bims-moremu 2025-02-02 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2025–02–02
thirty-one papers selected by
Anna Vainshtein, Craft Science Inc.

Markers of mitochondrial function and oxidative metabolism in female skeletal muscle do not display intrinsic circadian regulation.
Fibroblast growth factor-inducible 14 regulates satellite cell self-renewal and expansion during skeletal muscle repair.
Achieving myoblast engraftment into intact skeletal muscle via extracellular matrix.
Epigenetic modification increases skeletal muscle resilience to metabolic stress.
Sugt1 loss in skeletal muscle stem cells impairs muscle regeneration and causes premature muscle aging.
Defective Cystic Fibrosis Transmembrane Conductance Regulator Accelerates Skeletal Muscle Aging by Impairing Autophagy/Myogenesis.
Temporal dynamics of the interstitial fluid proteome in human skeletal muscle following exhaustive exercise.
PrPC Glycoprotein Is Indispensable for Maintenance of Skeletal Muscle Homeostasis During Aging.
Tissue-resident skeletal muscle macrophages promote recovery from viral pneumonia-induced sarcopenia in normal aging.
Effects of endurance training under calorie restriction on energy substrate metabolism in mouse skeletal muscle and liver.
Transcriptomic Profiling Reveals 17β-Estradiol Treatment Represses Ubiquitin-Proteasomal Mediators in Skeletal Muscle of Ovariectomized Mice.
Limiting cap-dependent translation increases 20S proteasomal degradation and protects the proteomic integrity in autophagy-deficient skeletal muscle.
Upregulation of FAM129B protects against glucocorticoid-induced skeletal muscle atrophy via regulating long non-coding RNA NEAT1.
Norharmane prevents muscle aging via activation of SKN-1/NRF2 stress response pathways.
Responses of skeletal muscle to mechanical stimuli in female rats following and during muscle disuse atrophy.
Intramuscular inhibition of glycogen phosphorylase improves motor function in spinal cord injury.
Integrated Proteomic and Metabolomic Analysis of Muscle Atrophy Induced by Hindlimb Unloading.
MuSK regulates neuromuscular junction Nav1.4 localization and excitability.
Developing a ceRNA-based lncRNA-miRNA-mRNA regulatory network to uncover roles in skeletal muscle development.
Troponins and Skeletal Muscle Pathologies.
The ubiquitin-conjugating enzyme UBE2D maintains a youthful proteome and ensures protein quality control during aging by sustaining proteasome activity.
Label-free proteomic analysis of Duchenne and Becker muscular dystrophy showed decreased sarcomere proteins and increased ubiquitination-related proteins.
Changes to the Autophagy-Related Muscle Proteome Following Short-Term Treatment with Ectoine in the Duchenne Muscular Dystrophy Mouse Model mdx.
Characterization of SARS-CoV-2 Entry Genes in Skeletal Muscle and Impacts of In Vitro Versus In Vivo Infection.
CCL5 Induces a Sarcopenic-like Phenotype via the CCR5 Receptor.
ProBDNF as a Myokine in Skeletal Muscle Injury: Role in Inflammation and Potential for Therapeutic Modulation of p75NTR.
The juxtamembrane sequence of small ankyrin 1 mediates the binding of its cytoplasmic domain to SERCA1 and is required for inhibitory activity.
Deubiquitinating enzyme USP2 alleviates muscle atrophy by stabilizing PPARγ.
Evidence that engineered muscle could patch up failing hearts.
Kdm2a inhibition in skeletal muscle improves metabolic flexibility in obesity.
Muscle-derived small extracellular vesicles induce liver fibrosis during overtraining.

bioRxiv. 2025 Jan 13. pii: 2025.01.08.631231. [Epub ahead of print]

Markers of mitochondrial function and oxidative metabolism in female skeletal muscle do not display intrinsic circadian regulation.

Liam S Fitzgerald, Connor S Reynoso Spurrier, Nathan J Lau, Miles D Melamed, Lindsey A Burnett, Gretchen A Meyer, Chang Gui, Andrea L Hevener, James A Sanford, Simon Schenk.

Mitochondria are key regulators of metabolism and ATP supply in skeletal muscle, while circadian rhythms influence many physiological processes. However, whether mitochondrial function is intrinsically regulated in a circadian manner in mouse skeletal muscle is inadequately understood. Accordingly, we measured post-absorptive transcript abundance of markers of mitochondrial biogenesis, dynamics, and metabolism (extensor digitorum longus [EDL], soleus, gastrocnemius), protein abundance of electron transport chain complexes (EDL and soleus), enzymatic activity of SDH (tibialis anterior and plantaris), and maximum uncoupled respiration (tibialis anterior) in different skeletal muscles from female C57BL/6NJ mice at four zeitgeber times (ZT), ZT 1, 7, 13, and 19. Our findings demonstrate that markers of mitochondrial function and oxidative metabolism do not display intrinsic time-of-day regulation at the gene, protein, enzymatic, or functional level. The core-clock genes Bmal1 and Dbp exhibited intrinsic circadian rhythmicity in skeletal muscle (i.e., EDL, soleus, gastrocnemius) and circadian amplitude varied by muscle type. These findings demonstrate that female mouse skeletal muscle does not display circadian regulation of markers of mitochondrial function or oxidative metabolism over 24 hours.

DOI: https://doi.org/10.1101/2025.01.08.631231
JCI Insight. 2025 Jan 28. pii: e187825. [Epub ahead of print]

Fibroblast growth factor-inducible 14 regulates satellite cell self-renewal and expansion during skeletal muscle repair.

Meiricris Tomaz da Silva, Aniket S Joshi, Ashok Kumar.

  Skeletal muscle regeneration in adults is predominantly driven by satellite cells. Loss of satellite cell pool and function leads to skeletal muscle wasting in many conditions and disease states. Here, we demonstrate that the levels of fibroblast growth factor-inducible 14 (Fn14) were increased in satellite cells after muscle injury. Conditional ablation of Fn14 in Pax7-expressing satellite cells drastically reduced their expansion and skeletal muscle regeneration following injury. Fn14 was required for satellite cell self-renewal and proliferation as well as to prevent precocious differentiation. Targeted deletion of Fn14 inhibited Notch signaling but led to the spurious activation of STAT3 signaling in regenerating skeletal muscle and in cultured muscle progenitor cells. Silencing of STAT3 improved proliferation and inhibited premature differentiation of Fn14-deficient satellite cells. Furthermore, conditional ablation of Fn14 in satellite cells exacerbated myopathy in the mdx mouse model of Duchenne muscular dystrophy (DMD) whereas its overexpression improved the engraftment of exogenous muscle progenitor cells into the dystrophic muscle of mdx mice. Altogether, our study highlights the crucial role of Fn14 in the regulation of satellite cell fate and function and suggests that Fn14 can be a potential molecular target to improve muscle regeneration in muscular disorders.

Keywords:  Cell biology; Muscle biology; Neuromuscular disease; Signal transduction; Skeletal muscle; Stem cells

DOI:  https://doi.org/10.1172/jci.insight.187825
Front Cell Dev Biol. 2024 ;12 1502332

Achieving myoblast engraftment into intact skeletal muscle via extracellular matrix.

Kitora Dohi, Yasuko Manabe, Nobuharu L Fujii, Yasuro Furuichi.

  Cell therapy of skeletal muscles is a promising approach for the prevention of muscular diseases and age-related muscle atrophy. However, cell transplantation to treat muscle atrophy that does not involve disease, such as sarcopenia, is considered impossible because externally injected cells rarely engraft into non-injured muscle tissue. Additionally, skeletal muscle-specific somatic stem cells, called satellite cells, lose their ability to adhere to tissue after being cultured in vitro and transforming into myoblasts. To overcome these hurdles, we explored using extracellular matrix (ECM) components to create a niche environment conducive for myoblasts during transplantation. We demonstrated that myoblasts mixed with ECM components can be engrafted into intact skeletal muscle and significantly increase muscle mass in a mouse model. These findings implicate cell transplantation therapy as a viable option for the treatment of sarcopenia. The findings will inform advancements in regenerative medicine for skeletal muscles.

