 in cultured skeletal muscle cells under mechanical stress.
Opposing roles for AMPK in regulating distinct mitophagy pathways.
Platelet-rich plasma ameliorates dexamethasone-induced myopathy by suppressing autophagy and enhancing myogenic potential through modulation of Myo-D, Pax-7, and myogenin expression.
Cumulative effects of H+ and Pi on force and power of skeletal muscle fibres from young and older adults.
Neuromuscular Regeneration of Volumetric Muscle Loss Injury in Response to Agrin-Functionalized Tissue Engineered Muscle Grafts and Rehabilitative Exercise.
Molecular, Histological, and Functional Changes in Acta1-MCM;FLExDUX4/+ Mice.
Fibin is a crucial mitochondrial regulatory gene in skeletal muscle development.
Selenium-mediated alleviation of skeletal muscle atrophy through enterotype modulation in mice.
Unraveling the bidirectional relationship between muscle inflammation and satellite cells activity: influencing factors and insights.
The muscle-intervertebral disc interaction mediated by L-BAIBA modulates extracellular matrix homeostasis and PANoptosis in nucleus pulposus cells.
Nrf2 Deficiency Exacerbates the Decline in Swallowing and Respiratory Muscle Mass and Function in Mice with Aspiration Pneumonia.
Cycling away from cancer: can aerobic training enhance interleukin-15 response to acute exercise?
The circular RNA circNFIX regulates MEF2C expression in muscle satellite cells in spastic cerebral palsy.
The Influence of Physical Training on Breast Cancer: The Role of Exercise-Induced Myokines in Regulating Breast Cancer Cell Growth and Survival.
Exercise training may reduce fragmented mitochondria in the ischemic-reperfused heart through DRP1.

Nat Commun. 2024 Nov 13. 15(1): 9826

The mitochondrial mRNA-stabilizing protein SLIRP regulates skeletal muscle mitochondrial structure and respiration by exercise-recoverable mechanisms.

Tang Cam Phung Pham, Steffen Henning Raun, Essi Havula, Carlos Henriquez-Olguín, Diana Rubalcava-Gracia, Emma Frank, Andreas Mæchel Fritzen, Paulo R Jannig, Nicoline Resen Andersen, Rikke Kruse, Mona Sadek Ali, Andrea Irazoki, Jens Frey Halling, Stine Ringholm, Elise J Needham, Solvejg Hansen, Anders Krogh Lemminger, Peter Schjerling, Maria Houborg Petersen, Martin Eisemann de Almeida, Thomas Elbenhardt Jensen, Bente Kiens, Morten Hostrup, Steen Larsen, Niels Ørtenblad, Kurt Højlund, Michael Kjær, Jorge L Ruas, Aleksandra Trifunovic, Jørgen Frank Pind Wojtaszewski, Joachim Nielsen, Klaus Qvortrup, Henriette Pilegaard, Erik Arne Richter, Lykke Sylow.

Decline in mitochondrial function is linked to decreased muscle mass and strength in conditions like sarcopenia and type 2 diabetes. Despite therapeutic opportunities, there is limited and equivocal data regarding molecular cues controlling muscle mitochondrial plasticity. Here we uncovered that the mitochondrial mRNA-stabilizing protein SLIRP, in complex with LRPPRC, is a PGC-1α target that regulates mitochondrial structure, respiration, and mtDNA-encoded-mRNA pools in skeletal muscle. Exercise training effectively counteracts mitochondrial defects caused by genetically-induced LRPPRC/SLIRP loss, despite sustained low mtDNA-encoded-mRNA pools, by increasing mitoribosome translation capacity and mitochondrial quality control. In humans, exercise training robustly increases muscle SLIRP and LRPPRC protein across exercise modalities and sexes, yet less prominently in individuals with type 2 diabetes. SLIRP muscle loss reduces Drosophila lifespan. Our data points to a mechanism of post-transcriptional mitochondrial regulation in muscle via mitochondrial mRNA stabilization, offering insights into how exercise enhances mitoribosome capacity and mitochondrial quality control to alleviate defects.

DOI: https://doi.org/10.1038/s41467-024-54183-4
Am J Physiol Cell Physiol. 2024 Nov 15.

Role of myofiber-specific FoxP1 in pancreatic cancer-induced muscle wasting.

Martin M Schonk, Jeremy B Ducharme, Daria Neyroud, Rachel L Nosacka, Haley O Tucker, Sarah M Judge, Andrew R Judge.

  Cancer cachexia affects up to 80% of cancer patients and results in reduced quality of life and survival. We previously demonstrated that the transcriptional repressor Forkhead box P1 (FoxP1) is upregulated in skeletal muscle of cachectic mice and people with cancer, and when overexpressed in skeletal muscle is sufficient to induce pathological features characteristic of cachexia. However, the role of myofiber-derived FoxP1 in both normal muscle physiology and cancer-induced muscle wasting remains largely unexplored. To address this gap, we generated a conditional mouse line with myofiber-specific ablation of FoxP1 (FoxP1SkmKO) and found that in cancer-free mice, deletion of FoxP1 in skeletal myofibers resulted in increased myofiber size in both males and females, with a significant increase in muscle mass in males. In response to murine KPC pancreatic tumor burden, we found that myofiber-derived FoxP1 is required for cancer-induced muscle wasting and diaphragm muscle weakness in male mice. In summary, our findings identify myofiber-specific FoxP1 as a negative regulator of skeletal muscle with sex-specific differences in the context of cancer.

Keywords:  Biological sex; Cancer cachexia; Forkhead box P1; Muscle wasting; Pancreatic cancer

DOI:  https://doi.org/10.1152/ajpcell.00701.2024
Cells. 2024 Oct 26. pii: 1773. [Epub ahead of print]13(21):

Mitochondrial Dynamics Drive Muscle Stem Cell Progression from Quiescence to Myogenic Differentiation.

Olivia Sommers, Rholls A Tomsine, Mireille Khacho.

  From quiescence to activation and myogenic differentiation, muscle stem cells (MuSCs) experience drastic alterations in their signaling activity and metabolism. Through balanced cycles of fission and fusion, mitochondria alter their morphology and metabolism, allowing them to affect their decisive role in modulating MuSC activity and fate decisions. This tightly regulated process contributes to MuSC regulation by mediating changes in redox signaling pathways, cell cycle progression, and cell fate decisions. In this review, we discuss the role of mitochondrial dynamics as an integral modulator of MuSC activity, fate, and maintenance. Understanding the influence of mitochondrial dynamics in MuSCs in health and disease will further the development of therapeutics that support MuSC integrity and thus may aid in restoring the regenerative capacity of skeletal muscle.

Keywords:  DRP1; OPA1; differentiation; glutathione; metabolism; mitochondria; mitochondrial dynamics; muscle stem cells; myogenesis; reactive oxygen species (ROS)

DOI:  https://doi.org/10.3390/cells13211773
Sci Rep. 2024 Nov 14. 14(1): 28079

Acute resistance exercise and training reduce desmin phosphorylation at serine 31 in human skeletal muscle, making the protein less prone to cleavage.

Daniel Jacko, Kirill Schaaf, Thorben Aussieker, Lukas Masur, Jonas Zacher, Käthe Bersiner, Wilhelm Bloch, Sebastian Gehlert.

  Desmin intermediate filaments play a crucial role in stress transmission and mechano-protection. The loss of its integrity triggers myofibril breakdown and muscle atrophy for which desmin phosphorylation (pDes) is a priming factor. We investigated whether eccentric accentuated resistance exercise (RE) influences the regulation of pDes, effecting its susceptibility to cleavage. Ten healthy persons performed 14 RE-sessions (2 per week). Muscle biopsies were collected in both untrained and trained conditions at rest (pre 1, pre 14) and one hour after RE (post 1, post 14). Western blotting and immunohistochemistry were utilized to assess desmin content, phosphorylation at several sites and susceptibility to cleavage. In untrained condition (pre 1, post 1), RE induced dephosphorylation of serin 31 and 60. Trained muscle exhibited more pronounced dephosphorylation at Serin 31 post-RE. Dephosphorylation was accompanied by reduced susceptibility of desmin to cleavage. Additionally, training increased total desmin content, upregulated baseline serine 31 phosphorylation and attenuated pDes at serine 60 and threonine 17. Our findings suggest that acute and repeated RE changes the phosphorylation pattern of desmin and its susceptibility to cleavage, highlighting pDes as an adaptive mechanism in skeletal muscle, contributing to the proteostatic regulation in response to recurring stress.

Keywords:  Desmin; Exercise; Human skeletal muscle; Intermediate filaments

DOI:  https://doi.org/10.1038/s41598-024-79385-0
FASEB J. 2024 Nov 30. 38(22): e70153

Time-series transcriptomics reveals distinctive mRNA expression dynamics associated with gene ontology specificity and protein expression in skeletal muscle after electrical stimulation-induced resistance exercise.

