bims-moremu 2025-08-17 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2025–08–17
37 papers selected by
Anna Vainshtein, Craft Science Inc.

Tribbles 3 blunts exercise-induced skeletal muscle adaptation.
Alterations of the skeletal muscle nuclear proteome after acute exercise reveals a post-transcriptional influence.
Exerkines and myokines in aging sarcopenia.
Resilience of the Mitochondrial Reticulum in Aging.
Multi-omic integration of single-cell data uncovers methylation profiles of super-enhancers in skeletal muscle stem cells.
REST/NRSF Preserves muscle stem cell identity by repressing alternate cell fate.
Distinct Endothelial Gene Responses to Acute Exercise in Skeletal Muscle.
Promoting mitochondrial fusion is protective against cancer-induced muscle detriments in males and females.
Editorial: Exploring regenerative pathways in muscle repair.
Identification of CaVβ1 Isoforms Required for Neuromuscular Junction Formation and Maintenance.
From Development to Regeneration: Insights into Flight Muscle Adaptations from Bat Muscle Cell Lines.
Stretch activation combats force loss from fatigue in fast-contracting mouse skeletal muscle fibers.
Research progress of sarcopenia: Diagnostic advancements, molecular mechanisms, and therapeutic strategies.
Androgen-Mediated Regulation of Skeletal Muscle Mass: A Ticking Clock.
Dystrophin interacts with Msp300 to regulate myonuclear positioning and microtubule organization.
Antiaging agents: pharmacological therapy targeted at preserving skeletal muscle size and function in aging adults.
Long-Term Engraftment and Satellite Cell Expansion from Human PSC Teratoma-Derived Myogenic Progenitors.
Differential pathology and susceptibility to MBNL loss across muscles in myotonic dystrophy mouse models.
Transcriptomic profiling of skeletal muscle in the DMDmdx rat model of Duchenne muscular dystrophy.
Human Pluripotent Stem Cell-Derived Skeletal Muscle Organoid Model of Aging-Induced Sarcopenia.
AAV-shDUX4 provides short-term benefits but limited long-term efficacy in a DUX4 mouse model of FSHD.
Glucocorticoid-Mediated Skeletal Muscle Atrophy: Molecular Mechanisms and Potential Therapeutic Targets.
Exploring the disconnect: mechanisms underpinning the absence of physical function improvement with SGLT2 inhibitors.
TRPV1 signaling in skeletal muscle: A mini review of physiological and pathological roles.
miRNA-182-5p promotes myogenic differentiation of C2C12 cells via the suppression of ZBTB7A.
Transcriptome analysis of injured muscle identifies new candidate genes for satellite cell growth and myofiber formation during early muscle regeneration.
Alpha-Ketoisocaproate Attenuates Muscle Atrophy in Cancer Cachexia Models.
Diverse Inhibitors of De Novo Purine Synthesis Promote AICAR-Induced AMPK Activation and Glucose Uptake in L6 Myotubes.
Identification of key modules and hub genes for sepsis-induced myopathy using weighted gene co-expression network analysis.
The Anti-Myogenic Role of Tetranectin and Its Inhibition by Epigallocatechin-3-Gallate Enhances Myogenesis.
The myokine FGF21 associates with enhanced survival in ALS and mitigates stress-induced cytotoxicity.
Sepsis Induces Long-Term Muscle and Mitochondrial Dysfunction due to Autophagy Disruption Amenable by Urolithin A.
Vitamin D and physical activity as co-modifiers of muscle health and function - a narrative exploration.
Transcriptional dynamics uncover the role of BNIP3 in mitophagy during muscle remodeling in Drosophila.
Whole-exome sequencing identifies TRIM72 as a candidate gene for autosomal recessive limb-girdle muscular dystrophy.
Muscle-brain crosstalk as a driver of brain health in aging.
Which Approach to Choose to Counteract Musculoskeletal Aging? A Comprehensive Review on the Multiple Effects of Exercise.

bioRxiv. 2025 Jul 19. pii: 2025.07.16.665065. [Epub ahead of print]

Tribbles 3 blunts exercise-induced skeletal muscle adaptation.

Ran Hee Choi, Abigail McConahay, Mackenzie B Johnson, Morgan Ojemuyiwa, Brooklyn J Phillips, Ha-Won Jeong, Ho-Jin Koh.

Tribbles 3 (TRB3) is a pseudokinase and its expression has been shown to disrupt glucose metabolism through the inhibition of Akt under obese and diabetic conditions. We recently found that overexpression of TRB3 in mouse skeletal muscle decreased skeletal muscle mass and function, leading to muscle atrophy. Here, we examined whether TRB3 affects exercise training-induced skeletal muscle adaptation. We trained muscle-specific TRB3 transgenic (TG) and wild-type (WT) littermates using a voluntary wheel running protocol for 6 weeks and found that TG mice ran significantly less weekly distances than WT littermates. To exclude the possibility that different skeletal muscle adaptations would be produced due to different training intensities, involuntary treadmill exercise (TM) was used as a training regimen. At the 5 th week of training, we measured glucose tolerance and found that trained TG mice showed glucose intolerance compared to WT littermates. Furthermore, overexpression of TRB3 significantly suppressed the expression of genes needed for glucose uptake and mitochondrial biogenesis, independent of training status. To further determine the role of TRB3 in exercise-induced adaptation, TRB3 knockout (KO) mice were trained by voluntary and involuntary exercise protocols. KO mice presented improved glucose tolerance compared to WT littermates independent of training status. However, we did not observe significant change in the expression of markers for glucose uptake and mitochondrial biogenesis. Taken together, our results indicate that TRB3 in skeletal muscle blunts the benefits of exercise-induced skeletal muscle adaptation.

DOI: https://doi.org/10.1101/2025.07.16.665065
Am J Physiol Cell Physiol. 2025 Aug 11.

Alterations of the skeletal muscle nuclear proteome after acute exercise reveals a post-transcriptional influence.

Ryan A Martin, Xiping Zhang, Mark R Viggars, James A Sanford, Zane W Taylor, Joshua R Hansen, Geremy C Clair, Collin M Douglas, Stuart James Hesketh, Joshua N Adkins, Karyn A Esser.

  Exercise is firmly established as a key contributor to overall well-being and is frequently employed as a therapeutic approach to mitigate various health conditions. One pivotal aspect of the impact of exercise lies in the systemic transcriptional response, which underpins its beneficial adaptations. While extensive research has been devoted to understanding the transcriptional response to exercise, our knowledge of the protein constituents of nuclear processes accompanying gene expression in skeletal muscle remains largely elusive. We hypothesize that alterations in the nuclear proteome following exercise hold vital clues for comprehending exercise-induced transcriptional regulation and related nuclear functions. We first detail the successful isolation of skeletal muscle nuclei from C57BL/6 mice encapsulating 2,030 proteins linked to nuclear processes such as transcription, RNA processing, chromatin modifications, and nuclear transport. We then used this approach to isolate muscle nuclei in sedentary, immediately post-, 1-hour, and 4-hours after a 30-minute treadmill running session, to gain insight into the nuclear proteome after exercise. We found 54 proteins linked to mRNA splicing and nucleocytoplasmic transport, many of which were substantially reduced immediately post-exercise followed by a rapid increase 1- and 4-hours post-exercise. Super resolution microscopy experiments highlight localization changes in mRNA processing proteins post-exercise, further suggesting changes in nuclear transport dynamics. Our data provides important insight into changes in the nuclear proteome following exercise. In particular it highlights proteins contributing to mRNA processing and splicing in addition to transcriptional processes with exercise offering broader changes in mechanisms modulating the molecular response to acute exercise.

Keywords:  Exercise; Muscle; Nuclear Proteome; Nuclei; Proteome

DOI:  https://doi.org/10.1152/ajpcell.00575.2024
Front Endocrinol (Lausanne). 2025 ;16 1592491

Exerkines and myokines in aging sarcopenia.

Huan Wang, Wenbi He, Peishan Chen, Haozhe Wang, Huiguo Wang, Lin Zhu, Xiaoguang Liu.

  Aging sarcopenia is an unavoidable condition that affects the majority of older adults in their later years. Exercise has been extensively researched as an effective intervention for sarcopenia. In particular, the release of exerkines and myokines during physical activity has beneficial effects on the body, which, as mediators, offer a novel therapeutic strategy for elucidating how exercise enhances skeletal muscle mass and function. In this review article, we summarize how exerkines exert protective effects on aging skeletal muscle mainly through the following mechanisms: (1) mediating energy diversion to skeletal muscle, ensuring more energy supply to the muscle; (2) enhancing the activity of skeletal muscle satellite cells to promote muscle repair and regeneration; (3) upregulating the expression of genes associated with muscle regeneration and, at the same time, inhibiting the expression of those genes that contribute to the atrophy of skeletal muscle; and (4) improving the function of the neuromuscular junction to improve the neural control of skeletal muscle. These combined effects constitute the protective mechanism of myokines on aging skeletal muscle.

Keywords:  exercise; exerkines; myokines; sarcopenia; skeletal muscle

DOI:  https://doi.org/10.3389/fendo.2025.1592491
Am J Physiol Endocrinol Metab. 2025 Aug 12.

Resilience of the Mitochondrial Reticulum in Aging.

Robert G Leija, José Pablo Vázquez-Medina, George A Brooks.

