Skeletal Muscle最新文献

{"title":"Insights into the heterogeneous muscle lipidome of dysferlin-deficient mice: effects of age, muscle type, and sex.","authors":"Stacey N Keenan, Jackie Bayliss, Olivia Lee, Erin M Lloyd, Peter J Meikle, Miranda D Grounds, Matthew J Watt","doi":"10.1186/s13395-026-00427-4","DOIUrl":"10.1186/s13395-026-00427-4","url":null,"abstract":"<p><p>Dysferlinopathy is an age-dependent muscular dystrophy caused by loss of the membrane-associated protein dysferlin. Disease severity increases with age and selectively affects specific muscle groups, yet the molecular basis for this vulnerability remains unclear. Since lipid remodeling is a hallmark of dysferlinopathy and aging, we investigated how age, sex, and muscle fiber type interact to shape the muscle lipidome in dysferlin-deficient mice. We performed omics-scale lipid profiling across 738 lipid species and 30 lipid classes in quadriceps and gastrocnemius (fast-twitch muscles exhibiting pronounced pathology), soleus (slow-twitch) and extensor digitorum longus (EDL; fast-twitch, relatively spared) muscles from male and female dysferlin-deficient (BLA/J) and wildtype C57BL/6J (WT) mice aged 3, 10, and 26 months. Normal aging was associated with broad lipid remodeling, however, in the absence of dysferlin markedly amplified this remodeling, leading to elevations in specific triglycerides, diglycerides, cholesterol esters, gangliosides, ceramides, and sphingomyelin compared to WT muscle. Interestingly, we observed minimal sex differences between dysferlin-deficient muscles. Fast-twitch muscles, particularly quadriceps and gastrocnemius, exhibited the most extensive lipid alterations, whereas the slow-twitch soleus muscle showed relative lipid stability even at advanced age. Thus, fast-glycolytic muscles are more susceptible to age- and dysferlin-dependent lipid dysregulation than slow oxidative muscle. The preferential vulnerability of fast-twitch muscles to muscle wasting in dysferlinopathy suggests that fiber-type-dependent lipid handling contributes to selective muscle degeneration. This work defines a comprehensive lipidomic signature of disease progression and provides a framework for understanding how aging, sex, and muscle phenotype interact in muscular dystrophy.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13374254/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148006498","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Caloric restriction reprograms skeletal muscle molecular pathways in non-human primates: potential relevance to human aging biology.","authors":"Jayanta Kumar Das, Nirad Banskota, Stefano Donega, Nader Shehadeh, Yulan Piao, Nathan Price, Julie A Mattison, Julián Candia, Rafael de Cabo, Luigi Ferrucci","doi":"10.1186/s13395-026-00422-9","DOIUrl":"10.1186/s13395-026-00422-9","url":null,"abstract":"<p><strong>Background: </strong>Caloric restriction (CR), achieved by reducing energy intake without malnutrition, has been shown to preserve muscle function and delay age-related declines in strength and mobility by modulating key metabolic and molecular pathways involved in muscle maintenance. While most initial research on CR was done in rodents, non-human primates (NHPs) offer a higher translatable animal model for understanding CR effects due to their close genetic, physiological and cognitive similarities to humans.</p><p><strong>Methods: </strong>In this cross-sectional study, we investigated skeletal muscle gene expression changes induced by 30% CR in skeletal muscle in rhesus monkeys (n = 18 CR, n = 18 control). We performed high-depth RNA sequencing to profile gene expression and alternative splicing variants and identify pathways linked to aging, regeneration/degeneration, and energy metabolism.</p><p><strong>Results: </strong>Transcriptomic profiling revealed widespread gene expression differences between CR animals compared to controls. Genes that were overexpressed were mainly involved in pathways related to energy metabolism, mitochondrial function, signaling, and oxidative stress response. Conversely, underexpressed genes were connected to immune response, extracellular matrix organization, apoptosis, and ribosomal RNA processing. Further, we identify alternative splicing as a major mechanism by which CR modulates genes involved in muscle function, metabolism, and aging.