Tatsuya Kusano, Yuta Sotani, Reo Takeda, Atsushi Hatano, Kentaro Kawata, Ryotaro Kano, Masaki Matsumoto, Yutaka Kano, Daisuke Hoshino.

  Resistance exercise upregulates and downregulates the expression of a wide range of genes in skeletal muscle. However, detailed analysis of mRNA dynamics such as response rates and temporal patterns of the transcriptome after resistance exercise has not been performed. We aimed to clarify the dynamics of time-series transcriptomics after resistance exercise. We used electrical stimulation-induced muscle contraction as a resistance exercise model (5 sets × 10 times of 3 s of 100-Hz electrical stimulation) on the tibialis anterior muscle of rats and measured the transcriptome in the muscle before and at 0, 1, 3, 6, and 12 h after muscle contractions by RNA sequencing. We also examined the relationship between the parameters of mRNA dynamics and the increase in protein expression at 12 h after muscle contractions. We found that the function of the upregulated genes differed after muscle contractions depending on their response rate. Genes related to muscle differentiation and response to mechanical stimulus were enriched in the sustainedly upregulated genes. Furthermore, there was a positive correlation between the magnitude of upregulated mRNA expression and the corresponding protein expression level at 12 h after muscle contractions. Although it has been theoretically suggested, this study experimentally demonstrated that the magnitude of the mRNA response after electrical stimulation-induced resistance exercise contributes to skeletal muscle adaptation via increases in protein expression. These findings suggest that mRNA expression dynamics such as response rate, a sustained upregulated expression pattern, and the magnitude of the response contribute to mechanisms underlying adaptation to resistance exercise.

Keywords:  acute exercise; dynamics; mRNA expression; proteome; temporal patterns

DOI:  https://doi.org/10.1096/fj.202401420RR
Mol Med. 2024 Nov 15. 30(1): 218

Tetrandrine induces muscle atrophy involving ROS-mediated inhibition of Akt and FoxO3.

Xin-Qi Shan, Na Zhou, Chuang-Xin Pei, Xue Lu, Cai-Ping Chen, Hua-Qun Chen.

  Tetrandrine (Tet), a well-known drug of calcium channel blocker, has been broadly applied for anti-inflammatory and anti-fibrogenetic therapy. However, due to the functional diversity of ubiquitous calcium channels, potential side-effects may be expected. Our previous report revealed an inhibitory effect of Tet on myogenesis of skeletal muscle. Here, we found that Tet induced protein degradation resulting in the myofibril atrophy. Upon administration with a relative high dose (40 mg/kg) of Tet for 28 days, the mice displayed significantly reduced muscle mass, strength force, and myosin heavy chain (MyHC) protein levels. The MyHC reduction was further detected in C2C12 myotubes after treating with Tet. Interestingly, the expression of Atrogin-1 and Murf-1, the skeletal muscle specific E3 ligases of protein ubiquitin-proteasome system (UPS), was accordingly up-regulated, and the reduced MyHC was significantly mitigated by MG132, a 26S proteasome inhibitor, indicating a key role of UPS in the protein degradation of muscle cells. Further study showed that Tet induced autophagy also participated in the protein degradation. Mechanistically, Tet treatment caused ROS production in myotubes that in turn targeted on FoxO3/AKT signaling, resulting in the activation of UPS and autophagy processes that were involved in the protein degradation. Our study reveals a potential side-effect of Tet on skeletal muscle atrophy, particularly when the drug dose is relatively high.

Keywords:  Degradation; FoxO3/Akt; Myosin heavy chain; ROS; Tetrandrine

DOI:  https://doi.org/10.1186/s10020-024-00981-x
J Clin Invest. 2024 Nov 12. pii: e163648. [Epub ahead of print]

Nicotinamide and pyridoxine stimulate muscle stem cell expansion and enhance regenerative capacity during aging.

Sara Ancel, Joris Michaud, Eugenia Migliavacca, Charline Jomard, Aurélie Fessard, Pauline Garcia, Sonia Karaz, Sruthi Raja, Guillaume E Jacot, Thibaut Desgeorges, José-Luis Sánchez-García, Loic Tauzin, Yann Ratinaud, Benjamin Brinon, Sylviane Métairon, Lucas Pinero, Denis Barron, Stephanie Blum, Leonidas G Karagounis, Ramin Heshmat, Afshin Ostovar, Farshad Farzadfar, Isabella Scionti, Rémi Mounier, Julien Gondin, Pascal Stuelsatz, Jerome N Feige.

  Skeletal muscle relies on resident muscle stem cells (MuSCs) for growth and repair. Aging and muscle diseases impair MuSC function, leading to stem cell exhaustion and regenerative decline that contribute to the progressive loss of skeletal muscle mass and strength. In the absence of clinically available nutritional solutions specifically targeting MuSCs, we used a human myogenic progenitor (hMP) high-content imaging screen of natural molecules from food to identify nicotinamide (NAM) and pyridoxine (PN) as bioactive nutrients that stimulate MuSCs and have history of safe human use. NAM and PN synergize via CK1-mediated cytoplasmic β-catenin activation and AKT signaling to promote amplification and differentiation of MuSCs. Oral treatment with a combination of NAM/PN accelerates muscle regeneration in vivo by stimulating MuSCs, increases muscle strength during recovery, and overcomes MuSC dysfunction and regenerative failure during aging. Levels of NAM and bioactive PN spontaneously decline during aging in model organisms and inter-independently associate with muscle mass and walking speed in a human cohort of 186 aged people. Collectively, our results establish NAM/PN as a new nutritional intervention that stimulates MuSCs, enhances muscle regeneration, and alleviates age-related muscle decline with a direct opportunity for clinical translation.

Keywords:  Adult stem cells; Epidemiology; Muscle biology; Skeletal muscle; Stem cells

DOI:  https://doi.org/10.1172/JCI163648
Arch Biochem Biophys. 2024 Nov 13. pii: S0003-9861(24)00337-0. [Epub ahead of print] 110215

Tanshinone IIA alleviates inflammation-induced skeletal muscle atrophy by regulating mitochondrial dysfunction.

Dong Han, Yun-Biao Chen, Kai Zhao, Hong-Zhou Li, Xing-Yu Chen, Guo-Zheng Zhu, Chen Tu, Jia-Wen Gao, Jing-Shen Zhuang, Zhi-Yong Wu, Zhao-Ming Zhong.

  Skeletal muscle atrophy, characterized by loss of muscle mass and function, is often linked to systemic inflammation. Tanshinone IIA (Tan IIA), a major active constituent of Salvia miltiorrhiza, has anti-inflammatory and antioxidant properties. However, the effect of Tan IIA on inflammation-induced skeletal muscle atrophy remains unclear. Here, a mice model of the inflammatory muscle atrophy was established using lipopolysaccharide (LPS). Tan IIA intervention significantly increased muscle mass and strength, improved muscle fiber size, and maintained the integrity of skeletal muscle mitochondrial morphology in LPS-treated mice. Myotubes derived from myosatellite cells (MUSCs) were exposed to LPS in vitro. Tan IIA treatment inhibited LPS-induced muscle protein degradation and increased myotube diameter. Notably, Tan IIA attenuated LPS-induced inflammatory response and hyperactive mitophagy both in vivo and in vitro. In addition, Tan IIA treatment effectively diminished oxidative stress, inhibited the accumulation of mitochondrial reactive oxygen species (mtROS), and attenuated mitochondrial fission in LPS-treated myotubes. Reducing mtROS production helped to inhibit LPS-induced excessive mitophagy and myotubes atrophy. Together, our results reveal that Tan IIA can protect against inflammation-induced skeletal muscle atrophy by regulating mitochondrial dysfunction, presenting innovative potential therapeutics for skeletal muscle atrophy.

Keywords:  Inflammation; MUSCs; Mitophagy; Skeletal muscle atrophy; Tanshinone IIA; mtROS

DOI:  https://doi.org/10.1016/j.abb.2024.110215
Biol Pharm Bull. 2024 ;47(11): 1846-1850

Downregulation of Genes for Skeletal Muscle Extracellular Matrix Components by Cisplatin.

Yu Miyauchi, Miho Kiyama, Shinki Soga, Hayato Nanri, Takayuki Ogiwara, Shiori Yonamine, Risako Kon, Nobutomo Ikarashi, Yoshihiko Chiba, Tomoo Hosoe, Hiroyasu Sakai.

  The extracellular matrix (ECM) in skeletal muscle is involved in a variety of physiological functions beyond the mechanical support of muscle tissue, nerves, and blood vessels; however, the role of the ECM in skeletal muscle remains unclear. There is little information regarding changes in the expression of factors comprising the ECM during cisplatin-induced muscle atrophy. In the present study, we examined the changes in gene expressions for skeletal muscle extracellular matrix components in skeletal muscle during cisplatin-induced muscle atrophy. Intraperitoneal administration of cisplatin caused muscle atrophy in mice and during this cisplatin-induced muscle atrophy, the expression of many procollagen genes (Col1a1, Col1a2, Col3a1, Col4a1, Col5a1, and Col5a2), elastin (Eln), fibronectin (Fn1), Laminin (Lama1, Lama2, and Lamb1) decorin (Dcn), heparan sulphate proteoglycans (Hspg2) and integrin (Itgb1) constituting the ECM was suppressed. Additional studies are needed to elucidate the pathological significance and mechanisms of reduced gene expression of ECM components associated with cisplatin-induced muscle atrophy.