  Resting and maximal exercise respiratory rates (V̇O2) decline in aging. Those losses have been attributed to impaired mitochondrial function, but the data are inconsistent with healthy aging. To interrogate the hypothesis of mitochondrial dysregulation in aging, we studied hind limb skeletal muscles from young and older, male and female, NIA C57BL/6JN mice. We observed no age-associated changes in coupling efficiency (ADP:O) of mitochondrial reticulum preparations, but respiratory control (RCR) was decreased in older mice. Additionally, older skeletal muscle exhibited subtle yet significant reductions in the expression of proteins functionally related to substrate uptake and oxidation (mMCT1, mPC1, CPT1b, HADH). While there were no differences in mitochondrial contents per mg of muscle in older mice, there were significant losses of muscle, and hence mitochondrial mass as well as proteins associated with membrane dynamics (DRP1, FIS1, and MFN2). Further, 2D and 3D, cross- and longitudinal muscle sections showed alterations in mitochondrial reticulum organization in muscles of older mice. Therefore, aging is associated with subtle, but significant changes in the organization and functioning of muscle mitochondrial reticula.

Keywords:  Aging; Mitochondria; Mitochondrial Reticulum; Sarcopenia; skeletal muscle

DOI:  https://doi.org/10.1152/ajpendo.00110.2025
Epigenetics Chromatin. 2025 Aug 11. 18(1): 54

Multi-omic integration of single-cell data uncovers methylation profiles of super-enhancers in skeletal muscle stem cells.

Anyu Zeng, Hailong Liu, Shuling He, Xuming Luo, Zhiqi Zhang, Ming Fu, Baoxi Yu.

   INTRODUCTION: Skeletal muscle stem cells (MuSCs) have strong regenerative abilities, but as we age, their ability to regenerate decreases, leading to a decline in muscle function. Although the methylation reprogramming of super-enhancers (SEs) plays a pivotal role in regulating gene expression associated with the aging process, our understanding of the molecular diversity of stem cells during aging remains limited. This study aimed to identify the methylation profile of SEs in MuSCs and explore potential therapeutic molecular targets associated with aging.
METHODS: The ROSE software was employed to identify super enhancers from the ChIP-seq data obtained from the ENCODE database. Additionally, the ALLCools and Methylpy packages were applied to analyze the methylation profile of SEs and to identify differentially methylated regions (DMRs) between aged and control samples using single-cell bisulfite sequencing (scBS-seq) data from the Gene Expression Omnibus (GEO) database. Overlap analysis was used to assess the regions of SEs and DMRs. The target genes and motifs were analyzed using KEGG, GO, and HOMER to identify key biological pathways and functions, followed by validation through snATAC-seq and immunofluorescence techniques.
RESULTS: In conclusion, we conducted a multi-omics and cross-species analysis of MuSCs, creating a detailed methylation profile of SEs during aging. We identified key motifs and genes affected by SE methylation reprogramming, revealing important molecular pathways involved in aging. Notably, further analysis of the key gene PLXND1 revealed a decreasing expression trend in aged MuSCs, which appears to be linked to the hypermethylation of SE Rank 869. This epigenetic alteration is likely to contribute to the dysregulation of the SEMA3 signaling pathway, with profound implications for muscle regeneration in MuSCs during aging.
CONCLUSION: These findings suggest that epigenetic alterations in the methylation reprogramming of SEs are closely linked to the disruption of transcriptional networks during MuSCs aging. Moreover, our results offer valuable insights into the mechanisms driving SE methylation reprogramming, shedding light on how these epigenetic changes contribute to the molecular processes underlying aging.

Keywords:  Aging; Methylation reprogramming; Skeletal muscle stem cell; Super-enhancer

DOI:  https://doi.org/10.1186/s13072-025-00619-0
Nat Commun. 2025 Aug 12. 16(1): 7487

REST/NRSF Preserves muscle stem cell identity by repressing alternate cell fate.

Korin Sahinyan, Darren M Blackburn, Marie-Michelle Simon, Felicia Lazure, Tony Kwan, David H Wilson, Maryam Vahidyeganeh, Nawal Alsadi, Julia von Maltzahn, Yasuhiro Yamada, Arezu Jahani-Asl, Guillaume Bourque, Michael A Rudnicki, Vahab D Soleimani.

Cell fate and identity require timely activation of lineage-specific and concomitant repression of alternate-lineage genes. How this process is epigenetically encoded remains largely unknown. In skeletal muscle stem cells, the myogenic regulatory factors are well-established drivers of muscle gene activation but less is known about how non-muscle gene repression is achieved. Here, we show that the master epigenetic regulator, Repressor Element 1-Silencing Transcription factor (REST), also known as Neuron-Restrictive Silencer Factor (NRSF), is a key regulator of this process. We show that many non-lineage genes retain permissive chromatin state but are actively repressed by REST. Loss of functional REST in muscle stem cells and progenitors disrupts muscle specific epigenetic and transcriptional signatures, impairs differentiation, and triggers apoptosis in progenitor cells, leading to depletion of the stem cell pool. Consequently, REST-deficient skeletal muscle exhibits impaired regeneration and reduced myofiber growth postnatally. Collectively, our data suggests that REST plays a key role in safeguarding muscle stem cell identity by repressing multiple non-muscle lineage and developmentally regulated genes in adult mice.

DOI: https://doi.org/10.1038/s41467-025-62758-y
Am J Physiol Endocrinol Metab. 2025 Aug 11.

Distinct Endothelial Gene Responses to Acute Exercise in Skeletal Muscle.

Adele Addington, Rebecca M Wall, Xiaoran Wei, Sarah D Frate, Michelle L Olsen, Joshua C Drake, Siobhan Craige.

  Acute exercise causes a short-term stress, activating immediate gene expression responses. These responses are essential for cellular adaptation and resilience. Endothelial cells, positioned throughout the vasculature, play a central role in sensing and responding to these stress signals. As dynamic regulators of vascular tone, nutrient delivery, and cellular communication, endothelial cells are key integrators of metabolic adaptation. They coordinate intra- and inter-organ communication through the release of signaling molecules, shaping systemic responses to exercise. Despite their importance, the endothelial cell-specific transcriptional response to exercise remains poorly understood. To interrogate the transcriptional response to exercise in endothelial cells, we used NuTRAP (Nuclear Tagging and Translating Ribosome Affinity Purification) mouse technology which express EGFP/L10a under control of the vascular endothelial-cadherin promoter (NuTRAPEC). Following a single bout of acute exercise, ribosome-associated mRNA was isolated from endothelial cells from gastrocnemius of both exercised and sedentary animals. RNA sequencing confirmed endothelial cell-specific enrichment and revealed robust changes in gene expression. Exercise induced canonical early response genes (Nr4a2, Sik1, Slc25a25) and activated pathways related to angiogenesis, oxidative stress, stress kinase signaling, vascular remodeling and metabolic stress signaling. For context, we analyzed skeletal muscle fiber responses using NuTRAP mice driven by the human alpha-skeletal actin (NuTRAPSMF) mice. While some genes overlapped, skeletal muscle fiber-enriched pathways included hypoxia response and muscle development. These findings reveal a distinct microvascular endothelial transcriptional signature in skeletal muscle tissue in response to acute exercise, providing insight into the cell-type-specific mechanisms that underlie vascular adaptation and intercellular communication in response to physiologic stressors like exercise.

Keywords:  Acute exercise; endothelial cells; exerkines; transcriptomics; upstream regulators

DOI:  https://doi.org/10.1152/ajpendo.00250.2025
BMC Cancer. 2025 Aug 11. 25(1): 1300

Promoting mitochondrial fusion is protective against cancer-induced muscle detriments in males and females.

Francielly Morena, Seongkyun Lim, Ana Regina Cabrera, Toby L Chambers, Pieter J Koopmans, Stavroula Tsitkanou, Sabin Khadgi, Calvin Peterson, Eleanor R Schrems, Ruqaiza Muhyudin, Sepideh Shakeri, Kevin Zhao, Devan Mishra, Tyrone A Washington, Kevin A Murach, Nicholas P Greene.

   BACKGROUND: Skeletal muscle atrophy during cancer-induced cachexia remains a significant challenge in cancer management. Mitochondrial defects precede muscle mass and functional losses in models of cancer cachexia (CC). We hypothesized targeting Opa1-a key regulator of mitochondrial fusion-can attenuate LLC-induced CC outcomes.
METHODS: We utilized 1) in vivo transgenic Opa1 overexpression (OPA1 TG) in LLC-induced CC in vivo, and 2) BPG15 administration to induce Opa1 in vitro and in vivo.
RESULTS: OPA1 TG attenuated plantaris, gastrocnemius, and EDL loss with LLC in males and alleviated gastrocnemius loss in females. OPA1 TG had greater mitochondrial respiration in plantaris and white gastrocnemius, and lowered pMitoTimer Red Puncta (-63%), a proxy for mitophagy in males. OPA1 TG protected muscle contractility at physiological stimulation frequencies by up to 60% in female LLC mice. OPA1 TG enhanced the ratio of OPA1/DRP1 protein content-a proxy for fusion and fission balance-in males and females. In vitro, BGP-15 attenuated LLC conditioned media-induced myotube atrophy by ~ 9% concomitant with suppression of the transcriptional factor FoxO3, autophagy markers, and inflammatory cytokines. In vivo, BGP-15 improved contractility at lower frequencies (10-60 Hz), with LLC-BGP-15 showing up to 20% greater torque than LLC-control. BGP-15 treated LLC animals had 71% fewer pMitoTimer red puncta, suggesting attenuated mitophagy.
CONCLUSIONS: Promoting mitochondrial fusion via OPA1 induction improved cachectic outcomes in mice. Targeting OPA1providing provides a promising therapeutic approach for CC treatment.

