bims-moremu 2025-05-11 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2025–05–11
34 papers selected by
Anna Vainshtein, Craft Science Inc.

Perspectives on the interpretation of mitochondrial responses during skeletal muscle disuse-induced atrophy.
Integrated single-cell functional-proteomic profiling reveals a shift in myofibre specificity in human nemaline myopathy: A proof-of-principle study.
Effect of aging, endurance training, and denervation on innate immune signaling in skeletal muscle.
The association of mitochondrial morphology and supercomplex redistribution with skeletal muscle oxidative capacity in older adults.
Muscle peripheral circadian clock drives nocturnal protein degradation via raised Ror/Rev-erb balance and prevents premature sarcopenia.
Insights into human muscle biology from human primary skeletal muscle cell culture.
Adaptations in mitochondrial quality control and interactions with innate immune signaling within skeletal muscle: A narrative review.
Nutritional strategies targeting age-related skeletal muscle fibrosis: underlying mechanisms.
RNA-seq and ChIP-seq unveils thyroid hormone receptor α deficiency affects skeletal muscle myoblast proliferation and differentiation via Col6a1 during aging.
Pathogenic TNNT1 variants are associated with aberrant thin filament compliance and myofibre hyper-contractility.
The potential of TAOK1 as a new therapeutic target for the treatment of cancer cachexia-associated muscle atrophy.
The Functions and Regulatory Mechanisms of Histone Modifications in Skeletal Muscle Development and Disease.
Muscle metabolic resilience and enhanced exercise adaptation by Esr1-induced remodeling of mitochondrial cristae-nucleoid architecture in males.
The impact of frailty syndrome on skeletal muscle histology: preventive effects of exercise.
Signaling balance of MCTs and GPR81 controls lactate-induced metabolic function and cell death in skeletal muscle cells through Ranbp3l/Nfat5 and Atf4.
Biomarkers of Skeletal Muscle Atrophy Based on Atrogenes Evaluation: A Systematic Review and Meta-Analysis Study.
Identification of novel biomarkers and drug targets for frailty-related skeletal muscle aging: a multi-omics study.
cGAS-STING-NFκB pathway plays a role in burn injury-induced muscle wasting.
The repair capacity spectrum of human skeletal muscle injury from sports to surgical trauma settings.
Cyr61 Promotes D-gal-induced Aging C2C12 Cell Fibrosis by Modulating Wnt/β-catenin Signaling Pathways.
DUX4 activates common and context-specific intergenic transcripts and isoforms.
Glycations on Decellularized Muscle Matrix Reduce Muscle Regeneration and Increase Inflammation.
CEFIP-deficiency in mice enhances glucose tolerance despite compromised muscle function.
lncRNA AK159072 Promotes Myoblast Proliferation and Muscle Regeneration Through Activation of Akt/Foxo1 Pathway.
Exercise-induced MyoD mRNA Expression in Young and Older Human Skeletal Muscle: A Systematic Review and Meta-Analysis.
Forskolin treatment enhances muscle regeneration and shows therapeutic potential with limitations in Duchenne muscular dystrophy.
Cooling-induced changes in intracellular hydrogen peroxide and gene expression in mouse skeletal muscle in vivo.
Plasma Microvesicles May Contribute to Muscle Damage in the mdx Mouse Model of Duchenne Muscular Dystrophy.
Multi-therapeutic strategy targeting Akt-mTOR and FoxO1 pathway to counteract skeletal muscle atrophy consecutive to hypoxia.
Neuromuscular electrical stimulation alleviates stroke-related sarcopenia by promoting satellite cells myogenic differentiation via AMPK-ULK1-Autophagy axis.
Mature and Juvenile Neuromuscular Plasticity in Response to Unloading.
Sestrin2 is a central regulator of mitochondrial stress responses in disease and aging.
LC-MS/MS based metabolomics reveals the mechanism of skeletal muscle regeneration.
Low-Frequency Ultrasound Reverses Insulin Resistance and Diabetes Induced Changes in the Muscle Transcriptome in Aged Mice.

J Physiol. 2025 May 05.

Perspectives on the interpretation of mitochondrial responses during skeletal muscle disuse-induced atrophy.

Luca J Delfinis, Shahrzad Khajehzadehshoushtar, Christopher G R Perry.

  Reductions in skeletal muscle mitochondrial respiration or increases in mitochondrial reactive oxygen species (ROS) are often interpreted as 'mitochondrial dysfunctions'. However, such changes can also occur as intentional programmed responses to stressors. The term 'mitochondrial dysfunction' could therefore consider the net impact of such responses on other cellular functions. In the case of disuse-induced skeletal muscle atrophy, lower mitochondrial respiration, increased ROS and increased mitochondrial-linked apoptosis have been associated with muscle loss. Such observations support hypotheses that mitochondria contribute to atrophy. If true, there are exciting opportunities for exploring therapeutic strategies that prevent such changes in mitochondrial metabolism. These observations might also support alternative hypotheses where mitochondria are intentionally reprogrammed to serve specific purposes, such as a recalibration of ATP supply to reduced ATP demand during disuse. The goal of this review is to describe what is known regarding skeletal muscle mitochondrial functional responses to muscle disuse, as well as to discuss how these foundational discoveries might lead to new directions that determine whether mitochondrial responses to disuse are causal of atrophy or are adaptive in nature. Three critical questions for consideration include: (1) when is a change in mitochondrial function 'dysfunctional'; (2) how might changes in mitochondrial function represent intentional reprogramming to serve specific purposes; and (3) what factors should be considered when constructing experimental designs to determine the role of mitochondrial functional responses to disuse? Understanding when mitochondrial functional remodelling are dysfunctions or adaptive responses could inform new therapeutic approaches to maintain muscle mass during periods of disuse.

Keywords:  mitochondrial energetics; muscle disuse; skeletal muscle

DOI:  https://doi.org/10.1113/JP284160
J Physiol. 2025 May 05.

Integrated single-cell functional-proteomic profiling reveals a shift in myofibre specificity in human nemaline myopathy: A proof-of-principle study.

Robert A E Seaborne, Roger Moreno-Justicia, Jenni Laitila, Chris T A Lewis, Lola Savoure, Edmar Zanoteli, Michael W Lawlor, Heinz Jungbluth, Atul S Deshmukh, Julien Ochala.

  Skeletal muscle is a complex syncytial arrangement of an array of cell types and, in the case of muscle-specific cells (myofibres), subtypes. There exists extensive heterogeneity in skeletal muscle functional behaviour and molecular landscape at the cell composition, myofibre subtype and intra-myofibre subtype level. This heterogeneity highlights limitations in currently applied methodological approaches, which has stagnated our understanding of fundamental skeletal muscle biology in both healthy and myopathic contexts. Here we developed a novel approach that combines a fluorescence-based assay for the biophysical examination of the sarcomeric protein, myosin, coupled with same-myofibre high-sensitivity proteome profiling, termed single myofibre protein function-omics (SMPFO). Applying this approach as proof-of-principle we identify the integrated relationship between myofibre functionality and the underlying proteomic landscape that guides divergent, but physiologically important, behaviour in myofibre subtypes in healthy human skeletal muscle. By applying SMPFO to two forms of human nemaline myopathy (ACTA1 and TNNT1 mutations), we reveal significant reduction in the divergence of myofibre subtypes across both biophysical and proteomic behaviour. Collectively we demonstrate preliminary findings of SMPFO to support its use to study skeletal muscle with greater specificity, accuracy and resolution than currently applied methods, facilitating that advancement in understanding of skeletal muscle tissue in both healthy and diseased states. KEY POINTS: Skeletal muscle is a complex tissue made up of an array of cell and sub-cell types, with the resident muscle cell - myofibre - critical for contractile function. Although single myofibre studies have advanced, existing methods lack the precision for simultaneous multidata analysis, hindering developments in our understanding of skeletal muscle. We introduce single myofibre protein function-omics (SMPFO), a method enabling functional analysis of sarcomeric myosin alongside global protein abundance within the same myofibre. In healthy myofibres SMyoMFO reveals extensive biochemical diversity in myosin heads, correlating with the abundance of metabolic and sarcomeric proteins, including subtype-specific patterns in sarcoglycan delta (SGCD). In contrast SMyoMFO uniquely reveals a reduction in diversity of myosin function and the myofibre proteome in two forms of nemaline myopathy, highlighting disease-associated alterations. This innovative approach provides a robust framework for investigating myofibre regulation and dysfunction in skeletal muscle biology.

Keywords:  human muscle; myopathy; myosin; proteomics

DOI:  https://doi.org/10.1113/JP288363
J Appl Physiol (1985). 2025 May 08.

Effect of aging, endurance training, and denervation on innate immune signaling in skeletal muscle.

Priyanka Khemraj, Anastasiya Kuznyetsova, David A Hood.