Keywords:  cell transplantation; extracellular matrix; muscle stem cell; myoblast; skeletal muscle

DOI:  https://doi.org/10.3389/fcell.2024.1502332
Nat Metab. 2025 Jan 27.

Epigenetic modification increases skeletal muscle resilience to metabolic stress.

DOI: https://doi.org/10.1038/s42255-024-01211-8
Life Med. 2023 Aug;2(4): lnad039

Sugt1 loss in skeletal muscle stem cells impairs muscle regeneration and causes premature muscle aging.

Zhiming He, Xiaona Chen, Gexin Liu, Yuying Li, Feng Yang, Hao Sun, Huating Wang.

  Adult skeletal muscle stem cells (MuSCs) are essential for muscle homeostasis and regeneration. During aging, the number of MuSCs and their regenerative capacity gradually decline but the underlying mechanisms remain elusive. Here, we identify Sugt1 (suppressor of G2 allele of SKP1 homolog), which is a chaperone for kinetochore function during mitosis and is essential for muscle regeneration by regulating MuSC proliferation. Sugt1 expression level is low in quiescent MuSCs but highly induced when the cells become activated and expand as proliferating myoblasts. Inducible inactivation of Sugt1 in MuSCs causes impaired muscle regeneration upon acute injury by impairing MuSC proliferation. Furthermore, loss of Sugt1 leads to cell cycle arrest in the G2/M phase and cellular senescence. Moreover, long-term loss of Sugt1 in MuSCs results in precocious muscle aging by inhibiting MuSC cell proliferation and promoting cellular senescence. Mechanistically, we identify a cytosolic E3 ubiquitin-ligase, Trim21 as a protein interacting partner for Sugt1 in myoblast cells. We further demonstrate that Sugt1 promotes the ubiquitination of p21 via Trim21; and Sugt1 loss causes p21 accumulation to inhibit cell cycle progression and stimulates cellular senescence. Collectively, our findings uncover that Sugt1 is an essential regulator for MuSC regenerative function during muscle regeneration and aging.

Keywords:  Sugt1; Trim21; aging; cellular senescence; muscle stem cell

DOI:  https://doi.org/10.1093/lifemedi/lnad039
J Cachexia Sarcopenia Muscle. 2025 Feb;16(1): e13708

Defective Cystic Fibrosis Transmembrane Conductance Regulator Accelerates Skeletal Muscle Aging by Impairing Autophagy/Myogenesis.

Ziyi Chen, Jiankun Xu, Peijie Hu, Wanting Du, Junjiang Chen, Xiaotian Zhang, Wei Zhou, Jiayang Gao, Yuantao Zhang, Bingyang Dai, Guangshuai Nie, Jun Hu, Liangbin Zhou, Shunxiang Xu, Hisao Chang Chan, Wing-Hoi Cheung, Ye Chun Ruan, Ling Qin.

   BACKGROUND: Regenerative capacity of skeletal muscles decreases with age. Deficiency in cystic fibrosis transmembrane conductance regulator (CFTR) is associated with skeletal muscle weakness as well as epithelial cell senescence. However, whether and how CFTR plays a role in skeletal muscle regeneration and aging were unclear.
METHODS: Vastus lateralis biopsy samples from male and female human subjects (n = 23) of 7- to 86-year-old and gastrocnemii tissues from mice of 4- to 29-month-old were examined for CFTR expression. Skeletal muscle tissues or cultured myoblasts from mice carrying CFTR mutation (DF508) at 4- to 18-month-old were used for assessment of muscle mass, contractile force and regenerative capacity as well as myogenic and autophagy signalling. Overexpression of LC3-β, an autophagy mediator, was conducted to reverse myogenic defects in DF508 myoblasts. Adenoviruses containing CFTR gene or pharmaceuticals that enhance CFTR (VX809) were locally injected into the gastrocnemius or femoris quadricep to rescue age-related skeletal muscle defects in mice.
RESULTS: mRNA levels of CFTR in human vastus lateralis exhibited significantly negative correlations with age (r = -0.87 in males and -0.62 in females, p < 0.05). Gastrocnemius mRNA level of CFTR decreased by 77.7 ± 4.6% in 29-month-old wild-type mice compared to the 4-month-old. At 18-month-old, DF508 mice showed significantly reduced lean mass (by 35.6%), lower specific twitch force of the gastrocnemius (by 46.2%), decrease in fast/slow-twitch muscle isoform ratio as well as downregulation of myogenic (e.g., MYOD and MYOG) or autophagy/mitophagy (e.g., LC3-β) genes, compared to age-matched wild-types. Post-injury gastrocnemius regeneration was found impaired in DF508 mice. Myoblast cultures from DF508 mice showed defective myogenic differentiation, which was reversed by overexpressing LC3-β. In aged (> 15-month-old) mice, overexpressing CFTR or VX809 restored the expression of autophagy or myogenic genes, increased mitochondrial LC3-β level and improved skeletal muscle mass and function.
CONCLUSION: Age-related reduction in skeletal muscle expression of CFTR impairs autophagy and myogenesis, exacerbating skeletal muscle aging. Enhancing CFTR might be a potential treatment strategy for age-related skeletal muscle disorders.

Keywords:  CFTR; CFTR‐modulator; autophagy; mitochondria; myogenesis; skeletal muscle

DOI:  https://doi.org/10.1002/jcsm.13708
Sci Adv. 2025 Jan 31. 11(5): eadp8608

Temporal dynamics of the interstitial fluid proteome in human skeletal muscle following exhaustive exercise.

Ben Stocks, Julia Prats Quesada, Anthony M Mozzicato, Carolina Jacob, Simone Jensen, Kirstin A MacGregor, Jens Bangsbo, Juleen R Zierath, Morten Hostrup, Atul S Deshmukh.

The skeletal muscle interstitial space is the extracellular region around myofibers and mediates cross-talk between resident cell types. We applied a proteomic workflow to characterize the human skeletal muscle interstitial fluid proteome at rest and in response to exercise. Following exhaustive exercise, markers of skeletal muscle damage accumulate in the interstitial space followed by the appearance of immune cell-derived proteins. Among the proteins up-regulated after exercise, we identified cathelicidin-related antimicrobial peptide (CAMP) as a bioactive molecule regulating muscle fiber development. Treatment with the bioactive peptide derivative of CAMP (LL-37) resulted in the growth of larger C2C12 skeletal muscle myotubes. Phosphoproteomics revealed that LL-37 activated pathways central to muscle growth and proliferation, including phosphatidylinositol 3-kinase, AKT serine/threonine kinase 1, mitogen-activated protein kinases, and mammalian target of rapamycin. Our findings provide a proof of concept that the interstitial fluid proteome is quantifiable via microdialysis sampling in vivo. These data highlight the importance of cellular communication in the adaptive response to exercise.

DOI: https://doi.org/10.1126/sciadv.adp8608
J Cachexia Sarcopenia Muscle. 2025 Feb;16(1): e13706

PrPC Glycoprotein Is Indispensable for Maintenance of Skeletal Muscle Homeostasis During Aging.

Wenduo Liu, Thi Thu Trang Kieu, Zilin Wang, Hyun-Jaung Sim, Seohyeong Lee, Jeong-Chae Lee, Yoonjung Park, Sang Hyun Kim, Sung-Ho Kook.

