Skeletal Muscle最新文献

{"title":"Non-regenerative myogenesis in adult skeletal muscles: myofiber death-independent muscle satellite cell expansion.","authors":"So-Ichiro Fukada, Atsushi Kubo, Takashi Yamada, Takayuki Akimoto","doi":"10.1186/s13395-026-00412-x","DOIUrl":"10.1186/s13395-026-00412-x","url":null,"abstract":"<p><p>Muscle regeneration processes triggered by injuries following myofiber death have been extensively investigated owing to the availability of suitable in vivo animal models, including disease models. During muscle regeneration, skeletal muscle-resident stem cells, also known as muscle satellite cells (MuSCs), exit the quiescent state, become activated, and proliferate to generate new myofibers. These MuSC behaviors have also been observed in resistance- and endurance-training models. In these models, MuSC behaviors are thought to follow the same mechanisms as myogenesis observed during regeneration (regenerative myogenesis), as certain animal training models induce myofiber death; moreover, myofiber damage markers have been detected in human training samples. Nevertheless, accumulating evidence suggests that MuSCs can become activated, proliferate, and differentiate in the absence of overt signs of myofiber death. Considering the therapeutic potential of MuSCs for muscle atrophy, injury-independent myogenesis (non-regenerative myogenesis) must be investigated, as apparent and frequent myofiber death does not occur in many atrophic conditions. In this review, we introduce the concept and evidence for “non-regenerative myogenesis” in adult skeletal muscle and highlight its characteristics and the remaining research questions.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":" ","pages":"9"},"PeriodicalIF":3.9,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12908285/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145917974","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":"Necessity of Notch3 signaling in myofiber maturation in a pluripotent stem cell transplant model.","authors":"Aline M S Yamashita, Sarah B Crist, Bayardo I Garay, Hyunkee Kim, Karim Azzag, Darko Bosnakovski, Sergio H D M Faria, Juan E Abrahante, Phablo Abreu, Aaron Ahlquist, Rita C R Perlingeiro","doi":"10.1186/s13395-025-00403-4","DOIUrl":"10.1186/s13395-025-00403-4","url":null,"abstract":"<p><strong>Background: </strong>Pluripotent stem cell-derived myogenic progenitors change from an embryonic to a postnatal molecular signature upon engrafting as satellite cells, which coincides with upregulation of Notch3. Since a role for Notch3 in skeletal muscle maturation is unknown, here we investigate whether Notch3 is required for this in vivo molecular maturation switch.</p><p><strong>Results: </strong>Our results show that lack of Notch3 in transplanted progenitors (N3KO) does not impact degree of engraftment, but leads to increased numbers of embryonic myofibers. Conversely, transplantation of Notch3 overexpressing (N3OE) myogenic progenitors results in lower numbers of embryonic myofibers, but diminished muscle grafts when compared to empty vector (EV) controls. Secondary transplantation studies confirmed these effects, whereby Notch3 overexpression significantly reduced secondary engraftment. Further characterization of N3OE donor-derived satellite cells revealed reduced proliferation and downregulation of cell cycle genes. Importantly, secondary grafts from N3KO satellite cells had increased numbers of embryonic myofibers compared to N3OE and EV controls.</p><p><strong>Conclusions: </strong>Taken together, these findings demonstrate that Notch3 signaling is required for myofiber maturation, and that constant activation of Notch3 impairs proliferation and muscle regeneration. Transcriptional profiles of N3OE donor-derived satellite cells suggest that dampened regeneration may be driven by inhibitory alterations in cell cycle regulation.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":"16 1","pages":"1"},"PeriodicalIF":3.9,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12771941/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145906653","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":"Long-term DNA methylation changes induced by age and elevated CO₂ in skeletal muscle.","authors":"Joseph Balnis, Andy Madrid, Emily L Jackson, Lisa A Drake, Catherine E Vincent, Harold A Singer, Reid S Alisch, Ariel Jaitovich","doi":"10.1186/s13395-025-00406-1","DOIUrl":"10.1186/s13395-025-00406-1","url":null,"abstract":"<p><strong>Background: </strong>Skeletal muscle dysfunction and elevated CO₂ in the blood, or hypercapnia, are both associated with higher mortality in acute and chronic pulmonary diseases. Hypercapnia-, aging and autophagy dysfunction-induced skeletal muscle phenotypes are highly overlapping. While DNA methylation regulates aging-associated cellular processes, no comparative study of CO₂- and age-induced changes in skeletal muscle has ever been conducted. Moreover, while previously reported skeletal muscle DNA methylation analyses involve about 1% of the genomic areas susceptible to this epigenetic modification, hypercapnia- and age-induced DNA methylation changes have never been investigated at the whole genome level.