  Skeletal muscle function relies on mitochondria for energy and for mediating its unique adaptive plasticity. The NLRP3 inflammasome complex is an innate immune mechanism that responds to mitochondrial damage-associated molecular patterns (DAMPS), however its activity relative to mitochondrial dysfunction in muscle requires exploration. The purpose of this study was to characterize immune signaling and mitochondrial function in muscle during aging, endurance training, and disuse induced by denervation. Denervation led to decreases in muscle mass, mitochondrial content, and impaired respiration. Protein analyses revealed increases in NF-κB p65 and downstream inflammatory markers including NLRP3, caspase-1, GSDMD-N, STING and IL-1β, along with pro-apoptotic BAX and AIF. When assessing potential DAMPS, denervation led to increased ROS production but no changes in cytosolic mtDNA levels, relative to total mtDNA. Since we hypothesized that inflammasome activation would be increased with age, we studied young (6-8 months) and aged (21-22 months) mice that remained sedentary or underwent a 6-week voluntary running protocol. Aging resulted in marked increases in the expression of multiple pro-inflammatory and pro-apoptotic proteins. Remarkably, training uniformly attenuated age-related increases in BAX, NLRP3, caspase-1, STING, and GSDMD protein expression, and tended to reduce the elevated level of cytosolic mtDNA evident in aged muscle. Training adaptations were evident also in the aged animals by the preservation of muscle mass and improvements in oxygen consumption and endurance performance and were achieved despite a lower training distance than in young animals. Our results strongly implicate endurance training as a promising therapeutic for combatting disuse and age-related inflammation in skeletal muscle.

Keywords:  NLRP3 Inflammasome; exercise; mitochondria; mitochondrial biogenesis; muscle disuse

DOI:  https://doi.org/10.1152/japplphysiol.00038.2025
Physiol Rep. 2025 May;13(9): e70359

The association of mitochondrial morphology and supercomplex redistribution with skeletal muscle oxidative capacity in older adults.

Mauricio Castro Sepulveda, Sylviane Lagarrigue, Francesca Amati.

  Skeletal muscle maximal oxidative capacity (ATPmax) is a key component of age-related sarcopenia and muscle health. The contribution of mitochondrial morphology and electron transport chain supercomplex (SC) assemblies to ATPmax has yet to be determined in human muscle. ATPmax measured in vivo by 31phosphorus magnetic resonance spectroscopy in the quadriceps femoris of nine volunteers (65.5 ± 3.3 years old) was correlated with muscle biopsy outcomes before and after 4 months of supervised exercise. Mitochondrial morphology was assessed in electron micrographs, and SCs were measured by blue native gel electrophoresis. In the sedentary conditions, ATPmax was positively associated with complex (C) I and CIII in SC I+III2+IVn and negatively associated with CI and CIII in SC I+III2. Regarding mitochondrial morphology, ATPmax was positively associated with markers of mitochondrial elongation. Exercise training-induced increases in ATPmax were accompanied by mitochondrial elongation and by the redistribution of free complex III. Indicators of mitochondrial elongation were associated with the redistribution of specific complexes to SC I+III2+IVn. Higher skeletal muscle oxidative capacity in older adults is associated with mitochondrial elongation and the redistribution of electron transport chain complexes into higher rank SCs in the same muscle. Further, we provide evidence that mitochondrial elongation favors mitochondrial SC assembly.

Keywords:  ATPmax; electron transport chain; mitochondrial elongation; respirasome

DOI:  https://doi.org/10.14814/phy2.70359
Proc Natl Acad Sci U S A. 2025 May 13. 122(19): e2422446122

Muscle peripheral circadian clock drives nocturnal protein degradation via raised Ror/Rev-erb balance and prevents premature sarcopenia.

Jeffrey J Kelu, Simon M Hughes.

  How central and peripheral circadian clocks regulate protein metabolism and affect tissue mass homeostasis has been unclear. Circadian shifts in the balance between anabolism and catabolism control muscle growth rate in young zebrafish independent of behavioral cycles. Here, we show that the ubiquitin-proteasome system (UPS) and autophagy, which mediate muscle protein degradation, are each upregulated at night under the control of the muscle peripheral clock. Perturbation of the muscle transcriptional molecular clock disrupts nocturnal proteolysis, increases muscle growth measured over 12 h, and compromises muscle function. Mechanistically, the shifting circadian balance of Ror and Rev-erb regulates nocturnal UPS, autophagy, and muscle growth through altered TORC1 activity. Although environmental zeitgebers initially mitigate defects, lifelong muscle clock inhibition reduces muscle size and growth rate, accelerating aging-related loss of muscle mass and function. Circadian misalignment such as shift work, sleep deprivation, or dementia may thus unsettle muscle proteostasis, contributing to muscle wasting and sarcopenia.

Keywords:  autophagy; circadian clock; mTOR; muscle; proteasome

DOI:  https://doi.org/10.1073/pnas.2422446122
J Muscle Res Cell Motil. 2025 May 10.

Insights into human muscle biology from human primary skeletal muscle cell culture.

Thomas Francis, Casper Soendenbroe, Norman R Lazarus, Abigail L Mackey, Stephen D R Harridge.

  This review arises from the symposium held in honour of Prof Jenny Morgan at UCL in 2024 and the authors would like to acknowledge the outstanding contribution that Prof Morgan has made to the field of translational muscle cell biology. Prof Morgan published a review article in 2010 entitled: Are human and mice satellite cells really the same? In which the authors highlighted differences between species which are still pertinent to skeletal muscle cell culture studies today. To our knowledge there are no comprehensive reviews which outline the considerable work that has been undertaken using human primary skeletal muscle origin cells as the main model system. This review highlights the multitude of muscle biology that has been investigated using human primary cells, as well as discussing the advantages and disadvantages over other cell models. We also discuss future directions for primary cell culture models utilising the latest technologies in cell type specificity and culture systems.

Keywords:  Cell culture; Fibroblasts; Human; Myoblasts; Satellite cells; Skeletal muscle

DOI:  https://doi.org/10.1007/s10974-025-09696-w
J Sport Health Sci. 2025 May 01. pii: S2095-2546(25)00027-4. [Epub ahead of print] 101049

Adaptations in mitochondrial quality control and interactions with innate immune signaling within skeletal muscle: A narrative review.

Priyanka Khemraj, Anastasiya Kuznyetsova, David A Hood.

  Skeletal muscle health and function are essential determinants of metabolic health, physical performance, and overall quality of life. The quality of skeletal muscle is heavily dependent on the complex mitochondrial reticulum that contributes toward its unique adaptability. It is now recognized that mitochondrial perturbations can activate various innate immune pathways, such as the nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome complex by propagating inflammatory signaling in response to damage-associated molecular patterns (DAMPs). The NLRP3 inflammasome is a multimeric protein complex and is a prominent regulator of innate immunity and cell death by mediating the activation of caspase-1, pro-inflammatory cytokines interleukin-1β and interleukin-18 and pro-pyroptotic protein gasdermin-D. While several studies have begun to demonstrate the relationship between various mitochondrial DAMPs (mtDAMPs) and NLRP3 inflammasome activation, the influence of various metabolic states on the production of these DAMPs and subsequent inflammatory profile remains poorly understood. This narrative review aimed to address this by highlighting the effects of skeletal muscle use and disuse on mitochondrial quality mechanisms including mitochondrial biogenesis, fusion, fission and mitophagy. Secondly, this review summarized the impact of alterations in mitochondrial quality control mechanisms following muscle denervation, aging, and exercise training in relation to NLRP3 inflammasome activation. By consolidating the current body of literature, this work aimed to further the understanding of innate immune signaling within skeletal muscle, which can highlight areas for future research and therapeutic strategies to regulate NLRP3 inflammasome activation during divergent metabolic conditions.

Keywords:  Exercise; Innate immune signaling; Mitochondrial quality control; NLRP3 inflammasome; Skeletal muscle disuse

DOI:  https://doi.org/10.1016/j.jshs.2025.101049
Crit Rev Food Sci Nutr. 2025 May 08. 1-21

Nutritional strategies targeting age-related skeletal muscle fibrosis: underlying mechanisms.

Iris Cuijpers, Joey Katsburg, Luc J C van Loon, Freddy J Troost, Mireille M J P E Sthijns.

  Aging is associated with a reduced number and function of muscle stem cells (MuSC). This results in a decreased muscle regenerative capacity and increased formation of fibrotic tissue, impairing skeletal muscle function. This review provides an overview of in vitro and in vivo animal studies investigating nutritional interventions with the potential to inhibit pathophysiological mechanisms involved in the development of skeletal muscle fibrosis. Mechanism targets include 1) MuSC function and myogenic differentiation, 2) M1 to M2 macrophage polarization, 3) myofibroblast activity or extracellular matrix (ECM) deposition, and 4) reactive oxygen species (ROS) mediated pathways, such as NOX2/4 activity. Most promising nutrients described in this review are phytonutrients, vitamins and amino acids. Quercetin targets multiple pathways (showing decreased inflammation, ECM expression and NOX2/4 activity) in various cell types and tissues (kidney, aorta, liver and (heart) muscle) of rodents and rabbits, which could contribute to fibrosis development. Additionally, sulforaphane is a promising candidate as it inhibits inflammation, ECM expression, and ROS production in mouse skeletal muscle. After validation of the effects in human skeletal muscle, supplementation with these nutrients could be implemented in a multifaceted intervention (including exercise and adequate protein intake) targeting age-related skeletal muscle fibrosis.