</p><p><strong>Conclusions: </strong>Caloric restriction preserves skeletal muscle by enhancing metabolism, limiting degeneration and inflammation, and engaging conserved mechanisms across species.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13237944/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147856959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Senescence dynamics define therapeutic windows for Duchenne muscular dystrophy in DBA/2-mdx mice.","authors":"Aina Calls-Cobos, Aida Beà Tàrrega, Andrés Cisneros, Megan Rommelfanger, Silvia Campanario, Mercedes Grima-Terrén, Ignacio Ramírez-Pardo, Victoria Moiseeva, Vera Lukesova, Eva Andrés, Grace Chou, Yuewen Zheng, Nasun Hah, Albert Blasco-Roset, Ana Planavila, Carolina Soler-Botija, Antoni Bayés-Genís, Eusebio Perdiguero, Antonio L Serrano, Pura Muñoz-Cánoves","doi":"10.1186/s13395-026-00426-5","DOIUrl":"10.1186/s13395-026-00426-5","url":null,"abstract":"<p><strong>Background: </strong>Duchenne muscular dystrophy (DMD) is a severe X-linked disorder marked by progressive muscle degeneration and regeneration, inflammation and fibrosis. Cellular senescence has emerged as a potential driver of chronic muscle damage, yet its temporal dynamics and therapeutic relevance remain unclear.</p><p><strong>Methods: </strong>We analyzed senescent cell burden in skeletal and cardiac muscles of the DBA/2-mdx mouse model, which closely mimics features of human DMD. The senolytic combination of dasatinib and quercetin (D + Q) was administered during early or late disease phases to evaluate the impact of senescent cell clearance. Skeletal muscle strength was measured by grip strength and ex vivo force assays, while cardiac function was assessed by echocardiography. Fibrosis and senescence markers were quantified histologically, and transcriptional changes associated with senolysis were identified using bulk RNA sequencing (RNA-seq).</p><p><strong>Results: </strong>In skeletal muscle, senescent cells appear and peak during early stages of disease progression (3-5 months), coinciding with high degeneration and regeneration activity, and then decline with age as fibrosis increases. In contrast, in the heart, senescent cells emerge at late stages of disease progression (around 12 months), correlating with heart fibrogenesis. Notably, senolytic intervention in the DBA/2-mdx mice promotes a regenerative and antifibrotic gene signature in both tissues. However, the timing of senolytic therapy determines its efficacy: early treatment with D + Q reduces senescent cell burden, decreases fibrosis, and improves fiber size and contractile performance in skeletal muscle, while later treatment reduces cardiac senescence and fibrosis but does not improve skeletal muscle pathology.</p><p><strong>Conclusions: </strong>Cellular senescence is a dynamic and targetable feature in DMD, with tissue- and age-specific patterns. It represents a potential modifiable therapeutic target, and temporally optimized senolytic strategies could serve as effective adjuncts to current and emerging DMD treatments.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13288804/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147820586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"iPSC-derived skeletal muscle spheroids for Duchenne Muscular Dystrophy modeling.","authors":"Joyce Esposito, Felipe de Souza Leite, Igor Neves Barbosa, Thaís Maria da Mata Martins, Giovanna Gonçalves de Oliveira Olberg, Ziad Al Tanoury, Kayque Alves Telles-Silva, Mayana Cristina da Silva Pardo, Tatiana Jazedje, Raul Hernandes Bortolin, Mario Hiroyuki Hirata, Olivier Pourquié, Mayana Zatz","doi":"10.1186/s13395-026-00428-3","DOIUrl":"10.1186/s13395-026-00428-3","url":null,"abstract":"<p><strong>Background: </strong>The progressive skeletal muscle degeneration observed in Duchenne Muscular Dystrophy (DMD) patients requires multiple cycles of satellite cells (SCs) activation to promote tissue regeneration. Dystrophic SCs present intrinsic defects, and the disrupting fibrotic niche hinders appropriate muscle recovery. Traditional 2D culture systems face challenges in modeling the DMD muscle niche and SCs behavior. Our aim was to validate a 3D culture of skeletal muscle spheroids (iSMS) for DMD modeling, as compared to the traditional 2D culture, while investigating the pathophysiological mechanisms of dystrophin deficiency in vitro.