Keywords:  BGP-15; Lewis Lung Carcinoma; Mitochondrial dynamics; Muscle contractility; OPA1

DOI:  https://doi.org/10.1186/s12885-025-14630-x
Front Physiol. 2025 ;16 1665619

Editorial: Exploring regenerative pathways in muscle repair.

Jeffrey Scott Otis, Barbara St Pierre Schneider, Paula Tavares.



Keywords:  muscle growth and function; muscle physiology/performance; muscle regeneration; muscle repair mechanisms; skeletal muscle health

DOI:  https://doi.org/10.3389/fphys.2025.1665619
Cells. 2025 Aug 06. pii: 1210. [Epub ahead of print]14(15):

Identification of CaVβ1 Isoforms Required for Neuromuscular Junction Formation and Maintenance.

Amélie Vergnol, Aly Bourguiba, Stephanie Bauché, Massiré Traoré, Maxime Gelin, Christel Gentil, Sonia Pezet, Lucile Saillard, Pierre Meunier, Mégane Lemaitre, Julianne Perronnet, Frederic Tores, Candice Gautier, Zoheir Guesmia, Eric Allemand, Eric Batsché, France Pietri-Rouxel, Sestina Falcone.

  Voltage-gated Ca2+ channels (VGCCs) are regulated by four CaVβ subunits (CaVβ1-CaVβ4), each showing specific expression patterns in excitable cells. While primarily known for regulating VGCC function, CaVβ proteins also have channel-independent roles, including gene expression modulation. Among these, CaVβ1 is expressed in skeletal muscle as multiple isoforms. The adult isoform, CaVβ1D, localizes at the triad and modulates CaV1 activity during Excitation-Contraction Coupling (ECC). In this study, we investigated the lesser-known embryonic/perinatal CaVβ1 isoforms and their roles in neuromuscular junction (NMJ) formation, maturation, and maintenance. We found that CaVβ1 isoform expression is developmentally regulated through differential promoter activation. Specifically, CaVβ1A is expressed in embryonic muscle and reactivated in denervated adult muscle, alongside the known CaVβ1E isoform. Nerve injury in adult muscle triggers a shift in promoter usage, resulting in re-expression of embryonic/perinatal Cacnb1A and Cacnb1E transcripts. Functional analyses using aneural agrin-induced AChR clustering on primary myotubes demonstrated that these isoforms contribute to NMJ formation. Additionally, their expression during early post-natal development is essential for NMJ maturation and long-term maintenance. These findings reveal previously unrecognized roles of CaVβ1 isoforms beyond VGCC regulation, highlighting their significance in neuromuscular system development and homeostasis.

Keywords:  CaVβ isoforms; Cacnb1; Long-read sequencing; neuromuscular junctions; promoters; skeletal muscle

DOI:  https://doi.org/10.3390/cells14151210
Cells. 2025 Aug 01. pii: 1190. [Epub ahead of print]14(15):

From Development to Regeneration: Insights into Flight Muscle Adaptations from Bat Muscle Cell Lines.

Fengyan Deng, Valentina Peña, Pedro Morales-Sosa, Andrea Bernal-Rivera, Bowen Yang, Shengping Huang, Sonia Ghosh, Maria Katt, Luciana Andrea Castellano, Lucinda Maddera, Zulin Yu, Nicolas Rohner, Chongbei Zhao, Jasmin Camacho.

  Skeletal muscle regeneration depends on muscle stem cells, which give rise to myoblasts that drive muscle growth, repair, and maintenance. In bats-the only mammals capable of powered flight-these processes must also sustain contractile performance under extreme mechanical and metabolic stress. However, the cellular and molecular mechanisms underlying bat muscle physiology remain largely unknown. To enable mechanistic investigation of these traits, we established the first myoblast cell lines from the pectoralis muscle of Pteronotus mesoamericanus, a highly maneuverable aerial insectivore. Using both spontaneous immortalization and exogenous hTERT/CDK4 gene overexpression, we generated two stable cell lines that retain proliferative capacity and differentiate into contractile myotubes. These cells exhibit frequent spontaneous contractions, suggesting robust functional integrity at the neuromuscular junction. In parallel, we performed transcriptomic and metabolic profiling of native pectoralis tissue in the closely related Pteronotus parnellii to define molecular programs supporting muscle specialization. Gene expression analyses revealed enriched pathways for muscle metabolism, development, and regeneration, highlighting supporting roles in tissue maintenance and repair. Consistent with this profile, the flight muscle is triglyceride-rich, which serves as an important fuel source for energetically demanding processes, including muscle contraction and cellular recovery. Integration of transcriptomic and metabolic data identified three key metabolic modules-glucose utilization, lipid handling, and nutrient signaling-that likely coordinate ATP production and support metabolic flexibility. Together, these complementary tools and datasets provide the first in vitro platform for investigating bat muscle research, enabling direct exploration of muscle regeneration, metabolic resilience, and evolutionary physiology.

Keywords:  CDK4; bat; flight muscle biology; hTERT; myoblast cell line; myotube; proliferation and differentiation; regeneration

DOI:  https://doi.org/10.3390/cells14151190
J Gen Physiol. 2025 Sep 01. pii: e202413679. [Epub ahead of print]157(5):

Stretch activation combats force loss from fatigue in fast-contracting mouse skeletal muscle fibers.

Philip C Woods, Douglas M Swank, Mark S Miller.

Stretch activation (SA) is the delayed increase in force following a rapid stretch and improves muscle performance during repetitive cyclical contractions in insect flight and cardiac muscles. Although historically considered too low to be physiologically relevant in skeletal muscle, our recent work showed that higher phosphate concentrations ([Pi]) increased SA in mouse soleus fibers. These results suggest SA has a role combating fatigue, which increases [Pi], lowers pH, and reduces active calcium concentration ([Ca2+]). To test this, we measured SA during Active, High [Ca2+] Fatigue and Low [Ca2+] Fatigue conditions in myosin heavy chain (MHC) I, IIA, IIX, and IIB fibers from mouse soleus and extensor digitorum longus muscles. In the fast-contracting MHC II fibers, calcium-activated isometric tension (F0) decreased from Active to High [Ca2+] Fatigue to Low [Ca2+] Fatigue, as expected. Remarkably, SA tension (FSA) was not decreased but remained unchanged or increased under High and Low [Ca2+] Fatigue, except for a small decrease in MHC IIB fibers in Low [Ca2+] Fatigue compared with Active. This results in SA's percent contribution to total tension production (FSA/[F0 + FSA]) being much greater (58-114%) under fatiguing conditions in fast-contracting MHC II fibers. The SA tension peak for MHC I fibers was not visibly apparent under either fatigue condition, and the peak was about 20% of MHC II fibers' peaks under active conditions. Our results show SA improves force production under fatiguing conditions in MHC II fibers, which could play an important role in increasing endurance for muscles that are lengthened prior to shortening.

DOI: https://doi.org/10.1085/jgp.202413679
Exp Mol Pathol. 2025 Aug 14. pii: S0014-4800(25)00042-5. [Epub ahead of print]143 104992

Research progress of sarcopenia: Diagnostic advancements, molecular mechanisms, and therapeutic strategies.

Hao-Lin Wang, Long-Long Liu, Ze-Yu Tan, Yuan Zhou, Jing Zhang, Lin Zhai, Qian Xie, Rong-Hua Liu.

  Muscle atrophy or loss is an important sign of human aging. As the aging society approaches and human lifespan prolongs, sarcopenia has emerged as one of the significant risks influencing the quality of life of the elderly. Sarcopenia is a progressive geriatric syndrome characterized by the deterioration of skeletal muscle mass and function, which can result in an increased risk of falls, fractures, restricted physical activity, disability, mortality, and a remarkable escalation in the risk of cardiovascular diseases among the elderly. This work synthesizes recent advances in sarcopenia research, critically evaluating diagnostic frameworks, histopathological hallmarks, and molecular pathways driving disease progression. Additionally, we provide an in-depth analysis of evidence-based exercise and nutritional interventions, identifying key research gaps. These insights offer valuable references for future research on sarcopenia and clinical management, as well as lifestyle interventions such as exercise and nutrition.

Keywords:  Aging; Diagnostic; Molecular mechanisms; Sarcopenia; Therapeutic strategies

DOI:  https://doi.org/10.1016/j.yexmp.2025.104992
Function (Oxf). 2025 Aug 15. pii: zqaf040. [Epub ahead of print]

Androgen-Mediated Regulation of Skeletal Muscle Mass: A Ticking Clock.

David C Hughes, Zachary R Hettinger, Colleen S Deane.

DOI: https://doi.org/10.1093/function/zqaf040
J Cell Sci. 2025 Aug 11. pii: jcs.263712. [Epub ahead of print]

Dystrophin interacts with Msp300 to regulate myonuclear positioning and microtubule organization.