Keywords:  Aging; fibrosis; nutrition; skeletal muscle

DOI:  https://doi.org/10.1080/10408398.2025.2498676
J Muscle Res Cell Motil. 2025 May 03.

RNA-seq and ChIP-seq unveils thyroid hormone receptor α deficiency affects skeletal muscle myoblast proliferation and differentiation via Col6a1 during aging.

Runqing Shi, Gong Chen, Yusheng Zhang, Jiru Zhang, Lu Yan, Yu Duan.

  Primary sarcopenia, an age-related syndrome, is a serious threat to the health and longevity of the elderly. Our prior studies indicated that thyroid hormone (TH) activity within muscle tissue undergoes significant age-associated alterations, mainly evidenced by a reduction in thyroid hormone receptor α (TRα) expression over time. TRα regulates the transcription of downstream target genes to exert its biological effects. Although TH is essential for skeletal muscle growth and development, the specific regulatory mechanism and broader role of TH binding its receptors in skeletal muscle aging remain unclear. We used ChIP-seq and RNA-seq to explore the aging changes of TRα target genes in gastrocnemius muscle of natural aging mouse model. ChIP-seq analysis revealed that TRα target genes are involved in nutrient synthesis, energy production, hormone secretion, and ECM-related pathways, suggesting a potential role of TRα in muscle growth, metabolism and component regulation. Further integration of RNA-seq showed that a greater number of down-regulated TRα target genes are associated with skeletal muscle aging. Through GSEA analysis and RT-qPCR screening, Col6a1 was identified as a key target gene. Col6a1 encodes collagen VI which is an important component of the ECM, ECM disorders and abnormal expression of Col6a1 can affect cell proliferation and differentiation. We confirmed that knockdown of Col6a1 inhibited the proliferation and differentiation of C2C12 cells. ChIP-qPCR and TRα silencing in C2C12 cells showed that TRα positively regulates Col6a1 transcription, and TRα deficiency inhibits the proliferation and differentiation of myoblasts, which is probably associated with Col6a1. These findings provide new insights into the molecular mechanisms underlying skeletal muscle aging and the regulatory roles of TH-TRα interactions.

Keywords:  ChIP-seq; ECM; Proliferation and differentiation; RNA-seq; Sarcopenia; Thyroid hormone receptor α

DOI:  https://doi.org/10.1007/s10974-025-09694-y
J Physiol. 2025 May 05.

Pathogenic TNNT1 variants are associated with aberrant thin filament compliance and myofibre hyper-contractility.

Jenni Laitila, Christopher T A Lewis, Anthony L Hessel, Guido Primiano, Aurelio Hernandez-Lain, Chiara Fiorillo, Michael W Lawlor, Coen A C Ottenheijm, Heinz Jungbluth, Ka Fu Man, Arianna Fornili, Julien Ochala.

  In skeletal muscle, troponin T (TnT) exists in two isoforms, slow skeletal TnT (ssTnT) and fast skeletal TnT (fsTnT), encoded by the TNNT1 and TNNT3 genes, respectively. Nonsense or missense TNNT1 variants have been associated with skeletal muscle weakness and contractures and a histopathological appearance of nemaline myopathy (NM) on muscle biopsy. Little is known about how TNNT1 mutations ultimately lead to muscle dysfunction, preventing the development of targeted therapeutic interventions. Here, we aimed to identify the underlying molecular biophysical mechanisms, by investigating isolated skeletal myofibres from patients with TNNT1-related NM as well as from controls through a combination of structural and functional assays. Our studies revealed variable and unusual ssTnT and fsTnT expression patterns and post-translational modifications. We also observed that, in the presence of TNNT1 variants, the thin filament was more compliant, and this was associated with a higher myofibre Ca2+ sensitivity. Altogether, our findings suggest TnT remodelling as the key mechanism ultimately leading to molecular and cellular hyper-contractility, and then inhibitors of altered contractility as potential therapeutic modalities for TNNT1-associated NM. KEY POINTS: No therapeutic treatment exists for patients with genetic TNNT1 mutations and skeletal muscle weakness/contractures. In these patients, expression and post-translational modifications of troponin T are severely disrupted. These are associated with changes in thin filament compliance where troponin T is located. All these induce muscle fibre hyper-contractility that can be reversed by mavacamten, a myosin ATPase inhibitor.

Keywords:  congenital myopathy; contracture; force; skeletal muscle; troponin

DOI:  https://doi.org/10.1113/JP288109
Pharmacol Res. 2025 May 06. pii: S1043-6618(25)00188-4. [Epub ahead of print] 107763

The potential of TAOK1 as a new therapeutic target for the treatment of cancer cachexia-associated muscle atrophy.

Ruiqin Zhang, Nan Li, Ke Yu, Qiongsen Wang, Meng Fan, Xiongwen Zhang, Xuan Liu.

  Cancer cachexia, a multifactorial metabolic syndrome impacts 50-80% cancer patients, is mainly characterized by skeletal muscle atrophy. In this study, we demonstrated that the thousand-and-one amino acid kinase 1 (TAOK1) was activated in both C2C12 myotubes treated with simulated cancer cachexia injuries as well as in muscle tissues of mice inoculated with various types of tumor cells. Results of phosphoproteomic analysis also showed the increase in phosphorylation of TAOK1 in myotubes induced by simulated cancer cachexia injuries. Knockdown of TAOK1 in C2C12 myoblasts resulted in resistance to cancer cachexia-associated myotube atrophy. Comparing the protein expression profiles of C2C12-TAOK1-KO myotubes and that of control myotubes using proteomic analysis found that, TAOK1 knockout resulted in increased expression of muscle-related proteins and decreased expression of proteins related to MAPK pathway and ubiquitin-proteasome system (UPS). Results of Western blotting analysis confirmed the involvement of TAOK1/MAPK/FoxO3/UPS pathway in cancer cachexia-associated myotube atrophy, and suggested that TAOK1 knockout could ameliorate increased protein degradation but not decreased protein synthesis under cancer cachexia. CP43, a synthesized TAOK1 inhibitor, could ameliorate both in vitro myotube atrophy of C2C12 myotubes under simulated cancer cachexia injuries as well as in vivo muscle atrophy of cancer cachexia mice inoculating with C26 colon tumor cells. In conclusion, our study provides evidence that TAOK1 plays critical roles in activation of protein degradation under cancer cachexia thus targeting TAOK1 might be a potential therapy strategy for treatment of cancer cachexia-associated muscle atrophy.

Keywords:  C2C12 myotubes; MAPK pathway; TAOK1; cancer cachexia; muscle atrophy; tumor-bearing mice; ubiquitin-proteasome system

DOI:  https://doi.org/10.1016/j.phrs.2025.107763
Int J Mol Sci. 2025 Apr 12. pii: 3644. [Epub ahead of print]26(8):

The Functions and Regulatory Mechanisms of Histone Modifications in Skeletal Muscle Development and Disease.

Zining Huang, Linqing Hu, Zhiwei Liu, Shanshan Wang.

  Skeletal muscle development is a complex biological process regulated by many factors, such as transcription factors, signaling pathways, and epigenetic modifications. Histone modifications are important epigenetic regulatory factors involved in various biological processes, including skeletal muscle development, and play a crucial role in the pathogenesis of skeletal muscle diseases. Histone modification regulators affect the expression of many genes involved in skeletal muscle development and disease by adding or removing certain chemical modifications. In this review, we comprehensively summarize the functions and regulatory activities of the histone modification regulators involved in skeletal muscle development, regeneration, and disease.

Keywords:  histone modifications; muscle disease; skeletal muscle development

DOI:  https://doi.org/10.3390/ijms26083644
Cell Rep Med. 2025 May 02. pii: S2666-3791(25)00189-2. [Epub ahead of print] 102116

Muscle metabolic resilience and enhanced exercise adaptation by Esr1-induced remodeling of mitochondrial cristae-nucleoid architecture in males.

Zhenqi Zhou, Timothy M Moore, Alexander R Strumwasser, Vicent Ribas, Hirotaka Iwasaki, Noelle Morrow, Alice Ma, Peter H Tran, Jonathan Wanagat, Thomas Q de Aguiar Vallim, Bethan Clifford, Zhengyi Zhang, Tamer Sallam, Brian W Parks, Karen Reue, Orian Shirihai, Rebeca Acin-Perez, Marco Morselli, Matteo Pellegrini, Sushil K Mahata, Frode Norheim, Mingqi Zhou, Marcus M Seldin, Aldons J Lusis, Cathy C Lee, Mark O Goodarzi, Jerome I Rotter, Joshua R Hansen, Ben Drucker, Tyler J Sagendorf, Joshua N Adkins, James A Sanford, Francesco J DeMayo, Sylvia C Hewitt, Kenneth S Korach, Andrea L Hevener.