   BACKGROUND: The cellular prion protein (PrPC), a glycoprotein encoded by the PRNP gene, is known to modulate muscle mass and exercise capacity. However, the role of PrPC in the maintenance and regeneration of skeletal muscle during ageing remains unclear.
METHODS: This study investigated the change in PrPC expression during muscle formation using C2C12 cells and evaluated muscle function in Prnp wild-type (WT) and knock-out (KO) mice at different ages (1, 9 and 15 months). To determine the role of PrPC in skeletal muscle homeostasis during ageing, we conducted regeneration experiments via cardiotoxin injection in Prnp mice to assess the effects of PrPC deficiency on the senescence of satellite stem cells (SCs) and regenerative capacity in skeletal muscle.
RESULTS: Our data demonstrate that PrPC expression increased significantly during muscle differentiation (p < 0.01), correlating with myogenin (immunofluorescence at the differentiation stage). PrPC deficiency disrupted muscle homeostasis, leading to age-associated mitochondrial autophagy (Pink-1, +180%, p < 0.001; Parkin, +161%, p < 0.01) and endoplasmic reticulum stress (SERCA, -26%, p < 0.05; IRE1α, +195%, p < 0.001) while decreasing the level of mitochondrial biogenesis (SIRT-1, -50%, p < 0.01; PGC-1α, -36%, p < 0.05; VDAC, -27%, p < 0.001), and activated oxidative stress (serum myoglobin, +23%, p < 0.001; MDA, +23%, p < 0.05; NFκB, +117%, p < 0.05) during ageing, which accelerated reduced muscle growth or mass accumulation (tibialis anterior muscle mass, -23%, p < 0.001; gastrocnemius muscle mass, -30%, p < 0.001; muscle fibre size, -48%, p < 0.05; MSTN, +160%, p < 0.01; MAFbx, +83%, p < 0.05). Furthermore, PrPC deficiency induced the senescence (β-galactosidase, +60%, p < 0.05; p16, +103%, p < 0.001) of SCs, which was directly related to the defect in muscle recovery, with the senescence-mediated enhancement of adipogenesis (PPARγ, +74%, p < 0.05) during the regeneration process after cardiotoxin-induced muscle injury.
CONCLUSIONS: Our findings demonstrate that PrPC is indispensable for maintaining skeletal muscle homeostasis during ageing by modulating the functional integrity of mitochondria, ER and SCs.

Keywords:  ER stress; PrPC; mitochondria damage; satellite stem cell senescence; skeletal muscle homeostasis

DOI:  https://doi.org/10.1002/jcsm.13706
bioRxiv. 2025 Jan 14. pii: 2025.01.09.631996. [Epub ahead of print]

Tissue-resident skeletal muscle macrophages promote recovery from viral pneumonia-induced sarcopenia in normal aging.

Constance E Runyan, Lucy Luo, Lynn C Welch, Ziyan Lu, Fei Chen, Maxwell J Schleck, Radmila A Nafikova, Rogan A Grant, Raul Piseaux Aillon, Karolina J Senkow, Elsie G Bunyan, William T Plodzeen, Hiam Abdala-Valencia, Craig Weiss, Laura A Dada, Edward B Thorp, Jacob I Sznajder, Navdeep S Chandel, Alexander V Misharin, G R Scott Budinger.

Sarcopenia, which diminishes lifespan and healthspan in the elderly, is commonly exacerbated by viral pneumonia, including influenza and COVID-19. In a study of influenza A pneumonia in mice, young mice fully recovered from sarcopenia, while older mice did not. We identified a population of tissue-resident skeletal muscle macrophages that form a spatial niche with satellite cells and myofibers in young mice but are lost with age. Mice with a gain-of-function mutation in the Mertk receptor maintained this macrophage-myofiber interaction during aging and fully recovered from influenza-induced sarcopenia. In contrast, deletion of Mertk in macrophages or loss of Cx3cr1 disrupted this niche, preventing muscle regeneration. Heterochronic parabiosis did not restore the niche in old mice. These findings suggest that age-related loss of Mertk in muscle tissue-resident macrophages disrupts the cellular signaling necessary for muscle regeneration after viral pneumonia, offering a potential target to mitigate sarcopenia in aging.

DOI: https://doi.org/10.1101/2025.01.09.631996
J Physiol Sci. 2024 ;pii: S1880-6546(24)00116-1. [Epub ahead of print]74(1): 32

Effects of endurance training under calorie restriction on energy substrate metabolism in mouse skeletal muscle and liver.

Kenya Takahashi, Yu Kitaoka, Hideo Hatta.

  We investigated whether calorie restriction (CR) enhances metabolic adaptations to endurance training (ET). Ten-week-old male Institute of Cancer Research (ICR) mice were fed ad libitum or subjected to 30% CR. The mice were subdivided into sedentary and ET groups. The ET group performed treadmill running (20-25 m/min, 30 min, 5 days/week) for 5 weeks. We found that CR decreased glycolytic enzyme activity and monocarboxylate transporter (MCT) 4 protein content, while enhancing glucose transporter 4 protein content in the plantaris and soleus muscles. Although ET and CR individually increased citrate synthase activity in the plantaris muscle, the ET-induced increase in respiratory chain complex I protein content was counteracted by CR. In the soleus muscle, mitochondrial enzyme activity and protein levels were increased by ET, but decreased by CR. It has been suggested that CR partially interferes with skeletal muscle adaptation to ET.

Keywords:  Calorie restriction; Endurance training; Enzyme; Gluconeogenesis; Liver; Mitochondria; Skeletal muscle; Transporter

DOI:  https://doi.org/10.1186/s12576-024-00924-5
J Cachexia Sarcopenia Muscle. 2025 Feb;16(1): e13698

Transcriptomic Profiling Reveals 17β-Estradiol Treatment Represses Ubiquitin-Proteasomal Mediators in Skeletal Muscle of Ovariectomized Mice.

Georgios Kararigas, Mara C Ebeling, Gengyun Le, Shaojuan Lai, Chunmei Cui, Qinghua Cui, Dawn A Lowe.

   BACKGROUND: With a decline of 17β-estradiol (E2) at menopause, E2 has been implicated in the accompanied loss of skeletal muscle mass and strength. We aimed at characterizing transcriptomic responses of skeletal muscle to E2 in female mice, testing the hypothesis that genes and pathways related to contraction and maintenance of mass are differentially expressed in ovariectomized mice with and without E2 treatment.
METHODS: Soleus and tibialis anterior (TA) muscles from C57BL/6 ovariectomized mice treated with placebo (OVX) or E2 (OVX + E2) for 60 days, or from skeletal muscle-specific ERα knockout (skmERαKO) mice and wild-type littermates (skmERαWT), were used for genome-wide expression profiling, quantitative real-time PCR and immunoblotting. Computational detection of estrogen response elements (EREs) was performed with EREFINDER.
RESULTS: We found 155 significantly regulated probe sets in response to E2 (p ≤ 0.001). Pathway analyses identified proteasome and ubiquitin-mediated proteolysis as two downregulated pathways in the E2 group. We confirmed downregulation (p ≤ 0.05) in levels of Fbxw7, Psmb6, Ube2h and Ubxn1, as well as pro-apoptotic Bnip3 and inflammatory factor Nfkbia. Computational analysis identified ERE in the promoter regions of Psmb6, Ube2h, Bnip3 and Nfkbia. The overall content of ubiquitinated proteins was modestly but significantly lower in TA muscles from OVX + E2 vs. OVX mice (p = 0.039). There were no differences between skmERαKO and skmERαWT mice or between skmERαKO/OVX and skmERαKO/OVX + E2 mice for any genes assessed, indicating that ERα is required for E2 regulation of those genes.
CONCLUSIONS: These results suggest that a mechanism whereby E2 protects against losses of skeletal muscle mass and strength is regulation of ubiquitin-proteasomal mediators.

Keywords:  aging; estrogen; estrogen receptor α; estrogen response element

DOI:  https://doi.org/10.1002/jcsm.13698
Autophagy. 2025 Jan 29.

Limiting cap-dependent translation increases 20S proteasomal degradation and protects the proteomic integrity in autophagy-deficient skeletal muscle.

Han Dong, Yifan Lyu, Chien-Yung Huang, Shih-Yin Tsai.