Keywords:  cisplatin; collagen; extracellular matrix; muscle atrophy; procollagen

DOI:  https://doi.org/10.1248/bpb.b24-00428
Proc Nutr Soc. 2024 Nov 08. 1-9

Reactive oxygen species in age-related musculoskeletal decline: implications for nutritional intervention.

Malcolm J Jackson.

  Musculoskeletal disorders and age-related musculoskeletal decline are major contributors to the burden of ill health seen in older subjects. Despite this increased burden, these chronic disorders of old age receive a relatively small proportion of national research funds. Much has been learned about fundamental processes involved in ageing from basic science research and this is leading to identification of key pathways that mediate ageing which may help the search for interventions to reduce age-related musculoskeletal decline. This short review will focus on the role of reactive oxygen species in age-related skeletal muscle decline and on the implications of this work for potential nutritional interventions in sarcopenia. The key physiological role of reactive oxygen species is now known to be in mediating redox signalling in muscle and other tissues and ageing leads to disruption of such pathways. In muscle, this is reflected in an age-related attenuation of specific adaptations and responses to contractile activity that impacts the ability of skeletal muscle from ageing individuals to respond to exercise. These pathways provides potential targets for identification of logical interventions that may help maintain muscle mass and function during ageing.

Keywords:  Ageing; Redox; Skeletal muscle

DOI:  https://doi.org/10.1017/S0029665124004877
Sci Rep. 2024 Nov 15. 14(1): 28207

Endurance exercise attenuates Gαq-RNAi induced hereditary obesity and skeletal muscle dysfunction via improving skeletal muscle Srl/MRCC-I pathway in Drosophila.

Xin-Yuan Yin, Deng-Tai Wen, Han-Yu Li, Zhao-Qing Gao, YuZe Gao, WeiJia Hao.

  G protein alpha q subunit (Gαq) can binds to the G protein-coupled receptor (GPCR) for signaling and is closely related to lipid metabolism. Endurance exercise is an effective means of combating acquired obesity and its complications, but the mechanisms by which endurance exercise modulates hereditary obesity and its complications are unknown. In this study, we achieved knockdown of Gαq in drosophila adipose tissue and skeletal muscle by constructing the Gαq-UAS-RNAi/Ppl-Gal4 and Gαq-UAS-RNAi/Mef2-GAl4 systems. Drosophila were subjected a three-week endurance exercise intervention, and changes in relevant indicators were detected and observed by RT-PCR, ELISA, oil red staining, immunofluorescence staining, and transmission electron microscopy. The results showed that knockdown of Gαq in both adipose tissue and skeletal muscle induced a significant increase in triglycerides accompanied by a decrease in rapid climbing ability, a decrease in Superoxide Dismutase (SOD) activity level, and a decrease in Mitochondrial respiratory chain complexI (MRCC I) content in Drosophila whole body and skeletal muscle, and down-regulated the expression of the G protein alpha q subunit (Gαq), the skeletal muscle myosin heavy chain expression gene (Mhc), mitochondrial biogenesis gene Spargal(the PGC-1alpha homologue in Drosophila). Endurance exercise significantly improved the triglyceride levels in the whole body and skeletal muscle of drosophila with Gαq knockdown in adipose tissue and skeletal muscle, as well as their ability to climb, increased SOD activity level and MRCCI content level, and up-regulated the expression of Gαq, Mhc, and Spargal(Srl). Thus, the present findings suggest that genetic defects in the Gαq gene in adipose and skeletal muscle tissues induce hereditary obesity and skeletal muscle dysfunction, and that endurance exercise attenuates this hereditary obesity and concomitant skeletal muscle dysfunction in drosophila by improving skeletal muscle fiber contractile proteins, mitochondrial function and function, and antioxidant capacity via mediating the Gαq/Mhc, Gαq/Srl/MRCC-I, and Gαq/SOD pathways.

Keywords:   Gαq gene; Drosophila; Endurance exercise; Genetic obesity; Mitochondria; Skeletal muscle

DOI:  https://doi.org/10.1038/s41598-024-79415-x
Mol Biol Rep. 2024 Nov 12. 51(1): 1143

Myokine BDNF highly expressed in Type I fibers inhibits the differentiation of myotubes into Type II fibers.

Teng Hu, Yasuro Furuichi, Yasuko Manabe, Kenichiro Yamada, Kengo Katakura, Yuna Aoki, Kun Tang, Takaomi Sakai, Nobuharu L Fujii.

  BACKGROUND: Myofibers are broadly classified as slow-twitch (Type I) and fast-twitch (Type II) fibers. These two types of myofibers coexist within the same skeletal muscle tissue, determining the contractile and metabolic properties of skeletal muscle tissue by fiber type distribution.METHODS AND RESULTS: By examining each fiber type separately, we confirmed that brain-derived neurotrophic factor (BDNF) gene is highly expressed in Type I fibers. When exposed to BDNF, primary myotubes exhibited reduced expression of Myosin Heavy Chain (MyHC) II, a marker protein characteristic of Type II fibers. BDNF overexpression in regenerating muscle tissue led to a decrease in the distribution of Type IIA fibers.
CONCLUSIONS: We suggest that BDNF highly expressed in Type I fibers downregulates MyHC II expression in myotubes, eventually inhibiting Type IIA fiber generation.

Keywords:  BDNF; Muscle fiber type; Myokine; Myotube

DOI:  https://doi.org/10.1007/s11033-024-10044-3
J Cell Physiol. 2024 Nov 12.

Estrogen Regulates Mitochondrial Activity Through Inducing Brain-Derived Neurotrophic Factor Expression in Skeletal Muscle.

Margaret Chui Ling Tse, Brian Pak Shing Pang, Xinyi Bi, Teresa Xinci Ooi, Wing Suen Chan, Jiangwen Zhang, Chi Bun Chan.

  Estrogen is an essential hormone for the development and functional activities of reproductive organs. Recent studies showed that estrogen signaling is also an important regulator of lipid and glucose metabolism in a number of tissues, but the molecular mechanism is not fully understood. We report here that estrogen is a stimulator of brain-derived neurotrophic factor (BDNF) synthesis in the skeletal muscle. Estradiol (E2), but not testosterone, induces a dose- and time-dependent BDNF production in cultured myotubes. Estrogen depletion in ovariectomized mice significantly reduced Bdnf expression in the glycolytic myofibers, which could be rescued after E2 administration. Mechanistically, E2 stimulation triggered the tethering of estrogen receptor (ER) α, but not ERβ, to the estrogen-responsive element on promoter VI of the Bdnf gene in skeletal muscle. When Bdnf production was inhibited by shRNA in C2C12 myotubes, E2-induced mitochondria activation and pyruvate dehydrogenase kinase 4 expressions were jeopardized. Collectively, our results demonstrate that BDNF is an underrecognized effector of estrogen in regulating mitochondrial activity and fuel metabolism in the skeletal muscle.

Keywords:  brain‐derived neurotrophic factor; estrogen; mitochondrial activity; skeletal muscle

DOI:  https://doi.org/10.1002/jcp.31483
Commun Biol. 2024 Nov 12. 7(1): 1493

Optimisation of cell fate determination for cultivated muscle differentiation.

Lea Melzener, Lieke Schaeken, Marion Fros, Tobias Messmer, Dhruv Raina, Annemarie Kiessling, Tessa van Haaften, Sergio Spaans, Arin Doǧan, Mark J Post, Joshua E Flack.

Production of cultivated meat requires defined medium formulations for the robust differentiation of myogenic cells into mature skeletal muscle fibres in vitro. Although these formulations can drive myogenic differentiation levels comparable to serum-starvation-based protocols, the resulting cultures are often heterogeneous, with a significant proportion of cells not participating in myofusion, limiting maturation of the muscle. To address this problem, we employed RNA sequencing to analyse heterogeneity in differentiating bovine satellite cells at single-nucleus resolution, identifying distinct cellular subpopulations including proliferative cells that fail to exit the cell cycle and quiescent 'reserve cells' that do not commit to myogenic differentiation. Our findings indicate that the MEK/ERK, NOTCH, and RXR pathways are active during the initial stages of myogenic cell fate determination, and by targeting these pathways, we can promote cell cycle exit while reducing reserve cell formation. This optimised medium formulation consistently yields fusion indices close to 100% in 2D culture. Furthermore, we demonstrate that these conditions enhance myotube formation and actomyosin accumulation in 3D bovine skeletal muscle constructs, providing proof of principle for the generation of highly differentiated cultivated muscle with excellent mimicry to traditional muscle.