  Reduced estrogen action is associated with obesity and insulin resistance. However, the cell and tissue-specific actions of estradiol in maintaining metabolic health remain inadequately understood, especially in men. We observed that skeletal muscle ESR1/Esr1 (encodes estrogen receptor α [ERα]) is positively correlated with insulin sensitivity and metabolic health in humans and mice. Because skeletal muscle is a primary tissue involved in oxidative metabolism and insulin sensitivity, we generated muscle-selective Esr1 loss- and gain-of-expression mouse models. We determined that Esr1 links mitochondrial DNA replication and cristae-nucleoid architecture with metabolic function and insulin action in the skeletal muscle of male mice. Overexpression of human ERα in muscle protected male mice from diet-induced disruption of metabolic health and enhanced mitochondrial adaptation to exercise training intervention. Our findings indicate that muscle expression of Esr1 is critical for the maintenance of mitochondrial function and metabolic health in males and that tissue-selective activation of ERα can be leveraged to combat metabolic-related diseases in both sexes.

Keywords:  estrogen action; exercise adaptation; insulin sensitivity; mitochondrial cristae architecture; mitochondrial function; mtDNA replication; oxidative metabolism

DOI:  https://doi.org/10.1016/j.xcrm.2025.102116
FEBS Open Bio. 2025 May 05.

The impact of frailty syndrome on skeletal muscle histology: preventive effects of exercise.

Fujue Ji, Hae Sung Lee, Haesung Lee, Jong-Hee Kim.

  Frailty syndrome, a condition marked by increased vulnerability due to age-related physiological decline, exerts a profound impact on skeletal muscle structure and function. Despite its widespread prevalence, the underlying mechanisms contributing to frailty-associated muscle deterioration remain poorly elucidated. This study utilized histological and biochemical analyses in a murine model to investigate the effects of frailty syndrome on skeletal muscle. Mice were classified based on age and condition, including a subset subjected to an exercise intervention. Parameters evaluated included body weight, lean mass ratio, myofiber size and number, extracellular matrix (ECM) content, and myosin heavy chain isoform expression. Frailty syndrome led to increased body weight and ECM content, coupled with reductions in myofiber size and number, reflecting substantial structural and functional impairments in skeletal muscle. Exercise interventions effectively countered these deleterious changes, preserving myofiber morphology and reducing ECM expansion, thereby demonstrating the protective role of exercise in mitigating frailty-induced muscle deterioration. The study highlights the severe impact of frailty syndrome on skeletal muscle structure and integrity. Importantly, it underscores the potential of regular exercise as an effective therapeutic approach to prevent or reverse muscle deterioration associated with frailty, offering critical insights into managing age-related muscular degeneration.

Keywords:  exercise; frailty syndrome; histology; prevent; skeletal muscle

DOI:  https://doi.org/10.1002/2211-5463.70049
Cell Signal. 2025 May 01. pii: S0898-6568(25)00265-7. [Epub ahead of print]132 111852

Signaling balance of MCTs and GPR81 controls lactate-induced metabolic function and cell death in skeletal muscle cells through Ranbp3l/Nfat5 and Atf4.

Satayuki Matsuhashi, Arthur Choisez, Yidan Xu, Sepideh D Firouzjah, Kentaro Harada, Lingzi Zeng, Shion Osana, Hiroaki Takada, Ryoichi Nagatomi, Joji Kusuyama.

  Lactate, a byproduct of pyruvate in the glycolytic pathway, has been recognized as a signaling molecule and a regulator of gene expression. In skeletal muscles, lactate is dynamically regulated during exercise and influences muscular function, including myogenic differentiation and metabolism. The effects of lactate vary depending on lactate levels, which are influenced by exercise intensity, type, and duration. Furthermore, the effects of lactate on cellular signaling are different during the stages of myogenic differentiation. However, the distribution of lactate signaling in terms of lactate concentration, signaling types, and myogenesis has not been fully elucidated. In this study, we investigated the dual effects of lactate on myogenic differentiation and viability using C2C12 cells and C57BL/6 mice. Low levels of lactate treatment promoted myogenesis in the early stage of C2C12 differentiation, while high lactate concentrations or treatment with 3,5-DHBA, a GPR81 agonist, impaired cell viability during late myogenic differentiation. Transcriptomic analysis and knockdown experiments revealed that lactate promotes myogenesis and muscular metabolic functions through the induction of Ranbp3l and Nfat5 expressions. On the other hand, the detrimental effects of lactate on cell survival are mediated by the GPR81-induced PI3K-Akt/ERK-Atf4 axis. GPR81 signaling also feeds forward the expression of Hcar1 via Akt and ERK. These dual actions of lactate on skeletal muscle were also observed in vivo through lactate or 3,5-DHBA injections and exercise training models. Our study concludes that maintaining a balance in lactate signaling is crucial for regulating skeletal muscle phenotypes in response to exercise and lactate treatments.

Keywords:  Apoptosis; C2C12; Exercise; Glucose metabolism; Lactate; Lipid metabolism; Myogenesis

DOI:  https://doi.org/10.1016/j.cellsig.2025.111852
Int J Mol Sci. 2025 Apr 09. pii: 3516. [Epub ahead of print]26(8):

Biomarkers of Skeletal Muscle Atrophy Based on Atrogenes Evaluation: A Systematic Review and Meta-Analysis Study.

André Luiz Gouvêa de Souza, Anna Luisa Rosa Alves, Camila Guerra Martinez, Júlia Costa de Sousa, Eleonora Kurtenbach.

  Muscle atrophy leads to decreased muscle mass, weakness, inactivity, and increased mortality. E3 ubiquitin ligases, key regulators of protein degradation via the ubiquitin-proteasome system, play a critical role in atrophic mechanisms. This meta-analysis followed Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, and its objective was to evaluate the association between E3 ligases Muscle Atrophy F-box (MAFbx)/Atrogin-1 (Fbxo32) and Muscle RING-finger protein 1 (MuRF-1) (TRIM63) E3 ligase mRNA levels, reductions in skeletal muscle CSA measures, and atrophy conditions. We examined papers published on PubMed®, Scopus, and Web of Science that studied E3 ligase gene expression signatures for Fbxo32 (MAFbx/Atrogin-1) and Trim63 (MuRF1) in different types of muscle atrophy and hypertrophy murine models. Twenty-nine studies selected by two independent raters were analyzed. Standardized mean differences (SMDs)/effect sizes (ESs) and 95% confidence intervals (CIs) were calculated for the outcomes using fixed-effects models. We found that 6- and 4.8-fold upregulation, respectively, of Fbxo32 and Trim63 was sufficient to reduce the ES to -3.89 (95% CI: -4.45 to -3.32) for the muscle fiber cross-sectional area and the development of skeletal muscle atrophy. I² and Q test statistics did not indicate heterogeneous data. There was a low probability of bias after both the funnel plot and Egger's test analyses. These results were sustained independently of the atrophic model and muscle type. Therefore, the magnitude of the increase in muscle Fbxo32 and Trim63 mRNA is a feasible, reliable molecular marker for skeletal muscle atrophy in mice. The next step for the Ubiquitin-proteasome system (UPS) field involves elucidating the targets of E3 ligases, paving the way for diagnostic and treatment applications in humans.

Keywords:  E3 ligases; animal models; atrophy; molecular research; musculoskeletal; tissue alterations

DOI:  https://doi.org/10.3390/ijms26083516
QJM. 2025 May 09. pii: hcaf108. [Epub ahead of print]

Identification of novel biomarkers and drug targets for frailty-related skeletal muscle aging: a multi-omics study.

Qijun Wang, Xuan Zhao, Wei Wang, Xiaolong Chen, Shibao Lu.

   BACKGROUND: Skeletal muscle aging is the major cause and hallmark of frailty, which poses a significant challenge to the healthcare system.
AIM: This study aimed to identify the potential biomarkers for the early detection and therapeutic intervention of this age-related condition.
METHODS: A transcriptomics-based methodology using machine learning algorithms was performed to select the biomarker genes. A predictive machine learning model for (pre-)frailty based on the transcriptomic profile of the biomarker genes was constructed and validated. The cell-type specific changes of the biomarkers during muscle aging were investigated in a single-cell RNA sequencing dataset of human skeletal muscle. Summary data-based Mendelian randomization (SMR) and Bayesian colocalization analyses were performed to identify biomarker genes with therapeutic effects on frailty-related skeletal muscle aging, and drug candidates were explored in the DSigDB database.
RESULTS: We identified 24 biomarker genes, most of which were discovered for the first time. The optimal predictive model showed excellent performance in the external test set. Differential expression of the biomarkers in the single-cell dataset indicated a critical role of endothelial cells modulated by the marker genes MGP and ID1 in muscle degeneration. The SMR and colocalization analyses showed causal relationships between 2 marker genes (MGP and WAC) and frailty-related muscle aging. Potential therapeutics for MGP modulation were identified in the DSigDB database.
CONCLUSIONS: This multi-omics study identified biomarkers associated with frailty-related muscle aging and provided new insights into the etiology and therapeutic targets for this age-related condition.

Keywords:  Biomarker; Drug target; Frailty; Machine learning; Multi-omics; Skeletal muscle aging

DOI:  https://doi.org/10.1093/qjmed/hcaf108
Shock. 2025 Apr 28.

cGAS-STING-NFκB pathway plays a role in burn injury-induced muscle wasting.

Fei Xie, Zerong You, Bin Yan, Jiajia Dai, Jinsheng Yang, Shiyu Wang, Hiroki Ogata, Shingo Yasuhara, Ja Jeevendra Martyn.