  Postmitotic skeletal muscle critically depends on tightly regulated protein degradation to maintain proteomic stability. Impaired macroautophagy/autophagy-lysosomal or ubiquitin-proteasomal protein degradation causes the accumulation of damaged proteins, ultimately accelerating muscle dysfunction with age. While in vitro studies have demonstrated the complementary nature of these systems, their interplay at the organism levels remains poorly understood. Here, our study reveals novel insights into this complex relationship in autophagy-deficient skeletal muscle. We demonstrated that despite a compensatory increase in proteasome level in response to autophagy impairment, 26S proteasome activity was not proportionally enhanced in autophagy-deficient skeletal muscle. This functional deficit was partly attributed to reduced ATP levels to fuel the 26S proteasome. Remarkably, we found that activation of EIF4EBP1, a crucial inhibitor of cap-dependent translation, restored and even augmented proteasomal function through dual mechanisms. First, genetically activating EIF4EBP1 enhanced both ATP-dependent 26S proteasome and ATP-independent 20S proteasome activities, thereby expanding overall protein degradation capacity. Second, EIF4EBP1 activation caused muscle fiber transformation and increased mitochondrial biogenesis, thus replenishing ATP levels for 26S proteasome activation. Notably, the improved performance of the 20S proteasome in EIF4EBP1-activated skeletal muscle was attributed to an increased abundance of the immunoproteasome, a subtype specially adapted to function under oxidative stress conditions. This dual action of EIF4EBP1 activation preserved proteomic integrity in autophagy-deficient skeletal muscle. Our findings uncover a novel role of EIF4EBP1 in improving protein quality control, presenting a promising therapeutic strategy for autophagy-related muscular disorders and potentially other conditions characterized by proteostatic imbalance.

Keywords:  Autophagy; immunoproteasome; proteasome; protein quality control; skeletal muscle; translation

DOI:  https://doi.org/10.1080/15548627.2025.2457925
Int J Biol Macromol. 2025 Jan 22. pii: S0141-8130(25)00669-5. [Epub ahead of print] 140120

Upregulation of FAM129B protects against glucocorticoid-induced skeletal muscle atrophy via regulating long non-coding RNA NEAT1.

Yan Wang, Yushen Lu, Jinhui Hou, Yuyang Wang, Lihuan Luo, Zuneng Lu, Yuanlong Xie, Lin Cai, Zheman Xiao.

  Skeletal muscle atrophy, manifested by a reduction in muscle size and quantity, is primarily attributed to excessive protein catabolism. FAM129B, an antioxidant protein, has been previously implicated in muscle growth and development in cattle. Aim of this study is to elucidate the role of FAM129B in muscle atrophy. FAM129B was consistently down-regulation in muscle atrophy models in vitro and in vivo and in human steroid-treated gluteus muscles. FAM129B depletion resulted in myotubes atrophy with reduced diameter, increased MuRF-1 and Atrogin-1. Conversely, FAM129B overexpression ameliorated muscle atrophy by increasing myotube diameter and reducing Atrogin-1 and MuRF-1. Mice overexpressing FAM129B exhibited resistance to muscle atrophy, evidenced by increased grip strength, increased tibial anterior weight, increased myofiber cross-sectional area and decreased MuRF-1 and Atrogin-1. RNA sequencing revealed NEAT1 as a downstream gene of FAM129B. Mechanistically, FAM129B was found to influence the stability of NEAT1 by directly binding to it. The enhanced stability of NEAT1 subsequently led to increased FoxO1 expression and subsequent protein degradation. Our study has provided evidence that the upregulation of FAM129B rescues the Dex-induced skeletal muscle atrophy, suggesting that FAM129B may be a potential target for alleviating skeletal muscle atrophy.

Keywords:  FAM129B; NEAT1; Skeletal muscle atrophy

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.140120
Redox Biol. 2025 Jan 27. pii: S2213-2317(25)00025-4. [Epub ahead of print]80 103512

Norharmane prevents muscle aging via activation of SKN-1/NRF2 stress response pathways.

Farida S Nirmala, Hyunjung Lee, Yejin Cho, Min Young Um, Hyo Deok Seo, Chang Hwa Jung, Jeong-Hoon Hahm, Jiyun Ahn.

  Sarcopenia, the age-related decline in muscle mass and function, is a significant contributor to increased frailty and mortality in the elderly. Currently, no FDA-approved treatment exists for sarcopenia. Here, we identified norharmane (NR), a β-carboline alkaloid, as a potential therapeutic agent for mitigating muscle aging. We aimed to determine the ability of NR to delay muscle aging in Caenorhabditis elegans (C. elegans), mouse, and muscle cells in mice and humans. NR treatment improved swimming ability and increased the maximum velocity in aged C. elegans. Transcriptomic analysis revealed that NR upregulated detoxification genes in C. elegans, including cytochrome P450, UGT, and GST enzymes. NR-induced benefits were dependent on the SKN-1/Nrf2 stress response pathway. In mammalian models, NR delayed cellular senescence in human skeletal muscle myoblasts and enhanced myogenesis in C2C12 cells and primary aged myoblasts. NR supplementation in aged mice prevented muscle loss, improved muscle function, and reduced markers of cellular senescence. We found that the p38 MAPK pathway mediated NR activation of Nrf2 by disrupting the Nrf2-Keap1 interaction. NR also improved oxygen consumption rates and promoted mitochondrial biogenesis. These findings suggest that NR is a promising candidate for preventing sarcopenia and improving muscle health.

Keywords:  Mitochondrial function; Myogenesis; Norharmane; Nrf2; SKN-1; Sarcopenia

DOI:  https://doi.org/10.1016/j.redox.2025.103512
J Appl Physiol (1985). 2025 Jan 30.

Responses of skeletal muscle to mechanical stimuli in female rats following and during muscle disuse atrophy.

A B Sklivas, Z R Hettinger, S Rose, A Mantuano, A L Confides, S Rigsby, F F Peelor, B F Miller, T A Butterfield, E E Dupont-Versteegden.

  The purpose of this study was to investigate the ability of mechanotherapy to enhance recovery or prevent loss of muscle size with atrophy, in female rats. Female F344/BN rats were assigned to weight bearing (WB), hindlimb suspended (HS) for 14 days with reambulation for 7 days without (RA) or with (RAM) mechanotherapy (study 1), or to WB, HS for 7 days, with (HSM) or without mechanotherapy (study 2) to gastrocnemius. Muscle fiber cross sectional area (CSA) and type, collagen, satellite cell number, and protein synthesis (Ksyn) and degradation (Kdeg) were assessed. Study 1: muscle weight, but not CSA, was higher in RAM compared to HS, but CSA was higher in RA compared to HS. Myofibrillar Ksyn was higher in RA and RAM compared to WB and HS, but not different between RA and RAM. Myofibrillar Kdeg was lower with mechanotherapy compared to HS. Study 2: muscle weight, CSA, and myofibrillar Ksyn and Kdeg were not different with mechanotherapy. Collagen content was lower with mechanotherapy, but collagen Ksyn was not. Mechanotherapy was not associated with changes in fiber type, satellite cell or myonuclear number in either study. Compared to male, female rats had less muscle loss with HS, which was associated with less loss of myofibrillar Ksyn. Recovery from atrophy was associated with higher Ksyn in female and lower Kdeg in male rats. Conclusion: Female rat muscles do not exhibit a growth response to mechanotherapy with disuse or reambulation. Furthermore, male and female rats show distinct responses to different mechanical stimuli.

Keywords:  Disuse atrophy; massage; mechanosensing; muscle growth; sex differences

DOI:  https://doi.org/10.1152/japplphysiol.00802.2024
Biochem Biophys Res Commun. 2025 Jan 25. pii: S0006-291X(25)00109-3. [Epub ahead of print]750 151395

Intramuscular inhibition of glycogen phosphorylase improves motor function in spinal cord injury.

Ximeng Yang, Maho Kondo, Chihiro Tohda.