</p><p><strong>Methods: </strong>C57BL/6 mice previously exposed to normo- and hypercapnia were compared with room air-maintained aged animals of similar background. Muscles from these mice were processed for whole genome methylation sequencing (WGMS) and RNA sequencing. The overlap between hypercapnia- and age-induced DNA methylation and transcript expression levels were established. Skeletal muscle-specific autophagy genetic ablation and mass spectrometry analyses were conducted to investigate the potential mechanisms regulating hypercapnia-induced DNA methylation changes.</p><p><strong>Results: </strong>Hypercapnic mice demonstrate aberrant DNA methylation patterns in comparison to animals never exposed to elevated CO₂. These animals also elicit changes in myofiber type composition and protracted muscle mass deterioration even after returning to normocapnia. While aging leads to consistent DNA methylation changes over time, these epigenetic changes do not overlap with CO₂-induced differential methylation. Hypercapnia does not regulate the methylome via autophagy or substrate imbalance-related mechanisms.</p><p><strong>Conclusion: </strong>Hypercapnia causes durable muscle wasting that persists even after regaining ambient air environment, which is associated with a perturbed methylome landscape. High CO₂-induced DNA methylation changes do not overlap with age-induced differentially methylation positions and are independent of substrate imbalances and autophagy regulation.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":" ","pages":"7"},"PeriodicalIF":3.9,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12860122/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145794659","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":"Repairing the defective folding of alpha-sarcoglycan is needed to promote myogenic cell engraftment in 3D artificial muscle models of LGMDR3.","authors":"Edoardo Maghin, Alberto Benetollo, Martina Scano, Paola Caccin, Eugenia Carraro, Martina Piccoli, Dorianna Sandonà","doi":"10.1186/s13395-025-00408-z","DOIUrl":"10.1186/s13395-025-00408-z","url":null,"abstract":"<p><p>Limb-girdle muscular dystrophy 2D (or LGMDR3) is a rare autosomal recessive disorder caused by mutations in the SGCA gene, which encode α-sarcoglycan (α-SG). α-SG is a critical component of the dystrophin-associated protein complex, whose role in differentiated muscle is to distribute contraction force and protect the sarcolemma from mechanical damage. Most SGCA mutations are missense, leading to a folding-defective α-SG that is degraded by the ubiquitin-proteasome system, destabilizing the sarcolemma and causing progressive muscle weakness. Notably, pharmacological restoration of α-SG function using cystic fibrosis transmembrane conductance regulator (CFTR) correctors, such as C17, can rescue the SG-complex, improving muscle strength in an LGMDR3 mouse model. Our initial aim was to generate 3D diaphragm-like models of LGMDR3 by seeding patient-derived myoblasts onto a decellularised diaphragm scaffold, thereby mimicking the disease environment and enabling drug screening beyond the limitations of 2D cultures. While the models did not behave as anticipated, the unexpected outcome led us to uncover a previously underappreciated role of α-SG. Specifically, we found that α-SG expressed by immature myoblasts is crucial for cell adhesion and migration, key processes for muscle development, regeneration, and successful engraftment into a decellularized extracellular matrix. These processes, compromised in LGMDR3 cells, can be rescued through CFTR correctors, further supporting their potential therapeutic application in LGMDR3.