DOI: https://doi.org/10.1038/s42003-024-07201-6
Cell Rep. 2024 Nov 13. pii: S2211-1247(24)01326-3. [Epub ahead of print]43(11): 114975

The immune landscape of murine skeletal muscle regeneration and aging.

Neuza S Sousa, Marta Bica, Margarida F Brás, Ana C Sousa, Inês B Antunes, Isabel A Encarnação, Tiago M Costa, Inês B Martins, Nuno L Barbosa-Morais, Pedro Sousa-Victor, Joana Neves.

  Age-related alterations in the immune system are starting to emerge as key contributors to impairments found in aged organs. A decline in regenerative capacity is a hallmark of tissue aging; however, the contribution of immune aging to regenerative failure is just starting to be explored. Here, we apply a strategy combining single-cell RNA sequencing with flow cytometry, histological analysis, and functional assays to perform a complete analysis of the immune environment of the aged regenerating skeletal muscle on a time course following injury with single-cell resolution. Our results reveal an unanticipated complexity and functional heterogeneity in immune populations within the skeletal muscle that have been regarded as homogeneous. Furthermore, we uncover a profound remodeling of both myeloid and lymphoid compartments in aging. These discoveries challenge established notions on immune regulation of skeletal muscle regeneration, providing a set of potential targets to improve skeletal muscle health and regenerative capacity in aging.

Keywords:  CP: Immunology

DOI:  https://doi.org/10.1016/j.celrep.2024.114975
Skelet Muscle. 2024 Nov 11. 14(1): 27

3D-environment and muscle contraction regulate the heterogeneity of myonuclei.

Rosa Nicolas, Marie-Ange Bonnin, Cédrine Blavet, Joana Esteves de Lima, Cécile Legallais, Delphine Duprez.

  Skeletal muscle formation involves tight interactions between muscle cells and associated connective tissue fibroblasts. Every muscle displays the same type of organisation, they are innervated in the middle and attached at both extremities to tendons. Myonuclei are heterogeneous along myotubes and regionalised according to these middle and tip domains. During development, as soon as myotubes are formed, myonuclei at muscle tips facing developing tendons display their own molecular program. In addition to molecular heterogeneity, a subset of tip myonuclei has a fibroblastic origin different to the classical somitic origin, highlighting a cellular heterogeneity of myonuclei in foetal myotubes. To gain insights on the functional relevance of myonucleus heterogeneity during limb development, we used 2D culture and co-culture systems to dissociate autonomous processes (occurring in 2D-cultures) from 3D-environment of tissue development. We also assessed the role of muscle contraction in myonucleus heterogeneity in paralysed limb muscles. The regionalisation of cellular heterogeneity was not observed in 2D cell culture systems and paralyzed muscles. The molecular signature of MTJ myonuclei was lost in a dish and paralysed muscles indicating a requirement of 3D-enviroment and muscle contraction for MTJ formation. Tip genes that maintain a regionalized expression at myotube tips in cultures are linked to sarcomeres. The behaviour of regionalized markers in cultured myotubes and paralyzed muscles allows us to speculate whether the genes intervene in myogenesis, myotube attachment or MTJ formation.

Keywords:  Cell cultures; Chicken; Embryos; Fibroblast; Heterogeneity; Immobilization; Limbs; Myoblast; Myonuclei; Myotendinous junction; Quail; Regionalisation

DOI:  https://doi.org/10.1186/s13395-024-00359-x
Am J Physiol Cell Physiol. 2024 Nov 15.

No detectable loss of myonuclei from human muscle fibers after six weeks of immobilization following an Achilles tendon rupture.

Oscar Horwath, Kristoffer Toldnes Cumming, Einar Eftestøl, Björn Ekblom, Paul Ackermann, Truls Raastad, Kristian Gundersen, Niklas Psilander.

  Muscle disuse has rapid and debilitating effects on muscle mass and overall health, making it an important issue from both scientific and clinical perspectives. However, the myocellular adaptations to muscle disuse are not yet fully understood, particularly those related to the myonuclear permanence hypothesis. Therefore, in this study, we assessed fiber size, number of myonuclei, satellite cells, and capillaries in human gastrocnemius muscle after a period of immobilization following an Achilles tendon rupture. Six physically active patients (5M/1F, 43 {plus minus} 15 years) were recruited to participate after sustaining an acute unilateral Achilles tendon rupture. Muscle biopsies were obtained from the lateral part of the gastrocnemius before and after six weeks of immobilization using a plaster cast and orthosis. Muscle fiber characteristics were analyzed in tissue cross-sections and isolated single fibers using immunofluorescence and high-resolution microscopy. Immobilization did not change muscle fiber type composition nor cross-sectional area of type I or type II fibers, but muscle fiber volume tended to decline by 13% (p=0.077). After immobilization, the volume per myonucleus was significantly reduced by 20% (p=0.008). Myonuclei were not lost in response to immobilization but tended to increase in single fibers and type II fibers. No significant changes were observed for satellite cells or capillaries. Myonuclei were not lost in the gastrocnemius muscle after a prolonged period of immobilization, which may provide support to the myonuclear permanence hypothesis in human muscle. Capillaries remained stable throughout the immobilization period, whereas the response was variable for satellite cells, particularly in type II fibers.

Keywords:  DAPI; muscle fibers; muscle memory; syncytium

DOI:  https://doi.org/10.1152/ajpcell.00692.2024
J Appl Physiol (1985). 2024 Nov 15.

In vivo intracellular Ca2+ profiles after eccentric rat muscle contractions: Addressing the mechanistic bases for repeated bout protection.

Ayaka Tabuchi, Yudai Kikuchi, Ryo Takagi, Yoshinori Tanaka, Daisuke Hoshino, David C Poole, Yutaka Kano.

  Eccentric contractions (ECC) are accompanied by accumulation of intracellular calcium ions ([Ca2+]i) and induce skeletal muscle damage. Suppressed muscle damage in repeated bouts of ECC is well characterized, however, whether it is mediated by altered Ca2+ profiles remains unknown. PURPOSE: We tested the hypothesis that repeated ECC suppresses Ca2+ accumulation via adaptions in Ca2+ regulation. METHODS: Male Wistar rats were divided into two groups: ECC single bout (ECC-SB) and repeated bout (ECC-RB). Tibialis anterior (TA) muscles were subjected to ECC (40 times, 5 sets) once (ECC-SB), or twice 14 days apart (ECC-RB). Under anesthesia, the TA muscle was loaded with Ca2+ indicator Fura-2 AM and the 340/380 nm ratio was evaluated as [Ca2+]i. Ca2+ handling proteins were measured by western blots. RESULTS: ECC induced [Ca2+]i increase in both groups, but ECC-RB evinced a markedly suppressed [Ca2+]i (Time: P < 0.01, Group: P = 0.0357). 5 hours post-ECC, in contrast to the localized [Ca2+]i accumulation in ECC-SB, ECC-RB exhibited lower and more uniform [Ca2+]i (P < 0.01). In ECC-RB mitochondria Ca2+ uniporter complex components, MCU and MICU2, were significantly increased pre-second ECC bout (P < 0.01) and both SERCA1 and MICU1 were better preserved after contractions (P < 0.01). CONCLUSION: 14 days after novel ECC skeletal muscle mitochondrial Ca2+ regulating proteins were elevated. Following subsequent ECC [Ca2+]i accumulation and muscle damage were suppressed and SERCA1 and MICU1 preserved. These findings suggest that tolerance to a subsequent ECC bout is driven, at least in part, by enhanced mitochondrial and SR Ca2+ regulation.

Keywords:  Calcium ion; mitochondria; muscle damage; repeated bout effect

DOI:  https://doi.org/10.1152/japplphysiol.00164.2024
Development. 2024 Nov 07. pii: dev.202556. [Epub ahead of print]

The unique functions of Runx1 in skeletal muscle maintenance and regeneration are facilitated by an ETS interaction domain.

Meng Yu, Konrad Thorner, Sreeja Parameswaran, Wei Wei, Chuyue Yu, Xinhua Lin, Raphael Kopan, Matthew R Hass.

  The conserved Runt-related (RUNX) transcription factor family are master regulators of developmental and regenerative processes. Runx1 and Runx2 are expressed in satellite cells (SC) and in skeletal myotubes. Conditional deletion of Runx1 in adult SC negatively impacted self-renewal and impaired skeletal muscle maintenance even though Runx2 expression persisted. Runx1 deletion in C2C12 cells that retain Runx2 expression identified unique molecular functions of Runx1 that cannot be compensated by Runx2. The reduced myoblast fusion in vitro caused by Runx1 loss was due in part to ectopic expression of Mef2c, a target repressed by Runx1. Structure-function analysis demonstrated that the Ets-interacting MID/EID region of Runx1, absent from Runx2, is critical to Runx1 myoblast function and for Etv4 binding. Analysis of ChIP-seq datasets from Runx1 (T-cells, muscle) versus Runx2 (preosteoblasts) dependent tissues identified a composite Ets:Runx motif enriched in Runx1-dependent tissues. The Ets:Runx composite motif was enriched in peaks open exclusively in ATAC-seq datasets from WT cells compared to ATAC peaks unique to Runx1KO cells. Thus, engagement of a set of targets by the RUNX1/ETS complex define the non-redundant functions of Runx1.