   BACKGROUND: Muscle wasting (MW) is a ubiquitous and debilitating consequence of major burn injury (BI), leading to both short- and long-term health complications. The cGAS-STING-NFκB pathway is a key mediator of inflammatory responses triggered by infection, cellular stress, and tissue damage. This study investigated whether activation of this pathway contributes to BI-induced MW and whether C176, a STING inhibitor, could mitigate the MW of BI.
METHODS: Male C57BL/6 J mice received sham or 30% body BI, with or without daily C176 treatment for 14 days. Hindlimb muscles were analyzed at day 7 and 14 for cytokine expression (RT-qPCR, ELISA), immune cell infiltration (immunohistochemistry), cGAS-STING-NFκB signaling, muscle proteolytic proteins evidenced as MuRF1 and atrogin-1 expression (Western blot), and muscle weight. C2C12 cells (a murine skeletal muscle myoblast cell line) were transfected with Raw 264.7 murine macrophage cell-derived mitochondrial DNA (mtDNA) to mimic BI-induced damage-associated molecular pattern inflammation, with and without C176, to assess muscle inflammatory responses.
RESULTS: C176 treatment mitigated MW (22 % in tibialis, 13 % in gastrocnemius, p < 0.05) and inhibited the cGAS-STING-NFκB pathway in BI mice. It also decreased infiltration of inflammatory cells into muscle and preserved neuromuscular junction integrity in BI mice. In C2C12 cells, C176 suppressed not only LPS- and mtDNA-induced inflammatory cytokine (IL-1β, TNF-α) release but also muscle proteolytic proteins (MuRF1 and atrogin-1) expression.
CONCLUSIONS: Activation of the cGAS-STING-NFκB pathway contributes to BI-induced MW, and C176 effectively reduces muscle loss by inhibiting this inflammatory signaling pathway.

Keywords:  burn injury; cGAS-STING-NFκB; inflammatory cytokines; mitochondrial DNA; muscle wasting

DOI:  https://doi.org/10.1097/SHK.0000000000002613
J Physiol. 2025 May 05.

The repair capacity spectrum of human skeletal muscle injury from sports to surgical trauma settings.

Grith Højfeldt, Christian Hoegsbjerg, Arvind G von Keudell, Abigail L Mackey.

  Skeletal muscle injury and repair have been a major research focus for more than a century. Muscle injuries are defined by their cause and anatomical location and lie on a spectrum in terms of repair outcomes. From contraction-induced necrosis, which initiates regenerative myogenesis for complete restoration of tissue architecture and function to, at the other end of the spectrum, traumatic volumetric muscle loss (VML), where substantial portions (or the whole) of a muscle are lost, leaving the patient with permanent physical disability. Strain injuries are found between these two extremes and are characterised by healing with scar tissue formation and a high re-rupture rate. Across these injury types, a discriminating feature for a successful outcome is the preservation of the extracellular matrix (ECM) architecture of the muscle-tendon complex, in particular the myotendinous junction (MTJ). Numerous experimental models, imaging techniques and molecular analyses have led to a thorough understanding of how muscle stem cells interact with immune, vessel and stroma-associated cells during regenerative myogenesis. Paradoxically, treatment of muscle strain injury and VML has not improved, and regenerative engineering approaches remain a distant hope. Important issues for this field include matching the level of detail that exists for animal muscle regeneration with human data and identifying the site of tissue disruption during strain injury. We propose that a closer collaboration between cell biologists, physiologists, sports medicine practitioners and orthopaedic surgeons is required to improve patient outcomes, particularly for strain injuries and VML.

Keywords:  acute extremity compartment syndrome; myonecrosis; myotendinous junction; regenerative myogenesis; scar tissue; strain injury; tissue engineering; volumetric muscle loss

DOI:  https://doi.org/10.1113/JP286507
Mech Ageing Dev. 2025 May 06. pii: S0047-6374(25)00043-0. [Epub ahead of print] 112067

Cyr61 Promotes D-gal-induced Aging C2C12 Cell Fibrosis by Modulating Wnt/β-catenin Signaling Pathways.

Xinchen Huang, Xiaoling Kui, Jiyao Ma, Jiaxin Chen, Yilong Huang, Bo He.

  Sarcopenia is characterized by age-related muscle mass/function loss and fibrosis. Satellite cell (SC) dysfunction during aging promotes fibrotic transdifferentiation and extracellular matrix (ECM) deposition. Cyr61, a pro-fibrotic matricellular protein, and Wnt/β-catenin signaling pathway are implicated in muscle regeneration-fibrosis balance, but their interaction in sarcopenia remains unclear. This study first compared the expression of Cyr61 and fibrosis markers (TGF-β1, collagen type I and III) in skeletal muscle of young and old mice. In vitro, D-gal-induced C2C12 aging models were used to assess Cyr61 and Wnt signaling pathway by proliferation/apoptosis assays, ECM analysis, and detecting the changes of myogenic/fibrotic markers (MyoD, α-SMA). Pathway modulation (FH535 inhibitor/LiCl activator) and combined with Cyr61 overexpression and knockout experiments defined mechanistic roles. Cyr61 was upregulated in skeletal muscle of aged mice, which was positively correlated with increased TGF-β1 and collagen deposition. In D-gal-induced C2C12 cells showed suppressed cell proliferation, increased apoptosis and enhanced ECM deposition, accompanied by elevated Cyr61. Cyr61 knockdown or Wnt signaling pathway inhibition (FH535) reversed fibrosis (α-SMA, collagen) and restored myogenesis (MyoD).This study reveals for the first time that Cyr61 drives sarcopenic fibrosis via Wnt/β-catenin activation, promoting myocyte-to-fibrotic transition. Targeting the Cyr61-Wnt axis may ameliorate age-related muscle degeneration, warranting translational validation in preclinical models.

Keywords:  Aging; Cyr61; Fibrosis; Wnt signaling pathway; sarcopenia

DOI:  https://doi.org/10.1016/j.mad.2025.112067
Sci Adv. 2025 May 09. 11(19): eadt5356

DUX4 activates common and context-specific intergenic transcripts and isoforms.

Dongxu Zheng, Anita van den Heuvel, Judit Balog, Iris M Willemsen, Susan Kloet, Stephen J Tapscott, Ahmed Mahfouz, Silvère M van der Maarel.

DUX4 regulates the expression of genic and nongenic elements and modulates chromatin accessibility during zygotic genome activation in cleavage stage embryos. Its misexpression in skeletal muscle causes facioscapulohumeral dystrophy (FSHD). By leveraging full-length RNA isoform sequencing with short-read RNA sequencing of DUX4-inducible myoblasts, we elucidate an isoform-resolved transcriptome featuring numerous unannotated isoforms from known loci and novel intergenic loci. While DUX4 activates similar programs in early embryos and FSHD muscle, the isoform usage of known DUX4 targets is notably distinct between the two contexts. DUX4 also activates hundreds of previously unannotated intergenic loci dominated by repetitive elements. The transcriptional and epigenetic profiles of these loci in myogenic and embryonic contexts indicate that the usage of DUX4-binding sites at these intergenic loci is influenced by the cellular environment. These findings demonstrate that DUX4 induces context-specific transcriptomic programs, enriching our understanding of DUX4-induced muscle pathology.

DOI: https://doi.org/10.1126/sciadv.adt5356
Tissue Eng Part A. 2025 May 02.

Glycations on Decellularized Muscle Matrix Reduce Muscle Regeneration and Increase Inflammation.

Lucas C Olson, Ammar Y Jawad, Eirian S Crocker, Scott E Pennebaker, Brock P Lodato, David J Cohen, Zvi Schwartz, Michael J McClure.

  Volumetric muscle loss (VML) due to traumatic injury results in the abrupt loss of contractile units, stem cells, and connective tissue, leading to long-term muscle dysfunction and reduced regenerative potential. Muscle connective tissue contains a proregenerative extracellular matrix (ECM), and our lab harnesses the regenerative capacity of decellularized muscle matrix (DMM) to treat VML, a condition with limited treatment options. However, a major limitation is that muscle often comes from aged donors. Previous work from our lab showed that aged donor muscle contains higher levels of advanced glycation end-product (AGE) cross-links compared to muscle from younger donors. This study aimed to determine whether increased AGE cross-links reduce the regenerative capacity of DMM. To test this, we first generated AGEs in DMM with direct D-ribose incubation. We then removed ∼35% of the gastrocnemius muscle in a model and treated it with either AGE-DMM or standard DMM (no AGEs), comparing results to controls. Although muscle force results remained unchanged between AGE-DMM and DMM, AGEs led to reduced muscle mass in histological sections, fewer fibers, and smaller fiber diameters. AGEs also increased collagen levels in histology, but protein assays showed reduced collagen production. We investigated the canonical receptor for AGEs, the receptor for AGEs (RAGE), and found elevated levels in AGE-treated VML compared to DMM alone, along with increased levels of the noncanonical receptor galectin-3. Both RAGE and galectin-3 are associated with inflammation, and proteomics revealed higher inflammatory markers in AGE-treated muscle than in DMM alone. In conclusion, our data suggest that AGEs impair the regenerative potential of DMM, highlighting the importance of considering donor age when sourcing muscle for DMM therapies. Impact Statement This study investigates advanced glycation end-product cross-links in skeletal muscle extracellular matrix (ECM) as a way to model its deleterious effects on muscle regeneration in vivo. We demonstrate here that ECM glycations reduce muscle regeneration, enhance inflammatory markers, reduce ECM protein production, and proteomic analysis identified unique targets that could be explored in future research endeavors.