Jorel R Padilla, Yunshu Qiu, Gretchen Kimmel, Grace Aleck, Lillie Ferreira, Sharon Wu, William Gibbons, Torrey R Mandigo, Eric S Folker.

  During Drosophila myogenesis, myonuclei are actively moved during embryogenesis, and their spacing is maintained through an anchoring mechanism in the fully differentiated myofiber. While we have identified microtubule associated proteins, motors, and nuclear envelope proteins that regulate myonuclear spacing, the developmental time during which each gene functions has not been tested. Here we have identified a Dystrophin as required only for the maintenance of myonuclear spacing. Furthermore, we demonstrate that Dystrophin genetically interacts with the Msp300, a gene encoding a KASH-domain protein, to maintain myonuclear spacing. Mechanistically, both Dystrophin and Msp300 regulate microtubule organization. Specifically, in animals with disrupted expression of both Dystrophin and Msp300, microtubule colocalization with thin filaments is reduced. Taken altogether, these data indicate that the peripheral membrane protein Dystrophin, and the outer nuclear membrane protein Msp300, together regulate the organization of the microtubule network which then acts as an anchor to restrict myonuclear movement in contractile myofibers. These data are consistent with growing evidence that myonuclear movement and myonuclear spacing are critical to muscle development, muscle function, and muscle repair and provide a mechanism to connect disparate muscle diseases.

Keywords:  Dystrophin; LINC complex; Microtubule; Msp300; Muscle; Nuclear movement

DOI:  https://doi.org/10.1242/jcs.263712
Curr Opin Clin Nutr Metab Care. 2025 Aug 12.

Antiaging agents: pharmacological therapy targeted at preserving skeletal muscle size and function in aging adults.

Jeremy R Pearson, Jenna M Bartley, Arny A Ferrando, David D Church.

   PURPOSE OF REVIEW: Aging population rates are significantly increasing and improved quality of life during aging is a top priority. The decline in skeletal muscle mass and strength is a major concern with aging, as it impairs the ability to perform activities of daily living and significantly diminishes quality of life. Effective strategies to counteract this decline are necessary for supporting longevity and enhancing quality of life in older adults.
RECENT FINDINGS: In addition to exercise and nutritional interventions, pharmaceutical compounds are routinely explored as a means of maintaining muscle size, strength and function during the aging process. The addition of exercise would offer greater effects, although combined evidence is lacking. In this review, we highlight several pharmacological compounds, including anabolic agents, caloric restriction mimetics, metformin, and rapamycin, targeted at skeletal muscle that may enhance the effect of exercise. These trials have demonstrated muscle retention and growth, as well as improved strength and functional outcomes.
SUMMARY: Pharmacological therapy shows promise to improve skeletal muscle mass and function in older adults. The addition of exercise with these compounds would be expected to further enhance skeletal muscle adaptations and quality of life, especially in sarcopenic adults.

Keywords:  function; healthy aging; longevity; pharmaceuticals; skeletal muscle

DOI:  https://doi.org/10.1097/MCO.0000000000001159
Cells. 2025 Jul 25. pii: 1150. [Epub ahead of print]14(15):

Long-Term Engraftment and Satellite Cell Expansion from Human PSC Teratoma-Derived Myogenic Progenitors.

Zahra Khosrowpour, Nivedha Ramaswamy, Elise N Engquist, Berkay Dincer, Alisha M Shah, Hossam A N Soliman, Natalya A Goloviznina, Peter I Karachunski, Michael Kyba.

  Skeletal muscle regeneration requires a reliable source of myogenic progenitor cells capable of forming new fibers and creating a self-renewing satellite cell pool. Human induced pluripotent stem cell (hiPSC)-derived teratomas have emerged as a novel in vivo platform for generating skeletal myogenic progenitors, although in vivo studies to date have provided only an early single-time-point snapshot. In this study, we isolated a specific population of CD82+ ERBB3+ NGFR+ cells from human iPSC-derived teratomas and verified their long-term in vivo regenerative capacity following transplantation into NSG-mdx4Cv mice. Transplanted cells engrafted, expanded, and generated human Dystrophin+ muscle fibers that increased in size over time and persisted stably long-term. A dynamic population of PAX7+ human satellite cells was established, initially expanding post-transplantation and declining moderately between 4 and 8 months as fibers matured. MyHC isoform analysis revealed a time-based shift from embryonic to neonatal and slow fiber types, indicating a slow progressive maturation of the graft. We further show that these progenitors can be cryopreserved and maintain their engraftment potential. Together, these findings give insight into the evolution of teratoma-derived human myogenic stem cell grafts, and highlight the long-term regenerative potential of teratoma-derived human skeletal myogenic progenitors.

Keywords:  PAX7; iPS cells; regeneration; satellite cells; skeletal muscle; teratoma; transplantation; xenograft

DOI:  https://doi.org/10.3390/cells14151150
JCI Insight. 2025 Aug 14. pii: e195836. [Epub ahead of print]

Differential pathology and susceptibility to MBNL loss across muscles in myotonic dystrophy mouse models.

Mackenzie L Davenport, Amaya Fong, Gloria Montoya-Vazquez, Maria Fernanda Alves de Moura, Jodi L Bubenik, Maurice S Swanson.

  There are two subtypes of myotonic dystrophy, DM1 and DM2, each caused by repeat expansion mutations. The leading pathogenic mechanism is RNA mediated toxicity whereby (C)CUG expansions sequester the muscleblind-like (MBNL) family of RNA binding proteins. However, key differences exist in muscle involvement patterns and histopathology between DM1 and DM2. The cause of these disparities both in how the muscles are affected within each disease and between the two diseases is unknown, and it is unclear if current DM mouse models recapitulate these differences or develop differential muscle susceptibility. Here, we examined the expression of disease-relevant genes across healthy human muscles from a transcriptomic atlas and collected a series of muscles from Mbnl knockout mice to evaluate characteristic histologic and molecular features of DM pathology. Our results indicate that MBNL loss discordantly affects muscles, likely through a splicing independent mechanism, and results in a fiber atrophy profile more like DM1 than DM2. These findings point to a predominant role for MBNL loss in muscle pattern involvement in DM1, provide further evidence for additional DM2 pathomechanisms, and have important implications for muscle choice when performing analyses in new mouse models and evaluating therapeutic modalities and biomarkers.

Keywords:  Genetic diseases; Genetics; Mouse models; Muscle; Muscle biology

DOI:  https://doi.org/10.1172/jci.insight.195836
Sci Rep. 2025 Aug 11. 15(1): 29312

Transcriptomic profiling of skeletal muscle in the DMDmdx rat model of Duchenne muscular dystrophy.

Abdolvahab Ebrahimpour Gorji, Katarzyna Kliczkowska, Marcin Ollik, Caroline Le Guiner, Jacek Wilczak, Wojciech Bielecki, Piotr Ostaszewski, Masoud Shirali, Zahra Roudbari, Tomasz Sadkowski.

  Duchenne muscular dystrophy (DMD) is a severe X-linked recessive disorder caused by a mutation in the Dmd gene, leading to progressive muscle degradation, increasing weakness, and typically resulting in death before the third decade of life. To investigate the pathobiology of DMD, this study employed the Sprague-Dawley Dmd-mutated rat model (DMDmdx) and analyzed gene expression profiles and pathological molecular pathways. The methods used included histopathological, biochemical, and transcriptomic analyses of dystrophic skeletal muscle from DMDmdx and wild-type (WT) individuals. Histological analysis of skeletal muscle tissue from DMDmdx rats revealed multifocal necrosis, fibrosis, and inflammation, whereas WT rats displayed normal muscle architecture. Biochemical analysis revealed significant alterations in plasma markers of muscle damage and metabolism in DMDmdx rats compared to WT controls, including elevated AST, ALT, ALP, CPK, and LDH levels. Additionally, oxidative status measurements showed reduced antioxidant capacity and increased lipid peroxidation in dystrophic skeletal muscle, as evidenced by lower TAS, GR, GPx, and SOD activities and higher TBARS levels. RNA-seq analysis identified 3,615 differentially expressed genes between the two groups, associated with muscle contraction, extracellular matrix (ECM) organization, and cytoskeleton organization. Notably, Dmd, Actc1, Col6a1, and Mmp2 were significantly downregulated. Gene ontology and pathway enrichment analyses indicated dystrophic changes in skeletal muscle, disruptions in calcium homeostasis, and alterations in actin cytoskeleton regulation. KEGG and Reactome pathway analyses revealed upregulation of the MAPK signaling and immune system pathways and downregulation of the ECM organization pathway. These findings support the hypothesis that targeting complex intracellular signaling pathways in DMD may represent a promising therapeutic strategy. Given that the DMDmdx rat model closely mimics human DMD pathology compared to other animal models, it offers a more realistic platform for studying the molecular mechanisms of the disease and improving the translational potential of therapeutic approaches.

Keywords:  Duchenne muscular dystrophy (DMD); Dystrophin gene mutation; MAPK signaling pathway, DMD mdx rat model; RNA-seq gene expression analysis; Skeletal muscle degeneration

DOI:  https://doi.org/10.1038/s41598-025-14756-9
J Cachexia Sarcopenia Muscle. 2025 Aug;16(4): e70045

Human Pluripotent Stem Cell-Derived Skeletal Muscle Organoid Model of Aging-Induced Sarcopenia.