Keywords:  ETS; Muscle; Runx1

DOI:  https://doi.org/10.1242/dev.202556
Sci Rep. 2024 11 09. 14(1): 27425

AEBP1 is a negative regulator of skeletal muscle cell differentiation in oral squamous cell carcinoma.

Fumika Okazaki, Akira Yorozu, Shohei Sekiguchi, Takeshi Niinuma, Reo Maruyama, Hiroshi Kitajima, Eiichiro Yamamoto, Kazuya Ishiguro, Mutsumi Toyota, Yui Hatanaka, Koyo Nishiyama, Kazuhiro Ogi, Masahiro Kai, Kenichi Takano, Shingo Ichimiya, Akihiro Miyazaki, Hiromu Suzuki.

  The tumor microenvironment plays a pivotal role in cancer development. We recently reported that in oral squamous cell carcinoma (OSCC), adipocyte enhancer-binding protein 1 (AEBP1) is abundantly expressed in cancer-associated fibroblasts (CAFs), leading to CAF activation and inhibition of CD8 + T cell infiltration. In the present study, we investigated whether AEBP1 contributes to the destruction and atrophy of muscle tissues in OSCC. By analyzing human skeletal muscle myoblasts (HSMMs), we found that AEBP1 is downregulated during muscle cell differentiation. Transcriptome analysis revealed that AEBP1 knockdown significantly upregulates myogenesis-related genes in HSMMs, and qRT-PCR and western blot analyses confirmed the induction of muscle-related genes, including MYOG, in HSMMs after AEBP1 knockdown. Conversely, ectopic expression of AEBP1 strongly suppressed myogenesis-related genes in HSMMs. Notably, indirect co-culture of HSMMs with OSCC cells led to AEBP1 upregulation and robust suppression of muscle-related genes in HSMMs. Treatment with TGF-β1 also upregulated AEBP1 and suppressed expression of muscle-related genes in HSMMs. Our findings suggest that AEBP1 is a negative regulator of skeletal muscle cell differentiation and that OSCC cells inhibit muscle cell differentiation, at least in part, by inducing AEBP1.

Keywords:  ACLP; AEBP1; Muscle cell differentiation; Myoblast; OSCC

DOI:  https://doi.org/10.1038/s41598-024-79061-3
Biomed Pharmacother. 2024 Nov;pii: S0753-3322(24)00865-5. [Epub ahead of print]180 116981

Metformin restores autophagic flux and mitochondrial function in late passage myoblast to impede age-related muscle loss.

Sooyoon Bang, Dong-Eun Kim, Hee-Taik Kang, Jong Hun Lee.

  Sarcopenia, which refers to age-related muscle loss, presents a significant challenge for the aging population. Age-related changes that contribute to sarcopenia include cellular senescence, decreased muscle stem cell number and regenerative capacity, impaired autophagy, and mitochondrial dysfunction. Metformin, an anti-diabetic agent, activates AMP-activated protein kinase (AMPK) and affects various cellular processes in addition to reducing hepatic gluconeogenesis, lowering blood glucose levels, and improving insulin resistance. However, its effect on skeletal muscle cells remains unclear. This study aimed to investigate the effects of metformin on age-related muscle loss using a late passage C2C12 cell model. The results demonstrated that metformin alleviated hallmarks of cellular senescence, including SA-β-gal activity and p21 overexpression. Moreover, treatment with pharmacological concentrations of metformin restored the reduced differentiation capacity in late passage cells, evident through increased myotube formation ability and enhanced expression of myogenic differentiation markers such as MyoD, MyoG, and MHC. These effects of metformin were attributed to enhanced autophagic activity, normalization of mitochondrial membrane potential, and improved mitochondrial respiratory capacity. These results suggest that pharmacological concentrations of metformin alleviate the hallmarks of cellular senescence, restore differentiation capacity, and improve autophagic flux and mitochondrial function. These findings support the potential use of metformin for the treatment of sarcopenia.

Keywords:  Autophagy; Cellular senescence; Metformin; Mitochondrial dysfunction; Myogenic differentiation; Sarcopenia

DOI:  https://doi.org/10.1016/j.biopha.2024.116981
J Physiol. 2024 Nov 13.

Muscle déjà vu: are myonuclei the blueprint for muscle regrowth?

Claire Traversa, Alyasamin Alhamwi, Arianne Zabbal, Sarkis Hannaian.



Keywords:  muscle memory; muscle plasticity; myonuclear permanence; myonuclei; performance‐enhancing drugs; resistance training; skeletal muscle fibre

DOI:  https://doi.org/10.1113/JP287606
FASEB J. 2024 Nov 15. 38(21): e70157

The whole-body and skeletal muscle metabolic response to 14 days of highly controlled low energy availability in endurance-trained females.

Hannah G Caldwell, Jan S Jeppesen, Lone O Lossius, Jesper P Atti, Cody G Durrer, Mikkel Oxfeldt, Anna K Melin, Mette Hansen, Jens Bangsbo, Lasse Gliemann, Ylva Hellsten.

  This study investigated the effects of 14 days low energy availability (LEA) versus optimal energy availability (OEA) in endurance-trained females on substrate utilization, insulin sensitivity, and skeletal muscle mitochondrial oxidative capacity; and the impact of metabolic changes on exercise performance. Twelve endurance-trained females (V̇O2max 55.2 ± 5.1 mL × min-1 × kg-1) completed two 14-day randomized, blinded, cross-over, controlled dietary interventions: (1) OEA (51.9 ± 2.0 kcal × kg fat-free mass (FFM)-1 × day-1) and (2) LEA (22.3 ± 1.5 kcal × kg FFM-1 × day-1), followed by 3 days OEA. Participants maintained their exercise training volume during both interventions (approx. 8 h × week-1 at 79% heart rate max). Skeletal muscle mitochondrial respiratory capacity, glycogen, and maximal activity of CS, HAD, and PFK were unaltered with LEA. 20-min time trial endurance performance was impaired by 7.8% (Δ -16.8 W, 95% CI: -23.3 to -10.4, p < .001) which persisted following 3 days refueling post-LEA (p < .001). Fat utilization was increased post-LEA as evidenced by: (1) 99.4% (p < .001) increase in resting plasma free fatty acids (FFA); (2) 270% (p = .007) larger reduction in FFA in response to acute exercise; and (3) 28.2% (p = .015) increase in resting fat oxidation which persisted during submaximal exercise (p < .001). These responses were reversed with 3 days refueling. Daily glucose control (via CGM), HOMA-IR, HOMA-β, were unaffected by LEA. Skeletal muscle O2 utilization and carbohydrate availability were not limiting factors for aerobic exercise capacity and performance; therefore, whether LEA per se affects aspects of training quality/recovery requires investigation.

Keywords:  caloric restriction; fat oxidation; insulin sensitivity; metabolism; mitochondrial oxidative capacity

DOI:  https://doi.org/10.1096/fj.202401780R
Int J Mol Sci. 2024 Nov 04. pii: 11824. [Epub ahead of print]25(21):

Angiopoietin 1 Attenuates Dysregulated Angiogenesis in the Gastrocnemius of DMD Mice.

Andrew McClennan, Lisa Hoffman.

  Duchenne muscular dystrophy (DMD) is a degenerative neuromuscular disease caused by a lack of functional dystrophin. Ang 1 paracrine signalling maintains the endothelial barrier of blood vessels, preventing plasma leakage. Chronic inflammation, a consequence of DMD, causes endothelial barrier dysfunction in skeletal muscle. We aim to elucidate changes in the DMD mouse's gastrocnemius microvascular niche following local administration of Ang 1. Gastrocnemii were collected from eight-week-old mdx/utrn+/- and healthy mice. Additional DMD cohort received an intramuscular injection of Ang 1 to gastrocnemius and contralateral control. Gastrocnemii were collected for analysis after two weeks. Using immunohistochemistry and real-time quantitative reverse transcription, we demonstrated an abundance of endothelial cells in DMD mouse's gastrocnemius, but morphology and gene expression were altered. Myofiber perimeters were shorter in DMD mice. Following Ang 1 treatment, fewer endothelial cells were present, and microvessels were more circular. Vegfr1, Vegfr2, and Vegfa expression in Ang 1-treated gastronemii increased, while myofiber size distribution was consistent with vehicle-only gastrocnemii. These results suggest robust angiogenesis in DMD mice, but essential genes were underexpressed-furthermore, exogenous Ang 1 attenuated angiogenesis. Consequentially, gene expression increased. The impact must be investigated further, as Ang 1 therapy may be pivotal in restoring the skeletal muscle microvascular niche.