</p><p><strong>Methods: </strong>To compare iSMS with traditional 2D myogenic differentiation, we differentiated wild-type (WT), dystrophic (DMD) isogenic induced pluripotent stem cells (iPSCs), as well as iPSCs derived from DMD patients, characterized myogenic markers levels and assessed differences in proliferation and differentiation using RT-qPCR, immunofluorescence, and flow cytometry.</p><p><strong>Results: </strong>Our data showed that iSMS improved PAX7 expression in vitro, while MYOD1, MYOG, MYF5, and MYH3 expression were significantly reduced. These findings suggest that, at three weeks of myogenic differentiation, iSMS cultures retained satellite-like cells in a less activated, progenitor-like state. Accordingly, we identified higher expression of canonical Notch signaling genes such as JAG1 and NOTCH1 in iSMS compared to 2D. We also characterized the response of 2D and iSMS to terminal differentiation medium, providing a valuable comparison with muscle fibers derived from human adult myoblasts. Additionally, we showed that DMD iSMS-derived progenitors proliferated at reduced levels compared with WT, a characteristic not observed in progenitors derived from 2D cultures. Finally, we performed iSMS and 2D myogenic differentiation of iPSC lines from three patients with DMD.</p><p><strong>Conclusion: </strong>Our results highlight important advantages of using the iSMS differentiation platform over 2D for DMD in vitro modeling. Exploring these 3D systems may help to gain a deeper understanding of SCs behavior to advance in novel treatments for DMD, which might be applicable to other forms of muscular disorders.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13285661/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147820602","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stimulation of EGFR signaling in fibro-adipogenic precursors decreases adipogenesis in Duchenne muscular dystrophy.","authors":"Jules Guillemaud, Georgiana Panci, Aurélie Fessard, Léa Delivry, William Jarassier, Rémi Mounier, Julien Gondin, Stéphanie Gobert, Bénédicte Chazaud","doi":"10.1186/s13395-026-00429-2","DOIUrl":"10.1186/s13395-026-00429-2","url":null,"abstract":"<p><strong>Background: </strong>Duchenne Muscular Dystrophy (DMD) is characterized by the formation of fibrosis and fat deposits that progressively replace muscle fibers, resulting in the loss of muscle function. Both fibrosis and adipogenesis are operated by fibroadipogenic precursors (FAPs), but the molecular regulation and interactions between the two processes are not fully understood.</p><p><strong>Methods: </strong>Adipogenesis was investigated in vivo in the D2-mdx mouse, and in vitro using FAPs isolated from WT (DBA/2) and D2-mdx muscles. Epithelial Growth Factor (EGF) was overexpressed in the D2-mdx muscle via electroporation of an expression plasmid.</p><p><strong>Results: </strong>We found that the D2-mdx gastrocnemius muscle showed fat deposition from 10 weeks of age and increased until 18 weeks of age, coinciding with fibrosis. Fat deposition was exclusively found within fibrotic areas. In vitro, D2-mdx FAPs proliferated more, and were more prone to adipogenesis than WT FAPs. Cells from both genotypes showed equal fibrogenesis. Analysis of normal muscle snRNAseq data showed that the Epithelial Growth Factor Receptor (EGFR) was primarily expressed by FAPs. Both EGFR expression and EGFR-phosphorylation were decreased in D2-mdx FAPs as compared with WT FAPs. Stimulating FAPs with EGF decreased adipogenesis, more efficiently in D2-mdx FAPs than in WT FAPs. However, EGF stimulation of EGFR had no effect on their fibrogenic differentiation. Finally, in vivo overexpression of EGF in D2-mdx gastrocnemius muscles reduced both adipogenesis and fibrosis, and was associated with an increased muscle force.