  Motor dysfunction in various diseases and aging is often accompanied by skeletal muscle atrophy and reduced axonal projections from motor neurons to the skeletal muscles. While several studies have investigated the correlations and molecular mechanisms between muscle atrophy and motor neuron denervation to explain the pathology of motor diseases, it remains unclear whether skeletal muscle atrophy directly causes axonal denervation of motor neurons. Here, we used a casts-attached mouse model which represents muscle atrophy and motor dysfunction in the hindlimbs to explore how skeletal muscle atrophy affects motor neuronal axon projections. Retrograde neuronal tracing from the skeletal muscles to motor neurons revealed that axonal projections from motor neurons were reduced to the atrophied skeletal muscles compared to the healthy muscles. In addition, we identified glycogen phosphorylase (GP) as an upregulated protein in the plasma membrane of atrophied gastrocnemius muscles. The expression level of GP was also increased on the membrane of primary cultured myotubes treated with dexamethasone to induce muscle atrophy in vitro. Importantly, intramuscular injection of a GP inhibitor into the hindlimbs improved motor function in a mouse model of spinal cord injury. Furthermore, axonal projection from spinal cord neurons to dexamethasone-treated atrophied myotubes was reduced compared to healthy myotubes, whereas GP inhibitor treatment to atrophied myotubes promoted axonal growth of the spinal cord neurons overlayed on the myotubes. This study demonstrated that skeletal muscle atrophy induces attenuation of motor neuronal innervation and inhibition of GP in atrophied skeletal muscles may be a novel therapeutic approach for spinal cord injury by enhancing axonal projections from motor neurons to the skeletal muscles.

Keywords:  Axonal projection; Glycogen phosphorylase; Motor neurons; Muscle atrophy; Spinal cord injury

DOI:  https://doi.org/10.1016/j.bbrc.2025.151395
Biomolecules. 2024 Dec 26. pii: 14. [Epub ahead of print]15(1):

Integrated Proteomic and Metabolomic Analysis of Muscle Atrophy Induced by Hindlimb Unloading.

Yuan Wang, Xi Li, Na Li, Jiawei Du, Xiaodong Qin, Xiqing Sun, Yongchun Wang, Chengfei Li.

  Skeletal muscle atrophy, which is induced by factors such as disuse, spaceflight, certain medications, neurological disorders, and malnutrition, is a global health issue that lacks effective treatment. Hindlimb unloading is a commonly used model of muscle atrophy. However, the underlying mechanism of muscle atrophy induced by hindlimb unloading remains unclear, particularly from the perspective of the myocyte proteome and metabolism. We first used mass spectrometry for proteomic sequencing and untargeted metabolomics to analyze soleus muscle changes in rats with hindlimb unloading. The study found 1052 proteins and 377 metabolites (with the MS2 name) that were differentially expressed between the hindlimb unloading group and the control group. Proteins like ACTN3, MYH4, MYBPC2, and MYOZ1, typically found in fast-twitch muscles, were upregulated, along with metabolism-related proteins GLUL, GSTM4, and NDUFS4. Metabolites arachidylcarnitine and 7,8-dihydrobiopterin, as well as pathways like histidine, taurine, and hypotaurine metabolism, were linked to muscle atrophy. Protein and metabolism joint analyses revealed that some pathways, such as glutathione metabolism, ferroptosis, and lysosome pathways, were likely to be involved in soleus atrophy. In this study, we have applied integrated deep proteomic and metabolomic analyses. The upregulation of proteins that are expressed in fast-twitch fibers indicates the conversion of slow-twitch fibers to fast-twitch fibers under hindlimb unloading. In addition, some differentially abundant metabolites and pathways revealed the important role of metabolism in muscle atrophy of the soleus. As shown in the graphical abstract, our study provides insights into the pathogenesis and treatment of muscle atrophy that results from unloading by integrating proteomics and metabolomics of the soleus muscles.

Keywords:  hindlimb unloading; integrated analysis; metabolomics; muscle atrophy; proteomics

DOI:  https://doi.org/10.3390/biom15010014
J Neurosci. 2025 Jan 29. pii: e1279232025. [Epub ahead of print]

MuSK regulates neuromuscular junction Nav1.4 localization and excitability.

L A Fish, M D Ewing, K A Rich, C Xi, I Chen, D Jaime, Laura A Madigan, X Wang, J L Shahtout, R E Feder, K Funai, J L Christian, K A Wharton, M M Rich, W D Arnold, J R Fallon.

The neuromuscular junction (NMJ) is the linchpin of nerve-evoked muscle contraction. Broadly, the function of the NMJ is to transduce nerve action potentials into muscle fiber action potentials (MFAPs). Efficient neuromuscular transmission requires both cholinergic signaling, responsible for generation of endplate potentials (EPPs), and excitation, the amplification of the EPP by postsynaptic voltage-gated sodium channels (Nav1.4) to generate the MFAP. In contrast to the cholinergic component, the signaling pathways that organize Nav1.4 and mediate muscle fiber excitability are poorly characterized. Muscle-specific kinase (MuSK), in addition to its Ig1 domain-dependent role as the main organizer of acetylcholine receptors AChRs), also binds BMPs via its Ig3 domain and shapes BMP-induced signaling and transcriptional output. Here, using mice lacking the MuSK Ig3 domain ('ΔIg3-MuSK'), we probed the role of this domain at the NMJ. NMJs formed in ΔIg3-MuSK animals with pre- and post- synaptic specializations aligned at all ages examined. However, the ΔIg3-MuSK postsynaptic apparatus was fragmented from the first weeks of life. Synaptic electrophysiology showed that spontaneous and nerve-evoked acetylcholine release, AChR density, and endplate currents were comparable at WT and ΔIg3-MuSK NMJs. However, single fiber electromyography revealed that nerve-evoked MFAPs in ΔIg3-MuSK muscle were abnormal as evidenced by jitter and blocking. Further, nerve-evoked compound muscle action potentials and muscle force production were also diminished. Finally, Nav1.4 levels were reduced at ΔIg3-MuSK NMJs, but not at the sarcolemma broadly, indicating that the observed excitability defects result from impaired synaptic localization of this ion channel. We propose that MuSK plays distinct, domain-specific roles at the NMJ: the Ig1 domain mediates agrin-LRP4 mediated AChR localization, while the Ig3 domain maintains postsynaptic Nav1.4 density, conferring the muscle excitability required to amplify cholinergic signals and trigger action potentials.Significance Statement The neuromuscular junction (NMJ) is required for nerve-evoked muscle contraction and movement, and its function is compromised during aging and disease. Though the mechanisms underlying neurotransmitter release and cholinergic response at this synapse have been studied extensively, the machinery necessary for nerve-evoked muscle excitation are incompletely characterized. We show that the Ig3 domain of MuSK (muscle-specific kinase) regulates NMJ structure and the localization of voltage-gated sodium channels necessary for nerve-evoked muscle fiber excitation and force production. This function of MuSK is structurally and mechanistically distinct from its role in organizing cholinergic machinery. The Ig3 domain of MuSK thus emerges as a target for selectively modulating excitability, which is defective in conditions such as congenital myasthenic syndromes and age-related muscle weakness.

DOI: https://doi.org/10.1523/JNEUROSCI.1279-23.2025
Front Bioinform. 2024 ;4 1494717

Developing a ceRNA-based lncRNA-miRNA-mRNA regulatory network to uncover roles in skeletal muscle development.

Wang Wenlun, Yu Chaohang, Huang Yan, Li Wenbin, Zhou Nanqing, Hu Qianmin, Wu Shengcai, Yuan Qing, Yu Shirui, Zhang Feng, Zhu Lingyun.

  The precise role of lncRNAs in skeletal muscle development and atrophy remain elusive. We conducted a bioinformatic analysis of 26 GEO datasets from mouse studies, encompassing embryonic development, postnatal growth, regeneration, cell proliferation, and differentiation, using R and relevant packages (limma et al.). LncRNA-miRNA relationships were predicted using miRcode and lncBaseV2, with miRNA-mRNA pairs identified via miRcode, miRDB, and Targetscan7. Based on the ceRNA theory, we constructed and visualized the lncRNA-miRNA-mRNA regulatory network using ggalluvial among other R packages. GO, Reactome, KEGG, and GSEA explored interactions in muscle development and regeneration. We identified five candidate lncRNAs (Xist, Gas5, Pvt1, Airn, and Meg3) as potential mediators in these processes and microgravity-induced muscle wasting. Additionally, we created a detailed lncRNA-miRNA-mRNA regulatory network, including interactions such as lncRNA Xist/miR-126/IRS1, lncRNA Xist/miR-486-5p/GAB2, lncRNA Pvt1/miR-148/RAB34, and lncRNA Gas5/miR-455-5p/SOCS3. Significant signaling pathway changes (PI3K/Akt, MAPK, NF-κB, cell cycle, AMPK, Hippo, and cAMP) were observed during muscle development, regeneration, and atrophy. Despite bioinformatics challenges, our research underscores the significant roles of lncRNAs in muscle protein synthesis, degradation, cell proliferation, differentiation, function, and metabolism under both normal and microgravity conditions. This study offers new insights into the molecular mechanisms governing skeletal muscle development and regeneration.