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":" ","pages":"5"},"PeriodicalIF":3.9,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12817426/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145744208","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":"N-acetylglucosamine facilitates coordinated flow-like movement of myoblasts, forming a foundation for efficient myogenesis.","authors":"Masahiko S Satoh, Ann Rancourt, Guillaume St-Pierre, Elizabeth Bouchard, Maude Fillion, Kana Hagiwara, Kazuki Nakajima, Sachiko Sato","doi":"10.1186/s13395-025-00404-3","DOIUrl":"10.1186/s13395-025-00404-3","url":null,"abstract":"<p><strong>Background: </strong>Skeletal muscle comprises 30-40% of a mammal's body mass, maintaining its integrity through efficient muscle fiber regeneration, which involves myoblast differentiation into myotubes. Previously, we reported that N-acetylglucosamine (GlcNAc) promotes myogenesis in C2C12 cells, although the underlying processes remained unclear. GlcNAc's activated form, UDP-GlcNAc, is critical for the biosynthesis of highly branched (N-acetyllactosamine-rich) N-linked oligosaccharides, which are recognized by galectin-3 (Gal-3), a protein that facilitates dynamic cell-cell and cell-matrix interactions and modulating the motility dynamics of membrane-associated proteins.</p><p><strong>Methods: </strong>In this study, we used primary myoblasts from both wild-type and Gal-3 null (Gal-3KO) mice, observing myotube formation through long-term live-cell imaging and single-cell tracking to reveal the dynamic process that occurred during the myotube formation.</p><p><strong>Results: </strong>We found that GlcNAc enhances myoblast fusion in a dose-dependent manner, and that the addition of Gal-3 with GlcNAc leads to the formation of larger myotubes. Gal-3KO myoblasts exhibited a reduced capacity for myotube formation-a deficiency that was rectified by supplementing with GlcNAc and Gal-3. Our results highlight the role of Gal-3 interaction with oligosaccharides, whose synthesis is promoted by GlcNAc in facilitating myotube formation. Single-cell tracking revealed that GlcNAc and Gal-3 increase myoblast motility, leading to a faster, coordinated, flow-like movement-a collective behavior, along which myotubes form through cell fusion. Interestingly, myoblasts contributing to myotube formation were pre-positioned along the eventual shape of the myotubes before this flow-like movement was fully established. These myoblasts moved along the flow, paused, and even moved against it, suggesting that both coordinated flow and initial spatial positioning contribute to myoblast alignment along the axis of future myotubes.</p><p><strong>Conclusion: </strong>Our findings suggest that GlcNAc, in conjunction with Gal-3, enhances myotube formation by fostering an environment conducive to myoblast positioning, establishing optimal coordinated flow-like movement, and facilitating fusion. This suggests potential therapeutic applications of GlcNAc in muscle repair and muscle disorders.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":" ","pages":"6"},"PeriodicalIF":3.9,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12817516/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145744186","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":"The metabolic role of corticotropin-releasing hormone receptor 2 and its UCN peptides: emerging therapeutic potential.","authors":"Pablo Vidal, Natalie Janzen, Joseph T Brozinick","doi":"10.1186/s13395-025-00405-2","DOIUrl":"10.1186/s13395-025-00405-2","url":null,"abstract":"<p><p>Skeletal muscle is a highly plastic tissue that plays a crucial role in overall metabolic health, and in diseases such as obesity and type 2 diabetes. Recently, the importance of preserving muscle mass during weight loss has gained appreciation, especially with significant weight loss observed from incretin therapies, which includes loss of both fat and lean mass (Conte et al, JAMA 332:9-10, 2024). This has prompted investigation into pharmacological candidates that can prevent the loss of muscle mass seen during weight loss. Urocortins and their cognate receptors pose an interesting target, as recent evidence shows that they play a role in diseases such as heart failure, diabetes, and obesity. Urocortin treatment results in decreased food intake, muscle hypertrophy and improved skeletal muscle glucose uptake. However, the molecular mechanisms by which urocortins act have yet to be elucidated. The aim of this review is to highlight our current understanding of the effects of urocortins on metabolic adaptations.