Keywords:  advanced glycation end-products; collagen; decellularization; skeletal muscle aging; volumetric muscle loss

DOI:  https://doi.org/10.1089/ten.tea.2024.0284
Am J Physiol Endocrinol Metab. 2025 May 06.

CEFIP-deficiency in mice enhances glucose tolerance despite compromised muscle function.

Mazvita R Nyasha, Juri Tachikawa, Hikaru Komatsuzaki, Weijian Chen, Maya Onodera, Daiki Kojima, Fukie Yaoita, Makoto Kanzaki.

  Mechanotransduction in skeletal muscles is crucial for promoting global physical performance by coordinating muscular strength and metabolic properties, yet the underlying mechanisms and key regulatory molecules remain poorly understood. We identified CEFIP, a Z-disc localized protein upregulated upon contractility acquisition, as a potential integrator maintaining the balance between muscular performance and glucose metabolism. CEFIP deficiency resulted in decreased physical fitness, including lower running capabilities and weaker grip strength, even with no apparent myofiber disorganization. At the molecular levels, CEFIP-deficient mice exhibited dampened expression of STARS, a key mechanosensitive factor, while FHL1 and FHL3 were upregulated, with FHL1 expression further increasing in response to exercise. Despite the overall compromised physical performance, CEFIP-deficient mice unexpectedly led to enhanced insulin responsiveness, and increased muscular AMPK phosphorylation. Moreover, CEFIP-deficient mice exhibited heightened susceptibility to an exercise load, as evidenced by PGC-1a upregulation and augmented GLUT4 regulation, and enhanced insulin sensitivity, as indicated by sarcolemmal GLUT4 translocation. Taken together, our findings suggest that CEFIP serves as a key regulatory link between exercise performance and metabolic properties, potentially through Z-disc-mediated mechanosensitive processes in exercising skeletal muscles.

Keywords:  GLUT4; exercise; insulin sensitivity; metabolism; sarcomere

DOI:  https://doi.org/10.1152/ajpendo.00302.2024
J Biochem Mol Toxicol. 2025 May;39(5): e70292

lncRNA AK159072 Promotes Myoblast Proliferation and Muscle Regeneration Through Activation of Akt/Foxo1 Pathway.

Si Lei, Rui Chen, Huacai Shi, Shanyao Zhou, Yanling She.

  Long non-coding RNAs (lncRNAs) are significant regulators of myoblast proliferation, migration and regeneration. In our previous research, we identified that lncRNA AK159072 was differentially expressed during myoblast development. In this study, we would like to explore the regulatory role and the mechanisms of AK159072 in proliferation. We discovered that AK159072 was increasingly expressed during myoblast proliferation and was located in both the nucleus and cytoplasm of proliferating C2C12 myoblasts. Overexpression of AK159072 promoted the expression of proliferation-related genes c-Myc, cyclin-dependent kinase 2 (CDK2), CDK4, and CDK6 in C2C12 myoblasts. Additionally, the cell viability and EdU-positive cells were increased, while the wound size was decreased after overexpression AK159072. In contrast, cell proliferation was attenuated when AK159072 was successfully silenced. Furthermore, the cross sectional area (CSA) and proliferative markers were decreased after knockdown of AK159072 in the mouse hind leg muscles with CTX-induced injury in vivo, indicating that knockdown of AK159072 may delay muscle regeneration. The study further demonstrated that Akt/Foxo1 pathway mediated the effects of AK159072 overexpression and knockdown in myoblasts. Taken together, our results suggested that AK159072 may regulate myoblast proliferation and muscle regeneration via Akt/Foxo1 pathway. The study suggestd that modulating the expression of AK159072 could be a potential therapeutic strategy for muscle injuries, this could have significant clinical relevance for conditions such as muscular dystrophy, sarcopenia, and other muscle disorders.

Keywords:  Akt/Foxo1 pathway; long non‐coding RNA; muscle regeneration; proliferation

DOI:  https://doi.org/10.1002/jbt.70292
Sports Med. 2025 May 03.

Exercise-induced MyoD mRNA Expression in Young and Older Human Skeletal Muscle: A Systematic Review and Meta-Analysis.

Andrew Nicholls, M Brennan Harris, Luthfia Dewi, Chih-Yang Huang, Li-Ning Pang, Hsing-Jien Kung, Liang-Kung Chen, Chia-Hua Kuo.

BACKGROUND: Myoblast determination protein 1 (MyoD) is a master transcription factor that triggers myogenesis and drives muscle growth.
OBJECTIVE: The aim was to assess acute exercise-induced MyoD mRNA expression in skeletal muscle for young and older (age > 50) adults.
DESIGN: A meta-analysis and systematic review was conducted.
METHODS: A literature search was conducted for studies reporting MyoD mRNA changes in biopsied human muscle taken within 48 h after exercise. Fifty eligible studies with 822 participants (young 20-35 years; older 53-85 years) were included for meta-analysis.
RESULTS: Significant increases in MyoD mRNA expression in human skeletal muscle were observed 3-12 h post-exercise (standardized mean difference [SMD] = 1.39, p < 0.001), subsiding within 24-48 h (SMD = 0.47, p < 0.001). Older individuals showed a similar time pattern in MyoD mRNA expression post-exercise, but the response is weaker than in younger individuals. Intriguingly, resting levels of MyoD mRNA were higher in older individuals compared to younger individuals in most age-paired studies (SMD = 0.56, p < 0.01). Considering the decline in anabolic hormones during later life, this systematic review highlights age- and sex-related impacts on exercise-induced MyoD mRNA expression in human skeletal muscle, emphasizing the roles of sex hormones and insulin.
CONCLUSION: Pooled results from the eligible studies suggest a blunted exercise-induced increase in MyoD mRNA in skeletal muscle after age 50, likely due to elevated basal MyoD expression as a compensatory mechanism against persistent catabolic conditions in aging muscle.
PROTOCOL REGISTRATION: Registration number: CRD42023471840 (PROSPERO).

DOI: https://doi.org/10.1007/s40279-025-02207-4
Skelet Muscle. 2025 May 07. 15(1): 12

Forskolin treatment enhances muscle regeneration and shows therapeutic potential with limitations in Duchenne muscular dystrophy.

Andreea Iuliana Cojocaru, Kaouthar Kefi, Jean-Daniel Masson, Laurent Tiret, Frederic Relaix, Valentina Taglietti.

   BACKGROUND: Duchenne Muscular Dystrophy (DMD) is a progressive neuromuscular disorder characterized by impaired muscle repair. Forskolin (FSK), an adenylyl cyclase activator, has shown potential in enhancing muscle regeneration and limiting muscle stem cell senescence. This study aimed to evaluate the effects of FSK on muscle repair, fibrosis, inflammation, and long-term muscle function in DMD using a preclinical rat model.
METHODS: BaCl2-induced muscle injury was performed on 6-month-old DMD (R-DMDdel52) and wild-type (WT) rats. FSK was supplied via short-term and long-term administration. Muscle tissues were harvested 14 days post-injury for histological analysis, including hematoxylin and eosin and Sirius red staining. Immunofluorescence was used to assess fibroadipogenic progenitors (FAPs), regeneration, muscle stem cells, and macrophage phenotypes. Moreover, we performed a study by chronically administering FSK to DMD rats from 1 to 7 months of age, either intraperitoneally (IP) or subcutaneously (SC). Functional assessments included grip strength test, in vivo muscle force measurements, plethysmography and electrocardiograms. Post-sacrifice, Tibialis anterior, diaphragm and heart tissues were histologically analyzed, to evaluate muscle architecture, fibrosis, and histopathological indices.
RESULTS: FSK treatment significantly improved muscle histology and reduced fibrosis in both uninjured and injured DMD muscles by decreasing the number of FAPs. Long-term FSK treatment in the acute injury model enhanced muscle regeneration, increased MuSC proliferation, and reduced senescence. FSK also modulated inflammation by reducing pro-inflammatory macrophages and promoting a shift to a restorative phenotype. However, despite these histological improvements, FSK treatment from 1 to 7 months resulted in limited functional benefits and worsened ventricular histology in the heart.
CONCLUSIONS: FSK shows promising results in improving muscle regeneration and reducing fibrosis in DMD, but concerns remain regarding its limited chronic functional benefits and potential adverse effects on cardiac tissue. Our results highlight the need for optimized adenylyl cyclase activators for therapeutic use in DMD patients.

Keywords:  Cellular senescence; Duchenne muscular dystrophy; Fibrosis; Forskolin; Muscle regeneration; Muscle stem cells

DOI:  https://doi.org/10.1186/s13395-025-00381-7
Am J Physiol Regul Integr Comp Physiol. 2025 May 07.

Cooling-induced changes in intracellular hydrogen peroxide and gene expression in mouse skeletal muscle in vivo.