Keywords:  ceRNA network; cell proliferation and differentiation; lncRNA; muscle atrophy; muscle development and regeneration; signaling pathway

DOI:  https://doi.org/10.3389/fbinf.2024.1494717
Biochemistry (Mosc). 2024 Dec;89(12): 2083-2106

Troponins and Skeletal Muscle Pathologies.

Agnessa P Bogomolova, Ivan A Katrukha.

  Skeletal muscles account for ~30-40% of the total weight of human body and are responsible for its most important functions, including movement, respiration, thermogenesis, and glucose and protein metabolism. Skeletal muscle damage negatively impacts the whole-body functioning, leading to deterioration of the quality of life and, in severe cases, death. Therefore, timely diagnosis and therapy for skeletal muscle dysfunction are important goals of modern medicine. In this review, we focused on the skeletal troponins that are proteins in the thin filaments of muscle fibers. Skeletal troponins play a key role in regulation of muscle contraction. Biochemical properties of these proteins and their use as biomarkers of skeletal muscle damage are described in this review. One of the most convenient and sensitive methods of protein biomarker measurement in biological liquids is immunochemical analysis; hence, we examined the factors that influence immunochemical detection of skeletal troponins and should be taken into account when developing diagnostic test systems. Also, we reviewed the available data on the skeletal troponin mutations that are considered to be associated with pathologies leading to the development of diseases and discussed utilization of troponins as drug targets for treatment of the skeletal muscle disorders.

Keywords:  ageing; biomarker; monoclonal antibodies; myopathy; skeletal muscle; troponin

DOI:  https://doi.org/10.1134/S0006297924120010
PLoS Biol. 2025 Jan;23(1): e3002998

The ubiquitin-conjugating enzyme UBE2D maintains a youthful proteome and ensures protein quality control during aging by sustaining proteasome activity.

Liam C Hunt, Michelle Curley, Kudzai Nyamkondiwa, Anna Stephan, Jianqin Jiao, Kanisha Kavdia, Vishwajeeth R Pagala, Junmin Peng, Fabio Demontis.

Ubiquitin-conjugating enzymes (E2s) are key for protein turnover and quality control via ubiquitination. Some E2s also physically interact with the proteasome, but it remains undetermined which E2s maintain proteostasis during aging. Here, we find that E2s have diverse roles in handling a model aggregation-prone protein (huntingtin-polyQ) in the Drosophila retina: while some E2s mediate aggregate assembly, UBE2D/effete (eff) and other E2s are required for huntingtin-polyQ degradation. UBE2D/eff is key for proteostasis also in skeletal muscle: eff protein levels decline with aging, and muscle-specific eff knockdown causes an accelerated buildup in insoluble poly-ubiquitinated proteins (which progressively accumulate with aging) and shortens lifespan. Mechanistically, UBE2D/eff is necessary to maintain optimal proteasome function: UBE2D/eff knockdown reduces the proteolytic activity of the proteasome, and this is rescued by transgenic expression of human UBE2D2, an eff homolog. Likewise, human UBE2D2 partially rescues the lifespan and proteostasis deficits caused by muscle-specific effRNAi and re-establishes the physiological levels of effRNAi-regulated proteins. Interestingly, UBE2D/eff knockdown in young age reproduces part of the proteomic changes that normally occur in old muscles, suggesting that the decrease in UBE2D/eff protein levels that occurs with aging contributes to reshaping the composition of the muscle proteome. However, some of the proteins that are concertedly up-regulated by aging and effRNAi are proteostasis regulators (e.g., chaperones and Pomp) that are transcriptionally induced presumably as part of an adaptive stress response to the loss of proteostasis. Altogether, these findings indicate that UBE2D/eff is a key E2 ubiquitin-conjugating enzyme that ensures protein quality control and helps maintain a youthful proteome composition during aging.

DOI: https://doi.org/10.1371/journal.pbio.3002998
Sci Rep. 2025 Jan 26. 15(1): 3293

Label-free proteomic analysis of Duchenne and Becker muscular dystrophy showed decreased sarcomere proteins and increased ubiquitination-related proteins.

Juliana Cristina Tobar da Silva, Mariângela Rangel Alves Nogueira, Yara Martins da Silva, Fábio César Sousa Nogueira, Nathalie Henriques Silva Canedo, Katia Carneiro, Denise de Abreu Pereira.

Muscular dystrophies (MD) are a group of hereditary diseases marked by progressive muscle loss, leading to weakness and degeneration of skeletal muscles. These conditions often result from structural defects in the Dystrophin-Glycoprotein Complex (DGC), as seen in Duchenne Muscular Dystrophy (DMD) and Becker Muscular Dystrophy (BMD). Since MDs currently have no cure, research has focused on identifying potential therapeutic targets to improve patients' quality of life. In this study, skeletal muscle tissue samples from DMD and BMD patients, as well as non-dystrophic controls, were analyzed using label-free mass spectrometry (MS/MS) to characterize the proteomic profile of these conditions and identify biomarkers for differential diagnosis. In-silico analysis revealed that dystrophic muscle tissues are linked to biological processes related to cellular energy metabolism, including oxidation of organic compounds, energy production, and cellular respiration. Enrichment of functions associated with cell structure and RNA binding was also observed, including cytoskeletal protein binding and RNA binding. The human phenotypes most related to the proteomic signature were abnormal circulating metabolites, muscle physiology, and weakness. Quantitative analysis identified significant changes in proteins associated with sarcomere organization and protein ubiquitination, such as myomesin, myozenin, and E3 ubiquitin-protein ligase rififylin, suggesting these as potential therapeutic targets.

DOI: https://doi.org/10.1038/s41598-025-87995-5
Int J Mol Sci. 2025 Jan 07. pii: 439. [Epub ahead of print]26(2):

Changes to the Autophagy-Related Muscle Proteome Following Short-Term Treatment with Ectoine in the Duchenne Muscular Dystrophy Mouse Model mdx.

Eulàlia Gómez Armengol, Caroline Merckx, Hanne De Sutter, Jan L De Bleecker, Boel De Paepe.

  The most severe form of muscular dystrophy (MD), known as Duchenne MD (DMD), remains an incurable disease, hence the ongoing efforts to develop supportive therapies. The dysregulation of autophagy, a degradative yet protective mechanism activated when tissues are under severe and prolonged stress, is critically involved in DMD. Treatments that harness autophagic capacities therefore represent a promising therapeutic approach. Osmolytes are protective organic molecules that regulate osmotic pressure and cellular homeostasis and may support tissue-repairing autophagy. We therefore explored the effects of the osmolyte ectoine in the standard mouse model of DMD, the mdx, focusing on the autophagy-related proteome. Mice were treated with ectoine in their drinking water (150 mg/kg) or through daily intraperitoneal injection (177 mg/kg) until they were 5.5 weeks old. Hind limb muscles were dissected, and samples were prepared for Western blotting for protein quantification and for immunofluorescence for an evaluation of tissue distribution. We report changes in the protein levels of autophagy-related 5 (ATG5), Ser366-phosphorylated sequestosome 1 (SQSTM1), heat shock protein 70 (HSP70), activated microtubule-associated protein 1A/1B-light chain 3 (LC3 II) and mammalian target of rapamycin (mTOR). Most importantly, ectoine significantly improved the balance between LC3 II and SQSTM1 levels in mdx gastrocnemius muscle, and LC3 II immunostaining was most pronounced in muscle fibers of the tibialis anterior from treated mdx. These findings lend support for the further investigation of ectoine as a potential therapeutic intervention for DMD.