Keywords:  Duchenne muscular dystrophy (DMD); angiopoietin-1; inflammation; mdx/utrn+/−; microvasculature; vascular therapy

DOI:  https://doi.org/10.3390/ijms252111824
Sci Rep. 2024 11 09. 14(1): 27348

Protein phosphatase-1 regulates the binding of filamin C to FILIP1 in cultured skeletal muscle cells under mechanical stress.

Thomas Kokot, Johannes P Zimmermann, Anja N Schwäble, Lena Reimann, Anna L Herr, Nico Höfflin, Maja Köhn, Bettina Warscheid.

The actin-binding protein filamin c (FLNc) is a key mediator in the response of skeletal muscle cells to mechanical stress. In addition to its function as a structural scaffold, FLNc acts as a signaling adaptor which is phosphorylated at S2234 in its mechanosensitive domain 20 (d20) through AKT. Here, we discovered a strong dephosphorylation of FLNc-pS2234 in cultured skeletal myotubes under acute mechanical stress, despite high AKT activity. We found that all three protein phosphatase 1 (PP1) isoforms are part of the FLNc d18-21 interactome. Enzymatic assays demonstrate that PP1 efficiently dephosphorylates FLNc-pS2234 and in vitro and in cells upon PP1 activation using specific modulators. FLNc-pS2234 dephosphorylation promotes the interaction with FILIP1, a mediator for filamin degradation. Altogether, we present a model in which dephosphorylation of FLNc d20 by the dominant action of PP1c prevails over AKT activity to promote the binding of the filamin degradation-inducing factor FILIP1 during acute mechanical stress.

DOI: https://doi.org/10.1038/s41598-024-78953-8
Mol Cell. 2024 Nov 05. pii: S1097-2765(24)00865-7. [Epub ahead of print]

Opposing roles for AMPK in regulating distinct mitophagy pathways.

Marianna Longo, Aniketh Bishnu, Pierpaolo Risiglione, Lambert Montava-Garriga, Joyceline Cuenco, Kei Sakamoto, Carol MacKintosh, Ian G Ganley.

  Mitophagy degrades damaged mitochondria, but we show here that it can also target functional mitochondria. This latter scenario occurs during programmed mitophagy and involves the mitophagy receptors NIX and BNIP3. Although AMP-activated protein kinase (AMPK), the energy-sensing protein kinase, can influence damaged-induced mitophagy, its role in programmed mitophagy is unclear. We found that AMPK directly inhibits NIX-dependent mitophagy by triggering 14-3-3-mediated sequestration of ULK1, via ULK1 phosphorylation at two sites: Ser556 and an additional identified site, Ser694. By contrast, AMPK activation increases Parkin phosphorylation and enhances the rate of depolarization-induced mitophagy, independently of ULK1. We show that this happens both in cultured cells and tissues in vivo, using the mito-QC mouse model. Our work unveils a mechanism whereby AMPK activation downregulates mitophagy of functional mitochondria but enhances that of dysfunctional/damaged ones.

Keywords:  14-3-3; AMPK; NIX; Parkin; ULK1; autophagy; liver; mito-QC; mitophagy; skeletal muscle

DOI:  https://doi.org/10.1016/j.molcel.2024.10.025
Tissue Cell. 2024 Nov 05. pii: S0040-8166(24)00303-3. [Epub ahead of print]91 102602

Platelet-rich plasma ameliorates dexamethasone-induced myopathy by suppressing autophagy and enhancing myogenic potential through modulation of Myo-D, Pax-7, and myogenin expression.

Sally M Safwat, Dalia M Abdel Ghaffar, Mamdouh Eldesoqui, Sally Abdallah Mostafa, Eman A E Farrag, Fardous El-Senduny, Basma Osman, Eman Mohamad El Nashar, Shaker Hassan Alshehri, A Alhefzi, Mohammed Saeed Alasmry, Omar Aboubakr Elnashar, Zienab Helmy Eldken.

  BACKGROUND: Muscle tissue is essential for overall well-being that declines with age and different illnesses. Glucocorticoids, despite being efficient in treating inflammation, can induce muscle weakness (known as glucocorticoid-induced myopathy) by affecting protein breakdown and synthesis. Glucocorticoids have a negative impact on satellite cells, which play a role in muscle regeneration. Platelet rich plasma (PRP), containing concentrated growth factors, has a potential role in enhancing tissue repair and could be used to ameliorates combat muscle wasting caused by glucocorticoids.AIM: The purpose of this study was to identify how PRP can affect dexamethasone-induced myopathy in a rat model.
METHODS: Twenty-four male rats were divided into four equal groups: control, PRP, steroid (dexamethasone) treated for induction of myopathy, and steroid then treated with PRP for three weeks. Skeletal muscle contractile properties, protein content of the muscle, oxidative stress markers, histological structure, myogenin gene expression and immunohistochemical expression of Myo-D, Pax-7 and LC3 were assessed.
RESULTS: dexamethasone caused significant muscle weakness, decreased protein content, increased oxidative stress, decreased expression of myogenic genes and upregulated LC3 expression. PRP administration significantly improved muscle function, increased protein content, reduced oxidative stress, and upregulated myogenic genes. Histological results confirmed these findings. Additionally, PRP decreased autophagy marker LC3 expression and increased muscle stem cell markers MyoD and Pax7.
CONCLUSION: These results suggested that PRP could effectively prevent and reverse dexamethasone-induced muscle atrophy by promoting muscle protein synthesis, reducing oxidative stress, decreasing autophagy, and enhancing muscle stem cell activity. This study supports the potential role of PRP as a therapeutic strategy for muscle wasting disorders.

Keywords:  Autophagy; Glucocorticoids; Myogenic Genes; Myopathy; Oxidative stress; Platelet Rich Plasma

DOI:  https://doi.org/10.1016/j.tice.2024.102602
J Physiol. 2024 Nov 15.

Cumulative effects of H+ and Pi on force and power of skeletal muscle fibres from young and older adults.

Christopher W Sundberg, Laura E Teigen, Sandra K Hunter, Robert H Fitts.

  The cellular causes of the age-related loss in power output and increased fatigability are unresolved. We previously observed that the depressive effects of hydrogen (H+) (pH 6.2) and inorganic phosphate (Pi) (30 mm) did not differ in muscle fibres from young and older men. However, the effects may have been saturated in the severe fatigue-mimicking condition, potentially masking age differences in the sensitivity of the cross-bridge to these metabolites. Thus, we compared the contractile mechanics of muscle fibres from the vastus lateralis of 13 young (20-32 years, seven women) and 12 older adults (70-90 years, six women) in conditions mimicking quiescent muscle and a range of elevated H+ (pH 6.8-6.6-6.2) and Pi (12-20-30 mm). The older adult knee extensor muscles showed hallmark signs of ageing, including 19% lower thigh lean mass, 60% lower power and a greater fatigability compared to young adult muscles. Progressively increasing concentrations of H+ and Pi in the chemically-permeabilized fibre experiments caused a linear decrease in fibre force, velocity and power; however, the effects did not differ with age or sex. Fast fibre cross-sectional area was 41% smaller in older compared to young adults, which corresponded with lower absolute power. Size-specific power was greater in fibres from older compared to young adults, indicating the age-related decline in absolute power was explained by differences in fibre size. These data suggest the age-related loss in power is determined primarily by fast fibre atrophy in men and women, but the age-related increase in fatigability cannot be explained by an increased sensitivity of the cross-bridge to H+ and Pi. KEY POINTS: The causes of the age-related loss in muscle power output and the increase in fatigability during dynamic exercise remain elusive. We show that progressively increasing concentrations of hydrogen (H+) and inorganic phosphate (Pi) causes a linear decrease in muscle fibre force, velocity and power, but the depressive effects of these metabolites on cross-bridge function did not differ in fibres from older compared to young adults across a range of fatigue-mimicking conditions. We also found peak absolute power did not differ in slow fibres from young and older adults but it was ∼33% lower in older adult fast fibres, which was explained entirely by age differences in fibre size. These data suggest that fast fibre atrophy is a major factor contributing to the loss in power of older men and women, but that the age-related increase in fatigability cannot be explained by an increased sensitivity of the cross-bridge to H+ and Pi.

Keywords:  ageing; cross‐bridge cycle; inorganic phosphate; mechanical power; metabolites; muscle fatigue; pH; sarcopenia; shortening velocity

DOI:  https://doi.org/10.1113/JP286938
Adv Healthc Mater. 2024 Nov 10. e2403028

Neuromuscular Regeneration of Volumetric Muscle Loss Injury in Response to Agrin-Functionalized Tissue Engineered Muscle Grafts and Rehabilitative Exercise.

Eszter Mihaly, Neha Chellu, Shama R Iyer, Eileen Y Su, Dallas E Altamirano, Shaquielle T Dias, Warren L Grayson.