</p><p><strong>Conclusions: </strong>In a DMD context, FAPs are more likely to differentiate into adipocytes than in normal muscle, which is associated with decreased EGFR signaling. Stimulating EGFR signaling decreased adipogenesis in vitro and fat deposition in vivo. The impact of EGFR signaling on fibrogenesis is unclear, the reduced fibrosis observed in vivo may be due to indirect mechanisms. This study identifies EGFR signaling as a new molecular mechanism for controlling adipogenesis in skeletal muscle FAPs.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13285459/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147820562","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanobiological landscape of muscle stem cells.","authors":"Kotaro Hirano, Yuji Hara","doi":"10.1186/s13395-026-00425-6","DOIUrl":"10.1186/s13395-026-00425-6","url":null,"abstract":"<p><p>Skeletal muscle is distinguished by its remarkable regenerative capacity and mechanical resilience. Continuously challenged by mechanical stress, it adapts to increased load through hypertrophy but undergoes atrophy when mechanical stress is reduced. This regenerative plasticity depends on tissue-resident muscle stem cells (satellite cells; MuSCs), which orchestrate regeneration following injury. Recent studies reveal that change in the MuSCs microenvironment (niche) regulate their regenerative capacity, with particular attention being given to the mechanisms of mechanosensation. In this review, we summarize our current knowledge of the mechanosensory mechanisms through which MuSCs respond to mechanical perturbations in regenerating myofibers. We highlight recent advances in mechanosensitive receptors, including ion channels, and the downstream mechano-signaling pathways that shape MuSC fate. Finally, we discuss future directions in the field, emphasizing emerging biochemical and biomedical technologies that advance the study of MuSC mechanobiology.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13277067/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147780150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A 3D skeletal muscle system for disease modelling and secretome profiling of Duchenne muscular dystrophy.","authors":"Mariam Zouhair, Marianna Cosentino, Ludovica Apa, Desiree Genovese, Sasha Marco Maria Di Iorio, Carmine Nicoletti, Domenico Liguoro, Giorgia Nanni, Simone Dinarelli, Alessandro Palma, Caterina Boccia, Laura Forcina, Silvia Sideri, Rita Mancini, Monica Ballarino, Antonio Musarò","doi":"10.1186/s13395-026-00423-8","DOIUrl":"10.1186/s13395-026-00423-8","url":null,"abstract":"<p><p>BACKGROUND: Duchenne muscular dystrophy (DMD) is a severe X-linked genetic disease characterized by progressive muscle degeneration, exhaustion of the muscle stem cell pool, and extensive fibrotic remodelling, ultimately leading to loss of function and reduced quality of life. Although conventional cultures and mouse models have provided valuable insights into the pathogenesis of DMD, their mild phenotypes and prolonged disease progression require large sample sizes and lengthy experimental timelines. In turn, the field lacks experimental models that recapitulate the complexity of the dystrophic muscle phenotype in vitro for disease modelling or drug screening. METHODS: We developed a three-dimensional (3D) construct of dystrophic skeletal muscle using a scaffold-free approach, starting from primary cells isolated from the mdx4cv mouse strain, a widely used model of Duchenne muscular dystrophy (DMD). To assess the pathological fidelity of the DMD 3D model, we conducted a thorough morphological and functional characterization. Taking advantage of the controlled and isolated nature of the system, we explored the paracrine role of the derived muscle-extracellular vesicles (EVs), investigating their potential contribution to disease progression. RESULTS: The heterogeneous 3D skeletal muscle model of DMD faithfully reproduced the hallmark pathological features observed in patient-derived muscle tissue, including progressive muscle degeneration, fibrotic remodelling, and defective regenerative capacity. Furthermore, it enabled mechanistic investigations of muscle-derived EVs, revealing their ability to propagate both regenerative and catabolic signals. CONCLUSIONS: This 3D model provides a physiologically relevant and reproducible tool for studying the molecular mechanisms underlying DMD and evaluating potential therapeutic interventions, reducing the use of animal models. Its capacity to replicate key aspects of the muscle pathology holds significant potential for identifying novel biomarkers and therapeutic targets, with broad implications for translational research.