Keywords:  autophagy; mitophagy; muscular dystrophy; osmolytes

DOI:  https://doi.org/10.3390/ijms26020439
J Cachexia Sarcopenia Muscle. 2025 Feb;16(1): e13705

Characterization of SARS-CoV-2 Entry Genes in Skeletal Muscle and Impacts of In Vitro Versus In Vivo Infection.

Salyan Bhattarai, Eva Kaufmann, Feng Liang, Yumin Zheng, Ekaterina Gusev, Qutayba Hamid, Jun Ding, Maziar Divangahi, Basil J Petrof.

   BACKGROUND: COVID-19 has been associated with both respiratory (diaphragm) and non-respiratory (limb) muscle atrophy. It is unclear if SARS-CoV-2 infection of skeletal muscle plays a role in these changes. This study sought to: 1) determine if cells comprising skeletal muscle tissue, particularly myofibres, express the molecular components required for SARS-CoV-2 infection; 2) assess the capacity for direct SARS-CoV-2 infection and its impact on atrophy pathway genes in myogenic cells; and 3) in an animal model of COVID-19, examine the relationship between viral infection of skeletal muscle and myofibre atrophy within the diaphragm and limb muscles.
METHODS: We used in silico bioinformatics analysis of published human single cell RNA-seq datasets, as well as direct qPCR examination of human myotubes and diaphragm biopsies, to assess expression of key genes involved in SARS-CoV-2 cellular entry. In Vitro, we determined the ability of SARS-CoV-2 to directly infect myogenic cells and employed qPCR to assess the impact on muscle atrophy pathway genes (ubiquitin-proteasome, autophagy). In vivo, the diaphragm and quadriceps of Roborovski hamsters with SARS-CoV-2 respiratory infection were examined at day 3 post-inoculation to evaluate the relationship between atrophy pathway and SARS-CoV-2 transcripts by qPCR, as well as histological measurements of myofibre morphology.
RESULTS: Angiotensin converting enzyme 2 (ACE2), the primary receptor for SARS-CoV-2, as well as cooperating proteases (furin, cathepsins B and L), are expressed by myofibres. ACE2 expression was increased 5-fold (p = 0.01) in the diaphragms of mechanically ventilated human subjects compared to controls. In Vitro, a time-dependent increase of SARS-CoV-2 transcript levels was observed in myotubes directly exposed to the virus (p = 0.002). This was associated with downregulation of the ubiquitin ligase MuRF1 (by 64%, p = 0.002) and the autophagy gene LC3B (by 31%, p = 0.009). In contrast, in vivo infection led to upregulation of MuRF1 in quadriceps (23-fold, p = 0.0007) and autophagy genes in both quadriceps (5.2-fold for Gabarapl1, p = 0.03; 7-fold for p62, p = 0.0002) and diaphragm (2.2-fold for Gabarapl1, p = 0.03; 2.3-fold for p62, p = 0.057). In infected hamsters the diaphragm lacked viral transcripts but exhibited atrophy (48% decrease in myofibre area; p = 0.02), whereas the quadriceps lacked myofibre atrophy despite elevated viral transcripts in the muscle.
CONCLUSIONS: Although myogenic cells express the genes required for SARS-CoV-2 entry and can be directly infected, there was no evident relationship between viral transcript levels and manifestations of atrophy, either in vitro or in vivo. Our results do not support direct myofibre infection by SARS-CoV-2 as a likely cause of atrophy in COVID-19.

Keywords:  ACE2; COVID‐19; atrophy; diaphragm; viral entry

DOI:  https://doi.org/10.1002/jcsm.13705
Antioxidants (Basel). 2025 Jan 13. pii: 84. [Epub ahead of print]14(1):

CCL5 Induces a Sarcopenic-like Phenotype via the CCR5 Receptor.

Francisco Aguirre, Franco Tacchi, Mayalen Valero-Breton, Josué Orozco-Aguilar, Sabrina Conejeros-Lillo, Josefa Bonicioli, Renata Iturriaga-Jofré, Daniel Cabrera, Jorge A Soto, Mauricio Castro-Sepúlveda, Marianny Portal-Rodríguez, Álvaro A Elorza, Andrea Matamoros, Felipe Simon, Claudio Cabello-Verrugio.

  Sarcopenia corresponds to a decrease in muscle mass and strength. CCL5 is a new myokine whose expression, along with the CCR5 receptor, is increased in sarcopenic muscle. Therefore, we evaluated whether CCL5 and CCR5 induce a sarcopenic-like effect on skeletal muscle tissue and cultured muscle cells. Electroporation in the tibialis anterior (TA) muscle of mice was used to overexpress CCL5. The TA muscles were analyzed by measuring the fiber diameter, the content of sarcomeric proteins, and the gene expression of E3-ligases. C2C12 myotubes and single-isolated flexor digitorum brevis (FDB) fibers were also treated with recombinant CCL5 (rCCL5). The participation of CCR5 was evaluated using the antagonist maraviroc (MVC). Protein and structural analyses were performed. The results showed that TA overexpression of CCL5 led to sarcopenia by reducing muscle strength and mass, muscle-fiber diameter, and sarcomeric protein content, and by upregulating E3-ligases. The same sarcopenic phenotype was observed in myotubes and FDB fibers. We showed increased reactive oxygen species (ROS) production and carbonylated proteins, denoting oxidative stress induced by CCL5. When the CCR5 was antagonized, the effects produced by rCCL5 were prevented. In conclusion, we report for the first time that CCL5 is a novel myokine that exerts a sarcopenic-like effect through the CCR5 receptor.

Keywords:  CCL5; CCR5; gene electroporation; oxidative stress; protein synthesis; reactive oxygen species; sarcopenia; ubiquitin–proteasome system

DOI:  https://doi.org/10.3390/antiox14010084
Int J Mol Sci. 2025 Jan 05. pii: 401. [Epub ahead of print]26(1):

ProBDNF as a Myokine in Skeletal Muscle Injury: Role in Inflammation and Potential for Therapeutic Modulation of p75NTR.

Katherine Aby, Ryan Antony, Tao Yang, Frank M Longo, Yifan Li.

  Brain-derived neurotropic factor (BDNF) is expressed by skeletal muscle as a myokine. Our previous work showed that the active precursor, proBDNF, is the predominant form of BDNF expressed in skeletal muscle, and that following skeletal muscle injury, proBDNF levels are significantly increased. However, the function of the muscle-derived proBDNF in injury-induced inflammation has yet to be fully understood. Using a model of tourniquet-induced ischemia-reperfusion (IR) injury of the hindlimb, this study presents, for the first time, strong and novel evidence that following IR injury, proBDNF is released from skeletal muscle into circulation as an endocrine signaling molecule. Further, this study shows that 1 day post-IR injury, the proBDNF receptor, p75NTR, is upregulated 12-fold in splenic monocytes, which are known to be quickly mobilized to the injury site. We demonstrate that p75NTR plays a role in the activation of splenic monocytes, and that treatment with a p75NTR small-molecule modulator, LM11A-31, significantly reduced monocyte inflammatory responses upon lipopolysaccharide stimulation. Overall, the present study establishes proBDNF as a myokine that plays a significant role in skeletal muscle injury-induced inflammation through its receptor, p75NTR, which may be modulated using LM11A-31 as potential translational therapeutic against injury and inflammation.

Keywords:  LM11A-31; inflammation; ischemia–reperfusion; myokine; p75NTR; proBDNF; skeletal muscle injury; splenic monocytes

DOI:  https://doi.org/10.3390/ijms26010401
J Biol Chem. 2025 Jan 23. pii: S0021-9258(25)00063-8. [Epub ahead of print] 108216

The juxtamembrane sequence of small ankyrin 1 mediates the binding of its cytoplasmic domain to SERCA1 and is required for inhibitory activity.

Yi Li, Nathan T Wright, Robert J Bloch.