Ryotaro Kano, Reo Takeda, Yuta Sotani, Ryo Takagi, Ayaka Tabuchi, Hideki Shirakawa, David C Poole, Yutaka Kano, Daisuke Hoshino.

  Changes in intracellular hydrogen peroxide concentration ([H2O2]) constitute an important signal controlling cellular adaptations. In response to cooling, decreases in [H2O2] and changes in antioxidant-related gene expression have been observed in skeletal muscle. However, the specific temperature dependence of cooling-induced [H2O2] changes and their quantitative relationship to induced gene expression are unknown. This investigation tested the hypothesis that differences in muscle cytosolic and mitochondrial [H2O2] changes during cooling/rewarming determine the pattern of H2O2-related gene expression. H2O2-sensitive cytosolic (HyPer7) and mitochondrial (MLS-HyPer7) fluorescent proteins were expressed into tibialis anterior (TA) muscle of male C57BL/6J mice. The temperature dependence of [H2O2] was determined via in vivo imaging during 3-minute cooling protocol from 35°C to 0°C. Two cooling patterns (6 bouts of intermittent cooling, I-Cool vs. sustained cooling, S-Cool; both to 13°C) were applied over 60 min. Three hours after cooling, the muscles were removed and gene expression was evaluated using real-time PCR. The decrease in [H2O2] was observed in both cytosolic and mitochondrial compartments from 35°C to 13°C, but was of greater magnitude in the cytosol; in contrast, further cooling from 12°C to 0°C induced a rebound increase especially in cytosolic [H2O2]. I-Cool increased the mRNA level of Nrf2 (+15%, p < 0.001). S-Cool decreased the mRNA levels of Sod2, Cat, and Ucp3 (i.e., -20%, -23%, and -30%, respectively, p<0.05). In conclusion, the greatest decrease in temperature-dependent [H2O2] occurred at 13°C in the cytosolic and mitochondrial compartments of muscle fibers and I-Cool increased Nrf2 mRNA expression, while S-Cool decreased several antioxidant-related genes.

Keywords:  ROS; cooling; cytosol; gene expression; mitochondria

DOI:  https://doi.org/10.1152/ajpregu.00014.2025
Int J Mol Sci. 2025 Apr 08. pii: 3499. [Epub ahead of print]26(8):

Plasma Microvesicles May Contribute to Muscle Damage in the mdx Mouse Model of Duchenne Muscular Dystrophy.

Cynthia Machado Cascabulho, Samuel Iwao Maia Horita, Daniela Gois Beghini, Rubem Figueiredo Sadok Menna-Barreto, Ana Carolina Heber Max Guimarães Monsores, Alvaro Luiz Bertho, Andrea Henriques-Pons.

  Extracellular vesicles (EVs) are cell-derived lipid-bound vesicles divided into apoptotic bodies, microvesicles (MVs), and exosomes based on their biogenesis, release pathway, size, content, and functions. EVs are intercellular mediators that significantly affect muscle diseases such as Duchenne muscular dystrophy (DMD). DMD is a fatal X-linked disorder caused by mutations in the dystrophin gene, leading to muscle degeneration. Mdx mice are the most commonly used model to study the disease, and in this study, we phenotypically characterized plasma MVs from mdx mice by flow cytometry. Furthermore, we assessed the ability of plasma MVs to modulate muscle inflammation, damage, and/or regeneration by intramuscular injection of MVs from mdx mice into mdx or DBA/2 mice as a control. In both mouse lineages, platelets and erythrocytes were the primary sources of MVs, and CD3+ CD4+ MVs were observed only in mdx mice. We also observed that plasma MVs from mdx mice induced muscle damage in mdx mice but not in DBA/2 mice, while plasma MVs from DBA/2 mice did not induce muscle damage in either mouse lineage. These results indicate that plasma MVs from mdx are potentially pathogenic. However, this condition also depends on the muscular tissue status, which must be responsive due to active inflammatory or regenerative responses.

Keywords:  Duchenne muscular dystrophy; extracellular vesicles; mdx; microvesicles

DOI:  https://doi.org/10.3390/ijms26083499
Am J Physiol Cell Physiol. 2025 May 06.

Multi-therapeutic strategy targeting Akt-mTOR and FoxO1 pathway to counteract skeletal muscle atrophy consecutive to hypoxia.

Samir Bensaid, Fabre Claudine, Amir Yahya Rajaei, Charlotte Claeyssen, Frédéric N Daussin, Caroline Cieniewski-Bernard.

  Chronic oxygen deprivation, whether due to high altitude or certain diseases as cardiorespiratory pathologies, leads to muscle atrophy. To limit muscle loss, counteracting programs rely on only one therapeutic approach: return to sea level altitude, physical activity or nutritional supplementation; however, little effects are noticed on muscle mass of subjects presenting a severe hypoxemia. We hypothesized that the combination of several treatments (electrical stimulation and/or nutritional supplementation and/or oxygenation) would improve anabolic responses, counteracting thus efficiently hypoxia-induced muscle atrophy. In C2C12 myotubes submitted to hypoxia, we aim at testing several treatments based on the combination of electrical stimulation, amino acids supplementation and/or an oxygenation period. In comparison to untreated muscle cells under hypoxia, all treatments had an anabolic impact on myotubes morphology (myogenic fusion index, diameter and density of myotubes), on proteosynthesis pathway (Akt, mTOR, GSK-3β, 4E-BP1 and P70S6K), on proteolysis pathway (FoxO1, myostatin, ubiquitin-proteasome system) and on hypoxia marker (REDD1) protein level. Electrical stimulation alone resulted in hyperphosphorylation of Akt and FoxO1 while its combination with amino acids supplementation alleviated atrophy exemplified by fusion index and myotubes diameter increase up to 48 hours post-application. Electrical stimulation followed by a period of oxygenation of hypoxic muscle cells strongly increased the activation status of 4E-BP1 and P70S6K. Lastly, simultaneous application of all treatments (electrical stimulation, amino acids supplementation and oxygenation) was the only condition resulted in activation of mTOR concomitantly to myostatin level decrease. These results support that the activation of the mTOR pathway through the combined application of electrical stimulation and BCAAs is strongly influenced by oxygen availability, and that oxygen plays a critical role in optimizing protein synthesis pathway in hypoxic skeletal muscle cells.

Keywords:  Amino acids supplement; Electrical stimulation; Hypoxia; Oxygenation treatment; Protein homeostasis; Skeletal muscle

DOI:  https://doi.org/10.1152/ajpcell.00851.2024
J Orthop Translat. 2025 May;52 249-264

Neuromuscular electrical stimulation alleviates stroke-related sarcopenia by promoting satellite cells myogenic differentiation via AMPK-ULK1-Autophagy axis.

Xingdong Xiang, Lei Huang, Wenchen Luo, Lieyang Qin, Mengxuan Bian, Weisin Chen, Guanjie Han, Ning Wang, Guokang Mo, Cheng Zhang, Yongxing Zhang, Huilin Yang, Shunyi Lu, Jian Zhang, Tengfei Fu.

   Background: Stroke-related sarcopenia can result in muscle mass loss and muscle fibers abnormality, significantly affecting muscle function. The clinical management of stroke-related sarcopenia still requires further research and investigation. This study aims to explore a promising therapy to restore muscle function and promote muscle regeneration in stroke-related sarcopenia, providing a new theory for stroke-related sarcopenia treatment.
Methods: Stroke-related sarcopenia rat model was established by using permanent middle cerebral artery occlusion (pMCAO) rat and treated with neuromuscular electrical stimulation (NMES). Electrical stimulation (ES) treatment in vitro was mimicked to test the effect of NMES on muscle regeneration in rat skeletal muscle satellite cells (MuSCs). Catwalk, H&E and Masson's trichrome staining, immunofluorescence, transcriptomic analysis, transmission electron microscopy, MuSCs transfection, autophagy flux detection, quantitative real-time PCR analysis, Co-Immunoprecipitation and Western Blot were used to investigate the role of NMES and its mechanism in stroke-related sarcopenia in vivo.
Results: After NMES treatment, muscle mass and myogenic differentiation were significantly increased in stroke-related sarcopenia rats. The NMES group had more stable gait, neater footprints, higher muscle wet weight, more voluminous morphology and more regenerated muscle fibers. Additionally, ES treatment induced myogenic differentiation in rat MuSCs in vitro. Transcriptomic analysis also showed that "AMPK signaling pathway" was enriched and genes upregulated in ES-treated cells, revealing ES treatment could activate the autophagy in an AMPK-ULK1-dependent mechanism in MuSCs. Besides, it was also founded that infusion of AMPK or ULK1 inhibitor, knockdown of AMPK or ULK1 in MuSCs could block the effect of myotube formation of ES.
Conclusion: NMES not only restores muscle function but also enhances myogenic activity and muscle regeneration via AMPK-ULK1 autophagy in stroke-related sarcopenia rats. Our study provides a promising strategy for the treatment of stroke-related sarcopenia.
The translational potential of this article: This study first demonstrates that NMES alleviates stroke-related sarcopenia by promoting MuSCs differentiation through AMPK-ULK1-autophagy axis. The findings reveal a novel therapeutic mechanism, suggesting that NMES can restore muscle function and enhance regeneration in stroke patients. By combining NMES with MuSCs-based therapies, this approach offers a promising strategy for clinical rehabilitation, potentially improving muscle mass and function in stroke survivors. The translational potential lies in its applicability to non-invasive, cost-effective treatments for sarcopenia, enhancing patients' quality of life.