Seongjun Park, Min-Kyoung Shin, Dong Seok Jeong, Xin Yi Yeo, Yeo Jin Kim, Junaid Muhammad, Minju Kim, Seongeun Gu, Jeoung Eun Lee, Yunjin Park, Su Bin Lim, Ji Young Mun, Sangyong Jung, Dong Ryul Lee, Junghyun Jo.

   BACKGROUND: Sarcopenia is defined by the age-related loss of muscle mass and function, with an impaired regenerative capacity of satellite cells (SCs). Despite their recognized importance in muscle regeneration, human model-based studies on SCs in sarcopenia are still lacking, limiting our understanding of their role in age-related muscle loss. Here, we aimed to develop a sarcopenia model using human pluripotent stem cells (hPSCs)-derived skeletal muscle organoids (hSkMOs) and prevent the sarcopenia progression by testosterone treatment.
METHODS: The 3D hSkMOs were generated from hPSC and exhibited structurally and functionally mature muscle fibres and spinal-derived neurons including motor neurons and interneurons. The proportion of muscle and the diameter of muscle fibres were assessed. To investigate the acute pro-inflammatory response and intrinsic regenerative capacity of hSkMOs, we induced sarcopenia-like conditions by TNF-α treatment for 2 days and analysed. To model aging-induced sarcopenia and investigate the preventive effect of testosterone, chronic TNF-α treatment was applied, followed by testosterone administration. Histological, biochemical, molecular and electrophysiological analyses were conducted in various experiments.
RESULT: We employed a stepwise differentiation protocol from 2D paraxial mesodermal induction to 3D myogenic specification, concluding with a maturation culture system. We observed that the majority of cells were T/BRA- and TBX6-positive (+) paraxial mesodermal progenitors (T/BRA+, 82.04%; TBX6+, 78.18%), whereas the neuromesodermal progenitors demonstrated a relatively low proportion (T/BRA+/SOX2+, 15.91%; TBX6+/SOX2+, 11.45%). Single-nucleus RNA-sequencing and extensive immunohistochemistry confirmed the presence of the myogenic lineage cell types (myogenic progenitors/SCs, myocytes, muscle fibres) and the neural lineage cell types (spinal-derived interneurons, motor neurons, glial cells, Schwann cells). Additionally, the growth of MyHC+ muscle fibres reached twice the thickness on Day 100 compared to that on Day 50 (p < 0.0001). We subjected them to TNF-α treatment and analysed. Western blot analysis confirmed that TNF-α/NF-κB pathway associated factors such as NF-κB p65, IκB-α and AKT were highly phosphorylated (p < 0.05, p < 0.001). The administration of testosterone increased the proportion of activated SCs (PAX7+/MYOD+, 7.97%; PAX7+/Ki67+, 7.03%) compared to the TNF-α group (PAX7+/MYOD+, 2.29%; PAX7+/Ki67+, 2.07%, p < 0.001). The administration of testosterone increased the Cross-Sectional-Area (987.1 μm2) compared to the TNF-α group (644.7 μm2, p < 0.01).
CONCLUSIONS: We successfully developed a hSkMOs to demonstrate the structural maturity of the skeletal muscle and its functional interaction with spinal-derived interneurons and motor neurons. Furthermore, we demonstrated that our hSkMOs are useful for modelling aging-induced sarcopenia and providing a valuable platform for testing therapeutic interventions.

Keywords:  aging; human pluripotent stem cell; human skeletal muscle organoid; sarcopenia; satellite cell; testosterone

DOI:  https://doi.org/10.1002/jcsm.70045
Mol Ther Methods Clin Dev. 2025 Sep 11. 33(3): 101534

AAV-shDUX4 provides short-term benefits but limited long-term efficacy in a DUX4 mouse model of FSHD.

S Sohn, S Reid, M Bowen, C Hudon, E Corbex, B Morel, C Hourde, V Mariot, J Dumonceaux.

  The aberrant expression of the toxic transcription factor DUX4 in skeletal muscle is a hallmark of facioscapulohumeral muscular dystrophy. Effective therapeutic strategies will likely require the inhibition of DUX4, with adeno-associated virus (AAV)-mediated therapies being among the promising approaches. However, the regenerative nature of muscle tissue can impact the long-term efficacy of AAV transduction, leading to reduced transgene persistence and diminishing the sustainability of gene inhibition over time. In this study, we utilized an AAV vector carrying a short hairpin RNA targeting DUX4 (shDUX4) to suppress DUX4 expression in the ACTA1-MCM; FLExDUX4/+ mouse model, which exhibits progressive muscular dystrophy. One month following AAV administration, the treatment significantly mitigated the DUX4-associated pathological features, including molecular, histopathological, and functional force-velocity-endurance (FoVE) parameters. However, by 10 months post-treatment, the therapeutic effects had substantially diminished, with most pathological markers remaining uncorrected and no sustained improvement in muscle force. This decline in therapeutic effect was associated with reduced DUX4 knockdown and a concurrent loss of AAV genomes. These findings highlight that although AAV-mediated gene therapy holds significant promise for FSHD treatment, challenges such as muscle fiber turnover and AAV genome dilution must be overcome to achieve sustained therapeutic benefit.

Keywords:  AAV; DUX4; FSHD; RNA interference; facioscapulohumeral muscular dystrophy; muscle regeneration; skeletal muscle pathology; therapy; transgene persistence

DOI:  https://doi.org/10.1016/j.omtm.2025.101534
Int J Mol Sci. 2025 Aug 06. pii: 7616. [Epub ahead of print]26(15):

Glucocorticoid-Mediated Skeletal Muscle Atrophy: Molecular Mechanisms and Potential Therapeutic Targets.

Uttapol Permpoon, Jiyeong Moon, Chul Young Kim, Tae-Gyu Nam.

  Skeletal muscle atrophy is a critical health issue affecting the quality of life of elderly individuals and patients with chronic diseases. These conditions induce dysregulation of glucocorticoid (GC) secretion. GCs play a critical role in maintaining homeostasis in the stress response and glucose metabolism. However, prolonged exposure to GC is directly linked to muscle atrophy, which is characterized by a reduction in muscle size and weight, particularly affecting fast-twitch muscle fibers. The GC-activated glucocorticoid receptor (GR) decreases protein synthesis and facilitates protein breakdown. Numerous antagonists have been developed to mitigate GC-induced muscle atrophy, including 11β-HSD1 inhibitors and myostatin and activin receptor blockers. However, the clinical trial results have fallen short of the expected efficacy. Recently, several emerging pathways and targets have been identified. For instance, GC-induced sirtuin 6 isoform (SIRT6) expression suppresses AKT/mTORC1 signaling. Lysine-specific demethylase 1 (LSD1) cooperates with the GR for the transcription of atrogenes. The kynurenine pathway and indoleamine 2,3-dioxygenase 1 (IDO-1) also play crucial roles in protein synthesis and energy production in skeletal muscle. Therefore, a deeper understanding of the complexities of GR transactivation and transrepression will provide new strategies for the discovery of novel drugs to overcome the detrimental effects of GCs on muscle tissues.

Keywords:  IDO-1; LSD1; SIRT6; atrogenes; glucocorticoids; muscle atrophy

DOI:  https://doi.org/10.3390/ijms26157616
Front Syst Biol. 2025 ;5 1593229

Exploring the disconnect: mechanisms underpinning the absence of physical function improvement with SGLT2 inhibitors.

Cian Sutcliffe, Jack A Sargeant, Thomas Yates, Melanie J Davies, Luke A Baker.

  Current evidence suggests sodium-glucose cotransporter 2 inhibitors (SGLT2i) do not consistently improve patient physical function, despite improvements in clinical symptoms and reductions in both adiposity and body weight. We highlight heterogenous methodologies in SGLT2i physical function trials. We then provide context to these findings by collating new data which describes how reduced glycaemia with SGLT2i alters numerous physiological processes and discuss how these alterations may diminish or prevent expected functional improvements. Alterations include changes to energy homeostasis, pancreatic hormones, muscle metabolism, physical activity, and appetite regulation. Current evidence in humans is limited and the mechanistic interaction between SGLT2i, skeletal muscle, and physical function remains incompletely understood. Future investigations must embed comprehensive molecular techniques within suitably designed clinical trials to determine how skeletal muscle health and patient mobility is influenced by acute and long term SGLT2i prescription.

Keywords:  Glucagon-like peptide 1 (GLP-1) receptor agonist; SGLT2 (sodium-glucose cotransporter 2) inhibitor; glucose lowering medication; mobility and ageing; physical function; skeletal muscle

DOI:  https://doi.org/10.3389/fsysb.2025.1593229
Cell Calcium. 2025 Jul 28. pii: S0143-4160(25)00066-1. [Epub ahead of print]131 103057

TRPV1 signaling in skeletal muscle: A mini review of physiological and pathological roles.

Xiaoqing Ding, Chenyu Zhu, Qi Lu, Yuhao Zhang, Binghong Gao.