  Neuromuscular deficits compound the loss of contractile tissue in volumetric muscle loss (VML). Two avenues for promoting recovery are neuromuscular junction (NMJ)-promoting substrates (e.g., agrin) and endurance exercise. Although mechanical stimulation enhances agrin-induced NMJ formation, the two modalities have yet to be evaluated combinatorially. It is hypothesized that the implantation of human myogenic progenitor-seeded tissue-engineered muscle grafts (hTEMGs) in combination with agrin treatment and/or exercise will enhance neuromuscular recovery after VML. The hTEMGs alone transplant into VML defects promote significant regeneration with minimal scarring. A sex-appropriate, low-intensity continuous running exercise paradigm increases acetylcholine receptor (AChR) cluster density in male mice twofold relative to hTEMG alone after 7 weeks of treadmill training (p < 0.05). To further promote neuromuscular recovery, agrin is incorporated into the scaffolds via covalent tethering. In vitro, agrin increases the proliferation of hMPs, and trends toward greater myogenic maturity and AChR clustering. Upon transplantation, both hTEMGs + agrin and hTEMGs + exercise induce near 100% recovery of muscle mass and increase twitch and tetanic force output (p > 0.05). However, agrin treatment in combination with exercise produces no additional benefit. These data highlight the unprecedented regenerative potential of using hTEMGs together with either agrin or exercise supplementation to treat VML injuries.

Keywords:  agrin; human myogenic progenitors; neuromuscular regeneration; rehabilitative exercise; skeletal muscle; tissue regeneration; volumetric muscle loss

DOI:  https://doi.org/10.1002/adhm.202403028
Int J Mol Sci. 2024 Oct 23. pii: 11377. [Epub ahead of print]25(21):

Molecular, Histological, and Functional Changes in Acta1-MCM;FLExDUX4/+ Mice.

Solene Sohn, Sophie Reid, Maximilien Bowen, Emilio Corbex, Laura Le Gall, Eva Sidlauskaite, Christophe Hourde, Baptiste Morel, Virginie Mariot, Julie Dumonceaux.

  DUX4 is the major gene responsible for facioscapulohumeral dystrophy (FSHD). Several mouse models expressing DUX4 have been developed, the most commonly used by academic laboratories being ACTA1-MCM/FLExDUX4. In this study, molecular and histological modifications in the tibialis anterior and quadriceps muscles were investigated in this model at different time points. We investigated several changes that could be used as markers of therapeutic efficacy. Our results confirm the progressive muscular dystrophy previously described but also highlight biases associated with tamoxifen injections and the complexity of choosing the genes used to calculate a DUX4-pathway gene composite score. We also developed a comprehensive force test that better reflects the movements made in everyday life. This functional force-velocity-endurance model, which describes the force production capacities at all velocity and fatigue levels, was applied on 12-13-week-old animals without tamoxifen. Our data highlight that previously unsuspected muscle properties are also affected by the expression of DUX4, leading to a weaker muscle with a lower initial muscle force but with preserved power and endurance capacity. Importantly, this force-velocity-endurance approach can be used in humans for clinical evaluations.

Keywords:  DUX4; FSHD; biomarker; force test; mouse model; muscle; myopathy; strength

DOI:  https://doi.org/10.3390/ijms252111377
Int J Biol Macromol. 2024 Nov 13. pii: S0141-8130(24)08378-8. [Epub ahead of print] 137568

Fibin is a crucial mitochondrial regulatory gene in skeletal muscle development.

Xiaoyu Wang, Enru Li, Chenggan Li, Chong Zhang, Ziyun Liang, Rong Xu, Yihao Liu, Meilin Chen, Yongpeng Li, Hoika David Wu, Renqiang Yuan, Yanyun Xiong, Yaosheng Chen, Xiaohong Liu, Delin Mo.

  Fin bud initiation factor homolog (Fibin) is a secreted protein that is relatively conserved among species. It is closely related to fin bud development and can regulate a variety of cellular processes. In our previous high-throughput chromosome conformation capture (Hi-C) study of pig embryonic muscle development, it was found that Fibin has high expression and activity during the development of pig primary muscle fibers. Therefore, we speculated Fibin participated in myogenesis severely. Specific deletion of Fibin in mouse skeletal muscle resulted in abnormal primary muscle fiber development during the embryonic period and a substantial decrease in skeletal muscle mass in adulthood. In vitro, knocking out Fibin in C2C12 cells promoted cell proliferation; however, after myogenic induction, cells lacking Fibin had almost no ability to differentiate into myotubes. During myogenic differentiation, loss of Fibin disrupts the normal function of mitochondria and impairs oxidative phosphorylation, resulting in decrease of NADH and FADH in the electron transport chain. Transmission electron microscopy also showed that mitochondrial morphology of Fibin-deficient C2C12 was impaired. In conclusion, our research has unveiled a novel mechanism of myogenesis regulation in mitochondrial function and potential target Fibin, and improved understanding of a broad range of mitochondrial muscle diseases.

Keywords:  Fibin; Mitochondria; Myogenesis

DOI:  https://doi.org/10.1016/j.ijbiomac.2024.137568
Food Funct. 2024 Nov 08.

Selenium-mediated alleviation of skeletal muscle atrophy through enterotype modulation in mice.

Yixin Cheng, Xiaofan Liu, Yingao Hao, Shixu Wang, FangFang Wu, Lingzhuo Zhao, Du Peng, Du Yawen, Sun Sheng, Li Jianguo, Guangxu Ren.

Skeletal muscle is crucial for health, and glucocorticoid-induced atrophy poses a significant clinical challenge. This study utilized a dexamethasone (Dex)-induced mouse model to assess the impact of selenium supplementation on skeletal muscle atrophy during and after Dex treatment. Increasing evidence suggests the existence of a 'gut-muscle axis', where gut microbiota plays a regulatory role in muscle metabolism and function. We also examined changes in gut microbiota during selenium supplementation and applied the PAM (Partitioning Around Medoids, PAM) algorithm to identify key enterotypes influencing muscle health. Our findings show that selenium supplementation significantly mitigated Dex-induced muscle atrophy and hastened recovery post-treatment. Selenium intervention not only restructured the gut microbiota, enhancing diversity and promoting short-chain fatty acid producers, but also favored the Lactobacillus and Dubosiella enterotypes. These enterotypes are linked to improved amino acid and energy utilization, beneficial for muscle function. This study suggests that selenium may be a valuable nutritional supplement for combating Dex-induced skeletal muscle atrophy.

DOI: https://doi.org/10.1039/d4fo03889d
J Muscle Res Cell Motil. 2024 Nov 07.

Unraveling the bidirectional relationship between muscle inflammation and satellite cells activity: influencing factors and insights.

Esmail Karami, Behzad Bazgir, Hossein Shirvani, Mohammad Taghi Mohammadi, Mansoor Khaledi.

  Inflammation stands as a vital and innate function of the immune system, essential for maintaining physiological homeostasis. Its role in skeletal muscle regeneration is pivotal, with the activation of satellite cells (SCs) driving the repair and generation of new myofibers. However, the relationship between inflammation and SCs is intricate, influenced by various factors. Muscle injury and repair prompt significant infiltration of immune cells, particularly macrophages, into the muscle tissue. The interplay of cytokines and chemokines from diverse cell types, including immune cells, fibroadipogenic progenitors, and SCs, further shapes the inflammation-SCs dynamic. While some studies suggest heightened inflammation associates with reduced SC activity and increased fibro- or adipogenesis, others indicate an inflammatory stimulus benefits SC function. Yet, the existing literature struggles to delineate clearly between the stimulatory and inhibitory effects of inflammation on SCs and muscle regeneration. This paper comprehensively reviews studies exploring the impact of pharmacological agents, dietary interventions, genetic factors, and exercise regimes on the interplay between inflammation and SC activity.

Keywords:  Inflammation; Satellite cells; Skeletal muscle

DOI:  https://doi.org/10.1007/s10974-024-09683-7
Exp Mol Med. 2024 Nov 07.

The muscle-intervertebral disc interaction mediated by L-BAIBA modulates extracellular matrix homeostasis and PANoptosis in nucleus pulposus cells.

Tianyu Qin, Ming Shi, Chao Zhang, Jiajun Wu, Zhengqi Huang, Xiaohe Zhang, Shuangxing Li, Yuliang Wu, Weitao Han, Bo Gao, Kang Xu, Song Jin, Wei Ye.