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13196076/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147646465","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Pax7::Foxo1 conditional mouse strain.","authors":"G Roger Askew, Jonathan Gauntlett, Katherine Brechun, Harald Kranz, Nicholas Salters, Jess D Tate, Ellen Wang, Cassie Badger, Shireen Elhabian, Jared Schnider, Gillian St John, Samuel V Rasmussen, Narendra Bharathy, Charles Keller","doi":"10.1186/s13395-026-00424-7","DOIUrl":"10.1186/s13395-026-00424-7","url":null,"abstract":"<p><p>BACKGROUND: The PAX7::FOXO1 subtype of alveolar rhabdomyosarcoma (aRMS) is both understudied and an unmet clinical need. The biology of PAX7::FOXO1 aRMS is significantly different than PAX3::FOXO1 aRMS, presenting an opportunity to gain biological, clinical and therapeutic insights by murine genetic modeling of Pax7::Foxo1 for comparison to the existing conditional genetic mouse model of Pax3::Foxo1 aRMS. METHODS: Using gene targeting, a mouse strain harboring a Cre-LoxP activated conditional knock-in of Pax7::Foxo1 targeted to the murine Pax7 locus has been generated. RESULTS: Activation of the conditional knock-in of Pax7::Foxo1 allele in the prenatal Pax7 lineage recapitulates the birth defects (stunting and maxillofacial deformities) known for the conditional knock-in of Pax3::Foxo1 allele. Activation of the conditional knock-in of Pax7::Foxo1 allele in the prenatal Myf6 lineage is viable, fertile, and results in ongoing expression from Pax7 promoter in myofibers. CONCLUSIONS: This mouse strain is a resource for the rhabdomyosarcoma research community to explore lineage (cell) of origin, to define sufficiency for tumor initiation or the necessity of cooperative tumor initiating mutations, to uncover the biology of the PAX7::FOXO1 subtype of alveolar rhabdomyosarcoma, and to test therapies including immunotherapies.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13147794/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147521933","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CtBP1 sustains activity-dependent muscle properties and dampens synaptic, contractile and metabolic changes triggered by denervation.","authors":"Olivia Cattaneo, Gaetan Lopez, Jayasimman Rajendran, Florent Chabry, Nicolas Liaudet, Sergei Startchik, Alexandre Prola, Perrine Castets","doi":"10.1186/s13395-026-00421-w","DOIUrl":"10.1186/s13395-026-00421-w","url":null,"abstract":"<p><p>BACKGROUND: Denervation triggers dramatic atrophy of skeletal muscle, accompanied by synaptic, contractile and metabolic changes. Several factors were shown to contribute to genetic reprogramming and proteostasis changes after denervation. However, the mechanisms underlying the coordinated regulation of denervation-induced muscle fiber remodeling remain misunderstood. METHODS: We investigated the role of the transcriptional co-repressor CtBP1 in the regulation of denervation-induced responses in muscle fibers. To this end, we analyzed its expression and localization in innervated and denervated muscles and assessed the consequences of its knockdown induced in vivo with AAV9, on synaptic, contractile and metabolic properties of muscle fibers. RESULTS: CtBP1 was present both in sub- and non-synaptic myonuclei in innervated muscle. Although CtBP1 levels remained unchanged in denervated muscle, CtBP1 accumulated transiently in myonuclei after 2 days of denervation in TA/EDL muscles. Ctbp1 knockdown perturbed the expression of a large set of activity-independent and -dependent genes in innervated and denervated skeletal muscles. Reducing CtBP1 levels