  Transient receptor potential vanilloid subtype 1 (TRPV1) is a non-selective cation channel that is mainly sensitive to stimuli such as high temperature, acidic environment, and capsaicin. Studies have reported that TRPV1 is expressed in skeletal muscle tissues and is involved in the regulation of a variety of physiological and pathological processes in skeletal muscle, but its regulatory mechanisms have not been analyzed and discussed. For this reason, we summarized the role of TRPV1 in skeletal muscle function and the mechanism of its influence on skeletal muscle-related physiopathological changes, such as myotube formation, inflammation, autophagy, mitochondrial biogenesis, and energy metabolism, which provides a theoretical basis and therapeutic target for understanding TRPV1 regulation of skeletal muscle-related diseases.

Keywords:  Ca(2+); Muscle strength; Skeletal muscle; Transient receptor potential vanilloid 1 (TRPV1)

DOI:  https://doi.org/10.1016/j.ceca.2025.103057
Front Vet Sci. 2025 ;12 1637277

miRNA-182-5p promotes myogenic differentiation of C2C12 cells via the suppression of ZBTB7A.

Mengyuan Zhang, Yongheng Wang, Shan Shan, Siyu Liu.

   Introduction: Skeletal muscle possesses a significant regenerative capacity, which is largely mediated by myogenic satellite stem cells. MicroRNAs are known regulators of muscle development. miR-182-5p plays important roles in cell proliferation and migration in various cell types and pathologies. However, its specific role in myogenesis remains unclear. In this study, we elucidated the function of miR-182-5p in the differentiation of C2C12 myoblasts.
Methods: We evaluated the effects of overexpression and inhibition of miR-182-5p in C2C12 cells on its myogenic differentiation ability using Giemsa staining. We also determined the mRNA and protein levels of myogenic differentiation marker genes in these cells at different time points after the induction of differentiation in these cells. The target of miR-182-5p was predicted using bioinformatics tools and validated using luciferase reporter assay.
Results: Overexpression of miR-182-5p via mimic transfection promoted differentiation, while its inhibition by a specific compound attenuated this process. Furthermore, using bioinformatic prediction and validation via a dual-luciferase reporter assay, we identified zinc finger and BTB domain containing 7A (Zbtb7a) as a direct target gene of miR-182-5p during C2C12 myogenic differentiation.
Conclusion: Our findings indicate that miR-182-5p positively regulates C2C12 differentiation, partly via the suppression of Zbtb7a and suggest that appropriate miR-182-5p expression is essential for normal myogenesis.

Keywords:  C2C12; ZBTB7A; dual-luciferase reporter; miR-182-5p; myogenic differentiation

DOI:  https://doi.org/10.3389/fvets.2025.1637277
Anim Biosci. 2025 Aug 12.

Transcriptome analysis of injured muscle identifies new candidate genes for satellite cell growth and myofiber formation during early muscle regeneration.

Zhuning Yuan, Xian Tong, Xianyao Luo, Liping Pan, Hoi-Ka Wu, Rong Xu, Ziyun Liang, Xunhe Huang, Delin Mo.

   Objective: : The self-repair capacity of skeletal muscle arouses interest in studying satellite cell activity and myofiber formation. The major molecular networks of satellite cell activity have been extensively studied. However, the mechanism by which micro-environmental factors regulate satellite cell activity for early muscle regeneration still remains poorly understood.
Methods: : Hematoxylin and eosin (HE) staining and immunofluorescence for embryonic myosin heavy chain (eMyHC) were performed on control and injured muscle samples at 12-, 24-, 36-, 48-, 60-, 72-, and 84-hour post-injury. Additionally, eMyHC immunofluorescence was conducted on muscle samples collected 96 hours post-injury from three mice. RNA sequencing (RNA-seq) and quantitative PCR (qPCR) were performed on samples from 24 mice, including controls and samples at 12-, 24-, and 84-hour post-injury.
Results: : In this research, 516 immune-related and 177 hormone response-related genes were up-regulated significantly. Further, statistical analysis indicated that the number of differentially expressed genes (DEGs) between up- and down-regulated immune system-related DEGs was similar with that of hormone response-related DEGs. Notably, p53 signaling pathway was significantly enriched throughout early muscle regeneration. Based on patterns of crucial myogenic genes expression, 326 and 320 candidate genes related to satellite cell growth and myofiber formation were obtained, respectively. Furthermore, through interaction network analysis, 41 immune factors, including S100a9，Csf3r，Cxcl3，Ppbp，Ccl3，Il1rn were found, which may regulate satellite cell activation, migration and proliferation. Likewise, 16 cell adhesion factors (Col1a2, Cdh2, Thbs2, etc.) may be involved in myofiber formation.
Conclusion: : This study leveraged transcriptomic analysis to uncover key candidate genes and biological processes involved in early muscle regeneration. These findings enhance our understanding of the molecular mechanisms underlying muscle repair and offer insights for future therapeutic strategies.

Keywords:  Cell adhesion; Immune system; Myofiber formation; Satellite cell growth; Transcriptome

DOI:  https://doi.org/10.5713/ab.24.0859
J Cachexia Sarcopenia Muscle. 2025 Aug;16(4): e70044

Alpha-Ketoisocaproate Attenuates Muscle Atrophy in Cancer Cachexia Models.

Pooreum Lim, Sang Woo Woo, Jihye Han, Young Lim Lee, Jin Ju Lim, Yeong Hoon Kang, Ji Wook Moon, Jeong Min Nam, Jeong Hyeon Kim, Donghun Kim, Jae Ho Shim, Hyeon Soo Kim.

   BACKGROUND: Cancer-associated cachexia (CAC) is a multifactorial syndrome characterised by progressive loss of muscle mass with limited Food and Drug Administration treatments. Although emerging evidence suggests that l-leucine and β-hydroxy-β-methyl butyrate (HMB) have potential for treating CAC, the role of α-ketoisocaproate (KIC), a metabolite of l-leucine, remains unclear. Therefore, this study explored the use of KIC as a therapeutic agent for CAC-induced muscle atrophy by targeting myostatin.
METHODS: We evaluated the effect of KIC on muscle atrophy using BALB/c mice and C2C12 myotubes as models of C26- and 4T1-induced CAC. Male and female mice were injected with C26 and 4T1 cells, respectively. Grip strength was measured weekly, and mice were sacrificed 4 weeks post-injection for muscle collection. C2C12 myotubes were treated with conditioned media (CM) derived from C26 or 4T1 cells.
RESULTS: KIC suppressed mRNA expression of myostatin, a key regulator of muscle atrophy, more effectively than did l-leucine (-26.37 ± 4.11%, p < 0.01). KIC enhanced protein turnover in C2C12 myotubes and maintained 50% cell viability at high concentrations (KIC: 4.68 mM, HMB: 3.11 mM). Following CM treatment, KIC suppressed MuRF1 and MAFbx expression in a myostatin-dependent manner, thereby reducing their polyubiquitination. KIC restored Akt-FoxO3a phosphorylation, leading to improved myotube diameter (+63.8 ± 25.71%, p < 0.05) and fusion index (+51.9 ± 22.6%, p < 0.05). Immunofluorescence and nuclear fractionation revealed that KIC reduced FoxO3a nuclear accumulation. CM reduced p-Akt-FoxO3a interaction, which was rescued by KIC. In vivo, KIC administration increased body weight (11.11 ± 8.53%), grip strength (24.76 ± 10.58%), and skeletal muscle mass (p < 0.001) in C26 tumour-bearing mice. Protein expression of myostatin in the tibialis anterior (TA) muscle (-23.57 ± 12.22%, p < 0.05) and serum (-52.11 ± 3.56%, p < 0.001) was lower in KIC-treated mice (n = 12) compared with that in the controls. KIC increased the mean fibre cross-sectional area in TA (24.51 ± 14.14%, p < 0.01). In 4T1 tumour-bearing mice, KIC improved body weight (13.10 ± 10.76%) and grip strength (7.42 ± 4.33%) (p < 0.001, n = 10). Serum myostatin levels (-57.43 ± 9.46%, p < 0.001) and skeletal muscle weight were reduced in KIC-treated mice (n = 10).
CONCLUSION: Our findings demonstrate that KIC improves muscle function in CAC-induced muscle atrophy by regulating myostatin expression in skeletal muscle via the Akt-FoxO3a pathway. Thus, KIC has been proposed as a potential therapeutic agent against CAC.

Keywords:  Akt; FoxO3a; alpha‐ketoisocaproate; cancer cachexia; myostatin; protein turnover

DOI:  https://doi.org/10.1002/jcsm.70044
Biofactors. 2025 Jul-Aug;51(4):51(4): e70037

Diverse Inhibitors of De Novo Purine Synthesis Promote AICAR-Induced AMPK Activation and Glucose Uptake in L6 Myotubes.

Klemen Dolinar, Katarina Miš, Katja Šopar, Mateja Šutar, Meta Božič, Matic Kolar, Tim Hropot, Pablo M Garcia-Roves, Alexander V Chibalin, Sergej Pirkmajer.