Keywords:  Autophagy; Myogenic differentiation; Neuromuscular electrical stimulation; Satellite cells; Stroke-related sarcopenia

DOI:  https://doi.org/10.1016/j.jot.2025.03.021
Dev Neurobiol. 2025 Jul;85(3): e22966

Mature and Juvenile Neuromuscular Plasticity in Response to Unloading.

Michael R Deschenes, Max Rackley, Sophie Fernandez, Megan Heidebrecht.

  The neuromuscular junction (NMJ) is the synapse that enables the requisite electrical communication between the motor nervous system and the myofibers that respond to such electrical stimulation with movement and force development. Changes in an NMJ's normal activity pattern have been demonstrated to remodel both the synapse and the myofibers that comprise the NMJ. Significant amounts of research have been devoted to the study of aging on the neuromuscular system. Far less, however, has been focused on revealing the effects of reduced activity on the NMJ and myofibers comprising juvenile neuromuscular systems. In the present investigation, the consequences of decreased activity imposed by muscle unloading (UL) via hindlimb suspension for 2 weeks (a period known to induce muscle remodeling) were examined in both young adult, that is, mature (8 mo), and juvenile (3 mo) neuromuscular systems. In total, 4 treatment groups comprised of 10 animals (Juvenile-Control, Juvenile-Unloaded, Mature-Control, and Mature-Unloaded) were studied. Immunofluorescent procedures, coupled with confocal microscopy, were used to quantify remodeling of both the pre- and postsynaptic features of NMJs, as well as assessing the myofiber profiles of the soleus muscles housing the NMJs of interest. Results of ANOVA procedures revealed that there were significant (p < 0.05) main effects for both treatment, whereby UL consistently led to expanded size of the NMJ, and Age where expanded NMJ dimensions were consistently linked with mature compared to juvenile neuromuscular systems. Moreover, only sporadically was interaction between the main effects of Age and Treatment noted. Importantly, one variable that remained impressively resistant to the effects of both Age and Treatment was the critical parameter of pre- to postsynaptic coupling suggesting stability in effective communication at the NMJ throughout the lifespan and despite changes in activity patterns. The data presented here suggest that further inquiry must be performed regarding disuse-related plasticity of the neuromuscular system in adolescent individuals as those individuals regularly suffer injuries resulting in periods of muscle UL.

Keywords:  adolescence; aging; atrophy; disuse; synapse

DOI:  https://doi.org/10.1002/dneu.22966
Ageing Res Rev. 2025 May 02. pii: S1568-1637(25)00108-4. [Epub ahead of print]109 102762

Sestrin2 is a central regulator of mitochondrial stress responses in disease and aging.

Ivo F Machado, Carlos M Palmeira, Anabela P Rolo.

  Mitochondria supply most of the energy for cellular functions and coordinate numerous cellular pathways. Their dynamic nature allows them to adjust to stress and cellular metabolic demands, thus ensuring the preservation of cellular homeostasis. Loss of normal mitochondrial function compromises cell survival and has been implicated in the development of many diseases and in aging. Although exposure to continuous or severe stress has adverse effects on cells, mild mitochondrial stress enhances mitochondrial function and potentially extends health span through mitochondrial adaptive responses. Over the past few decades, sestrin2 (SESN2) has emerged as a pivotal regulator of stress responses. For instance, SESN2 responds to genotoxic, oxidative, and metabolic stress, promoting cellular defense against stress-associated damage. Here, we focus on recent findings that establish SESN2 as an orchestrator of mitochondrial stress adaptation, which is supported by its involvement in the integrated stress response, mitochondrial biogenesis, and mitophagy. Additionally, we discuss the integral role of SESN2 in mediating the health benefits of exercise as well as its impact on skeletal muscle, liver and heart injury, and aging.

Keywords:  Aging; Liver; Mitochondria; Mitohormesis; Muscle; Sestrin2

DOI:  https://doi.org/10.1016/j.arr.2025.102762
BMC Musculoskelet Disord. 2025 May 09. 26(1): 457

LC-MS/MS based metabolomics reveals the mechanism of skeletal muscle regeneration.

Lei Yi, Kaiming Wang, Sui Liufu, Wenwu Chen, Bohe Chen, Xiaolin Liu, Caihong Liu, Jingwen Liu, Xin Xu, Haiming Ma.

   BACKGROUND: Skeletal muscle possesses a robust regenerative capacity and can effectively repair itself following injury. However, research on the metabolic changes during skeletal muscle regeneration in large animals remains relatively limited. Therefore, in this study, we used pigs as a model and applied non-targeted LC-MS/MS metabolomic technology to reveal the metabolic changes during skeletal muscle regeneration, and conducted an in-depth exploration of important signaling pathways, which can provide a reference for further research on the mechanisms promoting skeletal muscle regeneration.
METHODS: In this study, we used 18 piglets aged 35 days and weighing 7.10 ± 0.90 kg to construct a skeletal muscle regeneration model. These piglets were randomly divided into three treatment groups (n = 6) and injected with cardiotoxins (CTX) in the right longissimus dorsi muscle. They were euthanized on the 1st, 4th, and 16th days post-injection to collect right longissimus dorsi muscle samples as the treatment group. Additionally, the left longissimus dorsi muscle of piglets on the 4th day post-injection was selected as the control group. Phenotypic changes in skeletal muscle regeneration were determined through H&E staining, immunofluorescence, and Western Blot analysis, and LC-MS/MS untargeted metabolomics technology was utilized to explore the differential expressed metabolites (DEMs) involved in skeletal muscle regeneration.
RESULTS: Phenotyping results showed that the regeneration model showed 3 stages of inflammation, regeneration and remodeling, which indicated successful model construction. Non-targeted LC-MS/MS metabolomics analysis showed significant differences in the structure of metabolites in these 3 stages. (1) In the inflammatory stage, a total of 198 DEMs were identified, which were mainly enriched in the pathways regulating the inflammatory response. (2) in the repair stage, 264 DEMs were identified, which were mainly enriched in pathways that inhibit inflammatory response and promote protein synthesis. (3) During the remodeling stage, 102 DEMs were identified, which were mainly enriched in the pathways that inhibit protein depletion and promote protein deposition. Temporal expression analysis revealed metabolites consistent with changes in the skeletal muscle regeneration process and found that these metabolite functions were mainly enriched in inhibiting inflammatory responses, alleviating myofibrillar lysis, and promoting muscle growth. Among them, (R)-Lipoic acid, 8-Hydroxyguanosine, and Uridine 5'-monophosphate maybe key metabolites associated with skeletal muscle regeneration.
CONCLUSION: The skeletal muscle regeneration mechanism was systematically explored, and the metabolite time series analysis during skeletal muscle regeneration revealed some key metabolites that reflect the degree of skeletal muscle damage.

Keywords:  LC-MS/MS; Metabolomics; Skeletal muscle regeneration

DOI:  https://doi.org/10.1186/s12891-025-08703-y
Am J Physiol Endocrinol Metab. 2025 May 05.

Low-Frequency Ultrasound Reverses Insulin Resistance and Diabetes Induced Changes in the Muscle Transcriptome in Aged Mice.

Erik D Marchant, Ekta Singh, Sanjay Kureel, Brandon Blair, Hanna Kalenta, Zachary D Von Ruff, Korri S Weldon, Zhao Lai, Michael P Sheetz, Blake B Rasmussen.

  The risk for developing insulin resistance and type II diabetes increases with age. Although lifestyle factors contribute to age-related insulin resistance, aging itself independently reduces insulin sensitivity, partially via an increase in inflammation and cellular senescence. Low-frequency ultrasound (LFU) has been shown to rejuvenate senescent cells and to reduce the proinflammatory senescence associated secretory phenotype. Because diabetes is more common in aged individuals, there is an increased need to develop effective therapeutics for aged individuals with this condition. This study investigated the effects of LFU treatment on muscle function, blood glucose control, and skeletal muscle gene expression in aged, insulin-resistant, and diabetic mice. Insulin resistance was induced via high-fat, high-sucrose (HFHS) diet, and diabetes was induced via HFHS diet plus a low dose of streptozotocin. Insulin resistant and diabetic mice exhibited impaired glucose metabolism and physical function, as well as an altered transcriptomic profile in skeletal muscle, indicating an increase in inflammation and an immune response. LFU treatment reversed much of the transcriptomic changes that occurred with insulin resistance and diabetes but had no effect on blood glucose control or physical function. LFU demonstrates potential as a non-invasive therapy for reducing inflammation and altering immune cell function in skeletal muscle in insulin resistant and diabetic populations.

Keywords:  Aging; RNAseq; diabetes; insulin resistance; low-frequency ultrasound; mitochondria; senescence; skeletal muscle

DOI:  https://doi.org/10.1152/ajpendo.00470.2024