had limited effect on the expression of most synaptic genes, but increased transcript levels of Chrne, encoding the adult ε sub-unit of acetylcholine receptors (AChR). However, it did not affect AChR turnover or maintenance of the post-synaptic compartment upon denervation. Importantly, we uncovered that Ctbp1 knockdown exacerbates denervation-induced changes in metabolic gene expression, including most genes encoding proteins of the respiratory chain complexes. Consistently, it induced a contractile shift towards slower fibers in innervated fast muscle, mimicking denervation, and enhanced the denervation-induced metabolic transition towards oxidative slow-twitch fibers. Moreover, Ctbp1 knockdown precipitated the profound ultrastructural remodeling of mitochondria network induced after denervation. CONCLUSIONS: Our study unveils that CtBP1 sustains the innervated muscle pattern and antagonizes the effect of denervation on synaptic, contractile and metabolic muscle properties, with important implications for CtBP1-related muscle diseases.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13130457/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147504679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrin αVβ5 regulates myoblast proliferation and differentiation in sarcopenia mice treated with FNDC5 gene delivery : Original article.","authors":"Guoxi Gao, Qiyang Wang, Yuqiong Zhang, Minghong Shao, Yiming Liang, Shumin Zhou, Sheng Lu","doi":"10.1186/s13395-026-00420-x","DOIUrl":"10.1186/s13395-026-00420-x","url":null,"abstract":"<p><strong>Background: </strong>Irisin which is encoded by FNDC5 gene, has emerged as a promising therapeutic candidate for alleviating sarcopenia; however, its long-term therapeutic application in muscle regeneration remains insufficiently developed.</p><p><strong>Methods: </strong>Our study investigated the potential of FNDC5 gene delivery in both cellular and animal levels via a virus vector. It was indicated that FNDC5 overexpression promoted myoblast proliferation while inhibiting myogenic differentiation, and vice versa. Mechanistically, we confirmed that the product of FNDC5 gene, irisin binds to integrin αVβ5 on the cell membrane of myoblasts, leading to activation of the downstream FAK/SRC complex using coimmunoprecipitation (co-IP) and confocal microscopy. RNA-Seq and qPCR analyses revealed that irisin exposure activated genes related to the extracellular matrix (ECM) and its ligands, thereby promoting the cell cycle and enhancing the proliferation of myoblast. Additionally, treatment with the integrin αVβ5 inhibitor cilengitide enhanced myogenic differentiation but suppressed cell proliferation, highlighting the crucial role of integrin αVβ5 in determining myoblasts' cell fate. Furthermore, in sarcopenia mouse models, AAV-mediated FNDC5 supplementation activated integrin αVβ5-related signaling as expected, resulting in increased muscle mass and alleviation of sarcopenia symptoms.</p><p><strong>Results: </strong>Our findings demonstrate that integrin αVβ5 acts as a key switch in regulating the proliferation and differentiation of myoblasts under FNDC5 gene delivery. When integrin αVβ5 is active, FNDC5 over-expression enhances cell proliferation rather than differentiation. Conversely, when integrin αVβ5 is inhibited, FNDC5 over-expression promotes myogenic differentiation over proliferation. Moreover, the binding of irisin to integrin αVβ5 induces the expression of ECM proteins in myoblasts and activates the Bgn-TLR4 signaling pathway, which further enhances cell proliferation. This FNDC5-ITGAVB5-FAK-mTOR-Bgn-TLR4 signaling axis was also validated in a sarcopenia mouse model.</p><p><strong>Conclusion: </strong>Integrin αVβ5 is a critical regulator of myoblast proliferation and differentiation in response to FNDC5 gene supplement. These findings provide new insights into FNDC5 biological functions and suggest potential therapeutic strategies for enhancing muscle regeneration and treating sarcopenia.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13347998/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147469167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}