  Methotrexate, an immunosuppressant and anticancer drug, promotes glucose uptake and lipid oxidation in skeletal muscle via activation of AMP-activated protein kinase (AMPK). Methotrexate promotes AMPK activation by inhibiting 5-aminoimidazole-4-carboxamide ribonucleotide (ZMP) formyltransferase/inosine monophosphate (IMP) cyclohydrolase (ATIC), which converts ZMP, an endogenous purine precursor and an active form of the pharmacological AMPK activator AICAR, to IMP during de novo purine synthesis. In addition to methotrexate, inhibition of purine synthesis underpins the therapeutic effects of a number of commonly used immunosuppressive, anticancer, and antimicrobial drugs, raising the question of whether activation of AMPK in skeletal muscle could be a recurrent feature of these drugs. Using L6 myotubes, we found that AICAR-induced AMPK activation and glucose uptake were enhanced by inhibitors of the conversion of IMP to GMP (mycophenolate mofetil) or of IMP to AMP (alanosine) as well as by indirect inhibitors of human (trimetrexate) and bacterial ATIC (sulfamethoxazole). 6-Mercaptopurine, which inhibits the conversion of IMP to GMP and AMP, activated AMPK, increased glucose uptake, and suppressed insulin signaling, but did not enhance the effect of AICAR. As determined by measuring oxygen consumption rate, none of these agents suppressed mitochondrial function. Overall, our results indicate that IMP metabolism is a gateway for the modulation of AMPK and its metabolic effects in skeletal muscle cells.

Keywords:  AMP‐activated protein kinase (AMPK); folate metabolism; glucose uptake; insulin signaling; purine metabolism; skeletal muscle cells

DOI:  https://doi.org/10.1002/biof.70037
Front Genet. 2025 ;16 1607575

Identification of key modules and hub genes for sepsis-induced myopathy using weighted gene co-expression network analysis.

Siming Lin, Kexin Cai, Ai Chen, Weibin Wu, Guili Lian, Shaodan Feng, Zhihong Lin, Liangdi Xie.

   Background: Sepsis-induced myopathy (SIM) is a severe complication of sepsis, leading to significant muscle dysfunction and increased mortality. The molecular mechanisms underlying SIM remain poorly understood, necessitating comprehensive studies to identify potential therapeutic targets. This study aims to explore the molecular basis of SIM through gene expression analysis and bioinformatics approaches.
Methods: In this study, we employed a lipopolysaccharide-induced mouse model to investigate the molecular basis of SIM. We conducted comprehensive RNA sequencing of the gastrocnemius muscle, which resulted in the identification of 1,166 genes exhibiting altered expression levels. To further analyze the data, we applied weighted gene co-expression network analysis (WGCNA) to distinguish critical gene clusters associated with SIM. Additionally, we performed functional enrichment analyses using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein-protein interaction (PPI) network approaches.
Results: Our findings revealed that the identified gene clusters predominantly pertained to immune response, inflammation, and apoptosis pathways. Notably, validation through real-time quantitative polymerase chain reaction (RT-qPCR) confirmed the significant upregulation of key hub genes, including Cxcl10, Il6, and Stat1. Receiver Operating Characteristic (ROC) curve analysis further indicated the potential diagnostic utility of these hub genes. Additionally, leveraging the Connectivity Map (CMAP) database allowed us to predict six potential pharmacological agents-halcinonide, lomitapide, TG-101348, GSK-690693, loteprednol, and indacaterol-that might serve as therapeutic interventions for SIM.
Conclusion: This research advances our understanding of the molecular basis of SIM, presenting new diagnostic biomarkers and potential drug targets. Further studies with larger clinical datasets are warranted to validate these findings and explore the therapeutic potential of the identified drugs.

Keywords:  WGCNA; bioinformatics; biomarkers; hub genes; sepsis-induced myopathy; skeletal muscle

DOI:  https://doi.org/10.3389/fgene.2025.1607575
Cells. 2025 Jul 28. pii: 1160. [Epub ahead of print]14(15):

The Anti-Myogenic Role of Tetranectin and Its Inhibition by Epigallocatechin-3-Gallate Enhances Myogenesis.

Amar Akash, Jihoe Kim.

  Tetranectin (TN) is a plasminogen-binding protein found in human serum. Although it has been suggested to be closely related to various stem cell differentiation, including myogenesis, the role of TN in muscle development remains unclear. In this study, we identified TN as an anti-myogenic factor during the differentiation of C2C12 satellite cells. The exogenous supplementation of TN inhibited myogenic differentiation, whereas differentiation was significantly enhanced in the TN-depleted medium. Epigallocatechin-3-gallate (EGCG), a catechin abundant in green tea, significantly enhanced myogenic differentiation by reducing TN levels in the medium and downregulating TN gene expression during the differentiation process. These results demonstrate that EGCG promotes myogenesis by inhibiting TN at both the transcriptional and functional levels, highlighting TN as a promising therapeutic target for muscle regeneration disorders.

Keywords:  anti-myogenic factor; epigallocatechin gallate; muscle regeneration; myogenesis; tetranectin

DOI:  https://doi.org/10.3390/cells14151160
Aging (Albany NY). 2025 Aug 09. 17

The myokine FGF21 associates with enhanced survival in ALS and mitigates stress-induced cytotoxicity.

Abhishek Guha, Ying Si, Reed Smith, Brijesh K Singh, Benisa Zogu, Angad Yadav, Katherine A Smith, Mohamed Kazamel, Nan Jiang, Ritchie Ho, Anna Thalacker-Mercer, Shaida A Andrabi, Joao D Tavares Da Silva Pereira, Juliana S Salgado, Manasi Agrawal, Emina Horvat Velic, Peter H King.

  Amyotrophic lateral sclerosis (ALS) is an age-related and fatal neurodegenerative disease characterized by progressive muscle weakness. There is marked heterogeneity in clinical presentation, progression, and pathophysiology with only modest treatments to slow disease progression. Molecular markers that provide insight into this heterogeneity are crucial for clinical management and identification of new therapeutic targets. In a prior muscle miRNA sequencing investigation, we identified altered FGF pathways in ALS muscle, leading us to investigate FGF21. We analyzed human ALS muscle biopsy samples and found a large increase in FGF21 expression with localization to atrophic myofibers and surrounding endomysium. A concomitant increase in FGF21 was detected in ALS spinal cords which correlated with muscle levels. FGF21 was increased in the SOD1G93A mouse beginning in presymptomatic stages. In parallel, there was dysregulation of the co-receptor, β-Klotho, with higher levels detected in ALS muscle biopsies and lower levels in post-mortem muscle compared to controls. Plasma FGF21 levels were increased in ALS patients and high levels correlated with slower disease progression, prolonged survival, and increased body mass index. In cellulo, FGF21 was induced in differentiating muscle cells and ectopic treatment with FGF21 enhanced muscle differentiation. Ectopic FGF21 mitigated oxidative stress-induced loss of viability in iPSC-derived ALS motor neurons and muscle cells expressing SOD1G93A. In summary, FGF21 is a novel biomarker in ALS which exerts trophic effects in the neuromuscular system.

Keywords:  ALS biomarker; fibroblast growth factor 21; human skeletal muscle; motor neurons; β-Klotho

DOI:  https://doi.org/10.18632/aging.206298
J Cachexia Sarcopenia Muscle. 2025 Aug;16(4): e70041

Sepsis Induces Long-Term Muscle and Mitochondrial Dysfunction due to Autophagy Disruption Amenable by Urolithin A.

Alexandre Pierre, Raphael Favory, Benoit Brassart, Claire Bourel, Raphael Romien, Sylvain Normandin, Arthur Dubech, Claire Vincent, Jeremy Lemaire, Gaelle Grolaux, Ophelie Not, Frederic Wallet, Frederic Daussin, Eric Boulanger, Arthur Durand, Marie Frimat, Alina Ghinet, Michael Howsam, William Laine, Philippe Marchetti, Jerome Kluza, Estelle Chatelain, Jimmy Vandel, Nicolas Barois, Valerie Montel, Bruno Bastide, Sebastien Preau, Steve Lancel.

   BACKGROUND: Sepsis survivors often experience sustained muscle weakness, leading to physical disability, with no pharmacological treatments available. Despite these well-documented long-term clinical consequences, research exploring the cellular and molecular mechanisms is sorely lacking.
METHODS: Bioinformatic analysis was performed in the vastus lateralis transcriptome of human ICU survivors 7 days after ICU discharge (D7), 6 months (M6) and age- and sex-matched controls. Enrichment analysis using Gene Ontology (GO) terms and Mitocarta3.0 was performed at D7 and M6 on differentially expressed genes (DEGs) and modules identified by weighted gene co-expression network analysis (WGCNA). Using a murine model of resuscitated sepsis induced by caecal slurry injection, pathways identified by the bioinformatics analysis were explored in 18- to 24-week-old sepsis-surviving (SS) mice at Day 10. Autophagy flux was investigated both in vivo and in vitro with chloroquine, a lysosomal inhibitor and urolithin A (UA), an autophagy inducer. Systemic metabolism was evaluated with indirect calorimetry, muscle phenotype with in situ and ex vivo contractility, muscle mass, myofibre cross-sectional area and typing and mitochondrial population with transmission electron microscopy (TEM), as well as mitochondrial function with high-resolution respirometry. Autophagic vacuole (AV) level was monitored using LC3B-II and P62 protein expression and TEM.
RESULTS: Pathways related to 'mitochondrion' were the only ones whose deregulation persisted between D7 and M6 (p < 0.05) and characterized WGCNA modules correlated with muscle mass, strength and physical function. Shared mitochondrial DEGs between D7 and M6 encoded matrix mitochondrial proteins related to 'metabolism' and 'mitochondrial dynamics'. SS mice exhibited reduced complex I-driven oxygen consumption (CI-JO2) (-45%), increased S-nitrosylation of complex I, damaged (+35%) and oxidized (+51%) mitochondria and AV accumulation (5 vs. 50 AVs/mm2) compared with sham pair-fed mice (p < 0.05) despite no differences in mitochondrial size or number. Autophagy flux was reduced in SS mice due to decreased AV degradation ratio (p < 0.05). UA restored a balanced autophagy flux (turnover ratio 0.96 vs. -0.17) by increasing AVs formation and degradation ratio (p < 0.05). UA also improved CI-JO2 (81 vs. 106 pmol/s/mg), tetanic force (215 vs. 244 mN/mm2) and hindlimb muscle weight in SS mice (p < 0.05).
CONCLUSION: Mitochondrial and autophagy disruption contributes to long-term muscle dysfunction in human and mouse sepsis survivors. We demonstrate for the first time that sepsis induces an autophagy flux blockade. Urolithin A prevents mitochondrial and muscle impairments both in vivo and in vitro by improving autophagy flux.