  Sarcoplasmic/endoplasmic reticulum Ca2+-ATPase1 (SERCA1) is responsible for the clearance of cytosolic Ca2+ in skeletal muscle. Due to its vital importance in regulating Ca2+ homeostasis, the regulation of SERCA1 has been intensively studied. Small ankyrin 1 (sAnk1, Ank1.5), a 17 kDa muscle-specific isoform of ANK1, binds to SERCA1 directly via both its transmembrane and cytoplasmic domains and inhibits SERCA1's ATPase activity. Here we characterize the interaction between the cytoplasmic domain of sAnk1 (sAnk1(29-155)) and SERCA1. The binding affinity for sAnk1 (29-155) to SERCA1 was 444 nM by blot overlay, about 7-fold weaker than the binding of sAnk1(29-155) to obscurin, a giant protein of the muscle cytoskeleton. Site-directed mutagenesis identified K38, H39, and H41, in the juxtamembrane region, as residues likely to mediate binding to SERCA1. These residues are not required for obscurin binding. Residues R64-K73, which do contribute to obscurin binding, are also required for binding to SERCA1, but only the hydrophobic residues in this sequence are required, not the positively charged residues necessary for obscurin binding. Circular dichroism analysis of sAnk1(29-155) indicates that most mutants show significant structural changes, with the exception of those containing alanines in place of K38, H39 and H41. Although the cytoplasmic domain of sAnk1 does not inhibit SERCA1's Ca2+-ATPase activity, with or without mutations in the juxtamembrane sequence, the inhibitory activity of full-length sAnk1 requires the WT juxtamembrane sequence. We used these data to model sAnk1 and the sAnk1-SERCA1 complex. Our results suggest that, in addition to its transmembrane domain, sAnk1 uses its juxtamembrane sequence and perhaps part of its obscurin binding site to bind to SERCA1, and that this binding contributes to their robust association in situ, as well as regulation of SERCA1's activity.

Keywords:  Alphafold; Ca-ATPase; ankyrin; circular dichroism (CD); complex; membrane transport; sarcoplasmic reticulum (SR); skeletal muscle; structural model

DOI:  https://doi.org/10.1016/j.jbc.2025.108216
Diabetes. 2025 Jan 28. pii: db240375. [Epub ahead of print]

Deubiquitinating enzyme USP2 alleviates muscle atrophy by stabilizing PPARγ.

Shu Yang, Lijiao Xiong, Tingfeng Liao, Lixing Li, Yanchun Li, Lin Kang, Guangyan Yang, Zhen Liang.

Insulin resistance, a hallmark of type 2 diabetes, accelerates muscle breakdown and impairs energy metabolism. However, the role of Ubiquitin Specific Peptidase 2 (USP2), a key regulator of insulin resistance, in sarcopenia remains unclear. Peroxisome proliferator activated receptor γ (PPARγ) plays a critical role in regulating muscle atrophy. This study investigates the role of deubiquitinase USP2 in mitigating muscle atrophy. Our findings revealed reduced USP2 expression in skeletal muscles of patients with type 2 diabetes. In mouse models of diabetes- and dexamethasone (DEX)-induced muscle atrophy, USP2 expression was downregulated in skeletal muscles. Usp2 knockout exacerbated muscle loss and functional impairment induced by diabetes or DEX. Moreover, skeletal muscle-specific Usp2 knockout further aggravated muscle loss and functional impairment induced by diabetes. Local injection of AAV-Usp2 into the gastrocnemius muscles of diabetic mice increased muscle mass, and improved skeletal muscle performance and endurance. It enhanced insulin sensitivity in diabetic mice, shown by lower fasting serum glucose and insulin levels and better glucose tolerance. Mechanistic analysis showed USP2 directly interacted with PPARγ by deubiquitinating it, stabilizing its protein levels, enhancing insulin signaling and sensitivity, and maintaining muscle mass. Loss of PPARγ abolishes the regulatory effects of USP2 on insulin sensitivity and muscle atrophy. MYOD1 activates USP2 transcription by binding to its promoter region. This study demonstrates the protective role of USP2 in mitigating muscle atrophy by stabilizing PPARγ through deubiquitination, particularly in models of diabetic and DEX-induced muscle atrophy. Targeting the USP2-PPARγ axis may offer promising therapeutic strategies for metabolic disorders and sarcopenia.

DOI: https://doi.org/10.2337/db24-0375
Nature. 2025 Jan 29.

Evidence that engineered muscle could patch up failing hearts.



Keywords:  Biotechnology; Diseases; Stem cells

DOI:  https://doi.org/10.1038/d41586-025-00193-1
Nat Metab. 2025 Jan 27.

Kdm2a inhibition in skeletal muscle improves metabolic flexibility in obesity.

Yuhan Wang, Hao Xie, Qianrui Liu, Na Wang, Xi Luo, Fei Sun, Jinghan Zhu, Ruihan Dong, Yi Wang, Jia Gao, Zhichao Gao, Teng Huang, Xin Liu, Qilin Yu, Ting Wang, Yang Li, Danni Song, Shiwei Liu, Shu Zhang, Hao Yin, Wen Kong, Cong-Yi Wang.

Skeletal muscle is a critical organ in maintaining homoeostasis against metabolic stress, and histone post-translational modifications are pivotal in those processes. However, the intricate nature of histone methylation in skeletal muscle and its impact on metabolic homoeostasis have yet to be elucidated. Here, we report that mitochondria-rich slow-twitch myofibers are characterized by significantly higher levels of H3K36me2 along with repressed expression of Kdm2a, an enzyme that specifically catalyses H3K36me2 demethylation. Deletion or inhibition of Kdm2a shifts fuel use from glucose under cold challenge to lipids under obese conditions by increasing the proportion of mitochondria-rich slow-twitch myofibers. This protects mice against cold insults and high-fat-diet-induced obesity and insulin resistance. Mechanistically, Kdm2a deficiency leads to a marked increase in H3K36me2 levels, which then promotes the recruitment of Mrg15 to the Esrrg locus to process its precursor messenger RNA splicing, thereby reshaping skeletal muscle metabolic profiles to induce slow-twitch myofiber transition. Collectively, our data support the role of Kdm2a as a viable target against metabolic stress.

DOI: https://doi.org/10.1038/s42255-024-01210-9
Cell Metab. 2025 Jan 22. pii: S1550-4131(24)00488-1. [Epub ahead of print]

Muscle-derived small extracellular vesicles induce liver fibrosis during overtraining.

Ya Liu, Rui Zhou, Yifan Guo, Biao Hu, Lingqi Xie, Yuze An, Jie Wen, Zheyu Liu, Min Zhou, Weihong Kuang, Yao Xiao, Min Wang, Genqing Xie, Haiyan Zhou, Renbin Lu, Hui Peng, Yan Huang.

  The benefits of exercise for metabolic health occur in a dose-dependent manner. However, the adverse effects of overtraining and their underlying mechanisms remain unclear. Here, we show that overtraining induces hepatic fibrosis. Mechanistically, we find that excessive lactate accumulation in skeletal muscle leads to the lactylation of SH3 domain-containing 3 (SORBS3), triggering its liquid-liquid phase separation (LLPS). LLPS of SORBS3 enhances its interaction with flotillin 1 and selectively facilitates the sorting of F-box protein 2 (FBXO2) into small extracellular vesicles, referred to as "lactate bodies." Lactate bodies induce hepatocyte apoptosis followed by hepatic stellate cell activation via myeloid cell leukemia sequence 1 (MCL1)-BAX/BAK signaling. Inhibition of SORBS3 lactylation or FBXO2 disrupts lactate bodies formation and alleviates overtraining-triggered liver fibrosis. Likewise, reduction of muscle lactate bodies formation by salidroside attenuates overtraining-induced liver fibrosis. Collectively, we identify a process by which overtraining induces hepatic fibrosis, highlighting a potential therapeutic target for liver health.

Keywords:  LLPS; lactylation; liver fibrosis; overtraining; small extracellular vesicles

DOI:  https://doi.org/10.1016/j.cmet.2024.12.005