Upon engaging in physical activity, skeletal muscle synthesizes myokines, which not only facilitate crosstalk with various organs, including the brain, adipose tissue, bone, liver, gut, pancreas, and skin but also promote intramuscular signaling. Crosstalk is vital for maintaining various physiological processes. However, the specific interactions between skeletal muscle and intervertebral discs remain largely unexplored. β-Aminoisobutyric acid (BAIBA), an exercise-induced myokine and a metabolite of branched-chain amino acids in skeletal muscle, has emerged as a key player in this context. Our study demonstrated that exercise significantly elevates BAIBA levels in skeletal muscle, plasma, and nucleus pulposus (NP) tissues. Moreover, exercise enhances extracellular matrix (ECM) synthesis in NP tissues and upregulates L-BAIBA synthase in skeletal muscle. Both in vivo and in vitro evidence revealed that L-BAIBA impedes PANoptosis and ECM degradation in NP cells by activating the AMPK/NF-κB signaling pathway. These findings suggest that exercise, coupled with the resulting increase in L-BAIBA, may serve as an effective intervention to decelerate the progression of intervertebral disc degeneration (IDD). Consequently, L-BAIBA, which originates from skeletal muscle, is a promising new therapeutic approach for IDD.

DOI: https://doi.org/10.1038/s12276-024-01345-5
Int J Mol Sci. 2024 Nov 04. pii: 11829. [Epub ahead of print]25(21):

Nrf2 Deficiency Exacerbates the Decline in Swallowing and Respiratory Muscle Mass and Function in Mice with Aspiration Pneumonia.

Hikaru Hashimoto, Tatsuma Okazaki, Yohei Honkura, Yuzhuo Ren, Peerada Ngamsnae, Takuma Hisaoka, Yasutoshi Koshiba, Jun Suzuki, Satoru Ebihara, Yukio Katori.

  Aspiration pneumonia exacerbates swallowing and respiratory muscle atrophy. It induces respiratory muscle atrophy through three steps: proinflammatory cytokine production, caspase-3 and calpain, and then ubiquitin-proteasome activations. In addition, autophagy induces swallowing muscle atrophy. Nrf2 is the central detoxifying and antioxidant gene whose function in aspiration pneumonia is unclear. We explored the role of Nrf2 in aspiration pneumonia by examining swallowing and respiratory muscle mass and function using wild-type and Nrf2-knockout mice. Pepsin and lipopolysaccharide aspiration challenges caused aspiration pneumonia. The swallowing (digastric muscles) and respiratory (diaphragm) muscles were isolated. Quantitative RT-PCR and Western blotting were used to assess their proteolysis cascade. Pathological and videofluoroscopic examinations evaluated atrophy and swallowing function, respectively. Nrf2-knockouts showed exacerbated aspiration pneumonia compared with wild-types. Nrf2-knockouts exhibited more persistent and intense proinflammatory cytokine elevation than wild-types. In both mice, the challenge activated calpains and caspase-3 in the diaphragm but not in the digastric muscles. The digastric muscles showed extended autophagy activation in Nrf2-knockouts compared to wild-types. The diaphragms exhibited autophagy activation only in Nrf2-knockouts. Nrf2-knockouts showed worsened muscle atrophies and swallowing function compared with wild-types. Thus, activation of Nrf2 may alleviate inflammation, muscle atrophy, and function in aspiration pneumonia, a major health problem for the aging population, and may become a therapeutic target.

Keywords:  Nrf2; aspiration pneumonia; muscle atrophy; respiratory muscles; swallowing muscles

DOI:  https://doi.org/10.3390/ijms252111829
J Physiol. 2024 Nov 08.

Cycling away from cancer: can aerobic training enhance interleukin-15 response to acute exercise?

Stine Bitsch-Olsen, Max Flemming Ravn Merkel, Maria Lisette Ravn Merkel.



Keywords:  IL‐15; acute exercise; aerobic training; interleukin‐15; myokines; survivors of cancer

DOI:  https://doi.org/10.1113/JP287749
J Biol Chem. 2024 Nov 12. pii: S0021-9258(24)02489-X. [Epub ahead of print] 107987

The circular RNA circNFIX regulates MEF2C expression in muscle satellite cells in spastic cerebral palsy.

Brigette Romero, Parsa Hoque, Karyn G Robinson, Stephanie K Lee, Tanvi Sinha, Amaresh Panda, Michael W Shrader, Vijay Parashar, Robert E Akins, Mona Batish.

  Cerebral palsy (CP) is a pediatric onset disorder with poorly understood molecular causes and progression, making early diagnosis difficult. Circular RNAs (circRNAs) are regulatory RNAs that show promise as biomarkers in various diseases but the role of circRNAs in CP is beginning to be understood. This study identified the role of circNFIX in regulating the expression of MEF2C, an important transcription factor for sarcomere development. We found that circNFIX is downregulated in the muscle cells of individuals with CP, and its localization shifts towards the nucleus as visualized using single molecule resolution imaging. The decreased expression of circNFIX, MEF2C, and MEF2C targets persisted throughout myoblasts to myotubes differentiation, and in the skeletal muscle tissue. Bioinformatic and experimental validation confirmed that circNFIX acts as a sponge for miR373-3p, a microRNA that represses MEF2C translation. In normal muscle, circNFIX de-represses MEF2C translation by sponging miR373-3p, allowing for normal sarcomere generation. In CP, reduced circNFIX expression results in loss of miRNA sponging, leading to lower MEF2C expression and downregulation of sarcomere genes, potentially causing shortened and dysfunctional muscle fibers. Knockdown of circNFIX (KD) reduced myogenic capacity of myoblasts to fuse and form myotubes similar to CP cells evident from the lower fusion index in CP and KD as compared to control myotubes. This the first study reporting reduction of MEF2C in CP and single molecule resolution imaging of circNFIX's subcellular distribution and its role in CP, suggesting circNFIX as a potential therapeutic target and biomarker for early CP diagnosis.

Keywords:  Biomarker; Cerebral palsy; CircFISH; MEF2C; Satellite cells; circNFIX; circular RNA; miR-373-3p; miRNA sponging; regulatory non-coding RNAs. Spastic Cerebral Palsy

DOI:  https://doi.org/10.1016/j.jbc.2024.107987
Int J Mol Sci. 2024 Oct 23. pii: 11379. [Epub ahead of print]25(21):

The Influence of Physical Training on Breast Cancer: The Role of Exercise-Induced Myokines in Regulating Breast Cancer Cell Growth and Survival.

Anirudh Natarajan, Rashmita Pradhan, Walburga Dieterich, Raphaela Schwappacher, Dejan Reljic, Hans J Herrmann, Markus F Neurath, Carolin C Hack, Matthias W Beckmann, Yurdagül Zopf.

  The beneficial impact of physical training in lowering cancer risk is well known. However, the precise mechanisms linking physical training and cancer are not fully understood. Skeletal muscle releases various myokines that seem to possess a direct anti-tumor effect. Although breast cancer (BC) is the prevalent form of cancer among women on a global scale, only limited data are available about the secretion of myokines following exercise in patients with BC. To study the effects of exercise on BC, the blood samples of patients with varied stages of BC were analyzed after 12 weeks of resistance training with whole-body electromyostimulation (WB-EMS). Following the training period, we observed that resistance training helps these patients to improve their physical characteristics and performance function by increasing skeletal muscle mass and strengthening their hand grip. Notably, the patient's serum was found to inhibit the growth and promote the apoptosis of BC cells in vitro. Moreover, the conditioned medium collected from in vitro stimulated human myotubes using electric pulse stimulation (EPS), an in vitro simulation of WB-EMS training, induced the cell death of BC cells. These results highlighted the direct cancer-protective effects of activated skeletal muscle. In line with our observed effects of serum from exercise-trained pancreatic and prostate cancer patients, the growth of BC cells was notably inhibited when supplemented directly with recombinant myokines C-X-C motif ligand 1 (CXCL1), Interleukin 10 (IL10), and C-C motif chemokine ligand 4 (CCL4). Notably, treatment with these myokines also increased the expression of caspase 3/7 (Casp3/7), resulting in enhanced BC cell death. Our data strongly suggest that physical exercise has a positive impact on skeletal muscle mass and hand grip strength in BC patients, along with a significant anti-tumor effect in BC cells. This shows promising potential for considering sports and physical training as supportive therapies for achieving more impactful cancer treatment.

Keywords:  apoptosis; breast cancer; electric pulse stimulation; myokines; proliferation; resistance training; whole-body electromyostimulation

DOI:  https://doi.org/10.3390/ijms252111379
J Gen Physiol. 2024 Dec 02. pii: e202313485. [Epub ahead of print]156(12):

Exercise training may reduce fragmented mitochondria in the ischemic-reperfused heart through DRP1.

Mathilde Dubois, Florian Pallot, Maxime Gouin-Gravezat, Doria Boulghobra, Florence Coste, Guillaume Walther, Gregory Meyer, Isabelle Bornard, Cyril Reboul.

Mitochondrial fission is a key trigger of cardiac ischemia-reperfusion injuries (IR). Exercise training is an efficient cardioprotective strategy, but its impact on mitochondrial fragmentation during IR remains unknown. Using isolated rat hearts, we found that exercise training limited the activation of dynamin-like protein 1 and limited mitochondrial fragmentation during IR. These results support the hypothesis that exercise training contributes to cardioprotection through its capacity to modulate the mitochondrial fragmentation during IR.

DOI: https://doi.org/10.1085/jgp.202313485