Keywords:  autophagy; mitochondria; muscle; sepsis

DOI:  https://doi.org/10.1002/jcsm.70041
Ann Med Surg (Lond). 2025 Aug;87(8): 5046-5055

Vitamin D and physical activity as co-modifiers of muscle health and function - a narrative exploration.

Inshal Jawed, Hafiza Quratul Ain, Farah Abdul Razaq, Muhammad Umair Qadir, Shafaq Jabeen, Farah Alam, Maham Javaid, Mehak Mobin, Danaish Kumar, Ruhul Rai, Syed Ali Farhan Abbas, Abu Huraira Bin Gulzar, Agha Muhammad Wali Mirza, Salma S Alrawa, Wajeeha Imam.

  Bone health requires different factors to grow. One of the main requirements is vitamin D. Much of the regulation of calcium levels also affects muscle strength and function, protein synthesis, and other cellular activities. Furthermore, the benefits of vitamin D on the muscular system are comparable to those of physical activity in terms of shaping the structural and functional changes in muscles. Our paper focuses on the synergistic effects of physical exercise and vitamin D on metabolism how they can impact muscle health, including the physiological rationale, outcomes of its deficiency, and measures for counteraction thereto. Here, we outline the effect of combined interventions for optimizing muscle strength.

Keywords:  bone; muscle strength; physical activity; vitamin D

DOI:  https://doi.org/10.1097/MS9.0000000000003502
Elife. 2025 Aug 13. pii: RP105834. [Epub ahead of print]14

Transcriptional dynamics uncover the role of BNIP3 in mitophagy during muscle remodeling in Drosophila.

Hiroki Taoka, Tadayoshi Murakawa, Kohei Kawaguchi, Michiko Koizumi, Tatsuya Kaminishi, Yuriko Sakamaki, Kaori Tanaka, Akihito Harada, Keiichi Inoue, Tomotake Kanki, Yasuyuki Ohkawa, Naonobu Fujita.

  Differentiated muscle cells contain myofibrils and well-organized organelles, enabling powerful contractions. Muscle cell reorganization occurs in response to various physiological stimuli; however, the mechanisms behind this remodeling remain enigmatic due to the lack of a genetically trackable system. Previously, we reported that a subset of larval muscle cells is remodeled into adult abdominal muscle through an autophagy-dependent mechanism in Drosophila. To unveil the underlying mechanisms of this remodeling, we performed a comparative time-course RNA-seq analysis of isolated muscle cells with or without autophagy. It revealed both transcriptional dynamics independent of autophagy and highlighted the significance of BNIP3-mediated mitophagy in muscle remodeling. Mechanistically, we found that BNIP3 recruits autophagic machinery to mitochondria through its LC3-interacting motif and minimal essential region, which interact with Atg8a and Atg18a, respectively. Loss of BNIP3 leads to a substantial accumulation of larval mitochondria, ultimately impairing muscle remodeling. In summary, this study demonstrates that BNIP3-dependent mitophagy is critical for orchestrating the dynamic process of muscle remodeling.

Keywords:  BNIP3; D. melanogaster; Drosophila; autophagy; cell biology; developmental biology; metamorphosis; mitochondria; muscle

DOI:  https://doi.org/10.7554/eLife.105834
Hum Genomics. 2025 Aug 13. 19(1): 91

Whole-exome sequencing identifies TRIM72 as a candidate gene for autosomal recessive limb-girdle muscular dystrophy.

Abdelaziz Tlili, Abdullah Al Mutery.

   BACKGROUND: Limb-girdle muscular dystrophies (LGMDs) constitute a genetically diverse group of disorders characterized by progressive proximal muscle weakness and atrophy. Despite advances in genetic diagnostics, numerous cases remain unresolved due to extensive genetic heterogeneity, emphasizing the necessity for continued identification of novel pathogenic variants.
RESULTS: Using whole-exome sequencing (WES) in a Saudi family affected by autosomal recessive LGMD, we identified a novel homozygous frameshift mutation (c.891delT; p.Ala298ArgfsTer64) in the TRIM72 (MG53) gene, which we propose as a strong candidate gene for LGMD. Segregation analysis via Sanger sequencing confirmed that the variant co-segregated precisely with the disease phenotype and was absent in ethnically matched control cohorts. TRIM72 encodes a muscle-specific E3 ubiquitin ligase involved in sarcolemmal membrane repair, critical for maintaining muscle cell integrity. Functional parallels between TRIM72 and the LGMD-associated TRIM32, alongside corroborating evidence from animal models and cellular studies, support the candidacy of TRIM72 in LGMD pathogenesis.
CONCLUSION: Our findings identify TRIM72 as a novel candidate gene implicated in autosomal recessive LGMD, expanding the genetic spectrum of this heterogeneous disease. This discovery underscores the critical roles of TRIM family proteins in muscle pathology and reinforces the value of advanced genetic sequencing methodologies in diagnosing unresolved muscular dystrophy cases.

Keywords:   TRIM72 gene; Autosomal recessive; Frameshift mutation; Limb-girdle muscular dystrophies

DOI:  https://doi.org/10.1186/s40246-025-00809-7
Geroscience. 2025 Aug 15.

Muscle-brain crosstalk as a driver of brain health in aging.

B L McNeish, I Miljkovic, T Liu-Ambrose, F Ambrosio, K Esser, M Fahnestock, C Rosano.

  Cognitive impairment and dementia in older adults represent significant global health challenges. Although the bidirectional relationship between physical function and brain health is well established, the mechanistic drivers of this link remain poorly understood. Muscle function and quality are central to physical function, and muscle's secretome is increasingly recognized for its systemic health effects-supporting the potential for muscle-to-brain crosstalk. This concept was explored at the 3rd International Research Symposium on Brain Health, jointly hosted by Vancouver Coastal Health and the University of British Columbia. We present the findings of this symposium, which reviewed the current state of the literature on muscle-to-brain crosstalk from multiple perspectives, spanning population studies to preclinical models. A key focus was the muscle secretome, particularly myokines and extracellular vesicles, as potential messengers influencing brain health. The symposium also identified critical takeaways and proposed next steps to further elucidate the underlying mechanisms of muscle-to-brain crosstalk and explore how these pathways might be harnessed through exercise or pharmacologic interventions to promote brain health in older adults.

Keywords:  Alzheimer’s disease; Brain health; Extracellular vesicles; Muscle-brain crosstalk; Myokines; Myosteatosis

DOI:  https://doi.org/10.1007/s11357-025-01833-0
Int J Mol Sci. 2025 Aug 05. pii: 7573. [Epub ahead of print]26(15):

Which Approach to Choose to Counteract Musculoskeletal Aging? A Comprehensive Review on the Multiple Effects of Exercise.

Angela Falvino, Roberto Bonanni, Umberto Tarantino, Virginia Tancredi, Ida Cariati.

  Aging is a complex physiological process that profoundly affects the functionality of the musculoskeletal system, contributing to an increase in the incidence of diseases such as osteoporosis, osteoarthritis, and sarcopenia. Cellular senescence plays a crucial role in these degenerative processes, promoting chronic inflammation and tissue dysfunction through the senescence-associated secretory phenotype (SASP). Recently, senotherapeutics have shown promising results in improving musculoskeletal health. Natural compounds such as resveratrol, rapamycin, quercetin, curcumin, vitamin E, genistein, fisetin, and epicatechin act on key signaling pathways, offering protective effects against musculoskeletal decline. On the other hand, molecules such as dasatinib, navitoclax, UBX0101, panobinostat, and metformin have been shown to be effective in eliminating or modulating senescent cells. However, understanding the mechanisms of action, long-term safety, and bioavailability remain areas for further investigation. In this context, physical exercise emerges as an effective non-pharmacological countermeasure, capable of directly modulating cellular senescence and promoting tissue regeneration, representing an integrated strategy to combat age-related diseases. Therefore, we have provided an overview of the main anti-aging compounds and examined the potential of physical exercise as a strategy in the management of age-related musculoskeletal disorders. Further studies should focus on identifying synergistic combinations of pharmacological and non-pharmacological interventions to optimize the effectiveness of anti-aging strategies and promoting healthier musculoskeletal aging.

Keywords:  aging; musculoskeletal system; physical exercise; physiology; prevention; senescence; senotherapeutic

DOI:  https://doi.org/10.3390/ijms26157573