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":" ","pages":"2"},"PeriodicalIF":3.9,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12781255/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145678755","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":"Displaced myonuclei are attributable to both resident myonuclear migration and stem cell fusion during mechanical loading in adult skeletal muscle.","authors":"Nathan Serrano, Pieter Jan Koopmans, Kevin A Murach","doi":"10.1186/s13395-025-00407-0","DOIUrl":"10.1186/s13395-025-00407-0","url":null,"abstract":"<p><p>Non-peripheral (displaced) myonuclei are characteristic of skeletal muscle pathology and severe injury but also appear after exercise and with aging. Displaced myonuclei are typically attributed to the activity of muscle stem cells, or satellite cells. We sought to address whether displaced myonuclei in adult skeletal muscle are exclusively from an exogenous source such as satellite cells or can result from resident myonuclear migration. To address this question, we used a murine recombination-independent muscle fibre-specific doxycycline-inducible fluorescent myonuclear labelling approach, EdU stem cell fate tracking, two durations of plantaris muscle mechanical overload (MOV, 3 days and 7 days), and fluorescent histology. Our findings show that: 1) displaced myonuclei emerge early during MOV in adult mice, 2) resident myonuclear movement occurs rapidly during MOV, and 3) the contribution of resident versus exogenous displaced myonuclei depends on the preferential effects of MOV for specific fibre types or fibre sizes with a given MOV duration. These observations provide fundamental insights on myonuclear motility in response to stress in vivo and reframe our understanding of how a recognized feature of mammalian skeletal muscle can emerge in response to stressors such as mechanical loading.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":" ","pages":"4"},"PeriodicalIF":3.9,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12797705/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145687942","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":"Complement-independent pathogenic influences of anti-HMGCR + and anti-SRP + immune-mediated necrotizing myopathy autoantibodies on engineered muscle function.","authors":"Heta Lad, Yekaterina Tiper, Ernest Myguel Esteban, Manish K Singh, Alexandrine Mahoudeau, Zhuoye Xie, Berenice Tendrel, Yves Allenbach, Olivier Benveniste, Penney M Gilbert","doi":"10.1186/s13395-025-00400-7","DOIUrl":"10.1186/s13395-025-00400-7","url":null,"abstract":"<p><strong>Background: </strong>Immune-mediated necrotizing myopathy (IMNM) is a subgroup of idiopathic inflammatory myopathies associated with anti-signal recognition particle (SRP) or anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) autoantibodies. The direct pathogenic effects of IMNM patient autoantibodies on skeletal muscle contractile force, independent of the downstream activation of the complement pathway, remain understudied.</p><p><strong>Methods: </strong>This study leverages a custom 3-D human skeletal muscle microtissue (hMMT) culture platform that encourages muscle cell contractile apparatus maturation and enables analysis of contractile function. Force generation competent hMMTs were treated with total immunoglobulins (IgGs) isolated from the plasma of IMNM patients with amplification of anti-SRP⁺ (n = 7) or anti-HMGCR⁺ (n = 7) autoantibodies and delivered in complement inactivated media for 4 days. hMMT function was then evaluated by quantifying the peak force and contraction kinetics in response to electrical field stimulation, followed by histological analysis of muscle cell gross morphology and sarcomere structure. To determine whether IgG from IMNM patients can enter muscle cells, 2-D myotube cultures were treated with donor total IgG delivered in complement replete media for 36 h, and then analyzed using immunostaining and confocal microscopy.</p><p><strong>Results: </strong>Exposure to total IgGs isolated from a subset of IMNM patients induced a decline in hMMT twitch and tetanus contractile force and were associated with sarcomere fragility and slowed muscle cell contraction and relaxation rates. Pathogenic influences on hMMT force generation were observed at a greater frequency in response to total IgGs isolated from IMNM patients with anti-HMGCR + autoantibodies. Substantial intracellular human IgG staining was observed in conditions where myotubes were treated with total IgGs from IMNM patients.</p><p><strong>Conclusions: </strong>This study demonstrates that total IgGs isolated from IMNM patients have the aberrant capacity to enter muscle cells in the absence of complement. Further, a subset of patient IgGs exert direct pathogenic influences on engineered muscle contractile function that are independent of the complement system. Together, these findings have important implications for the advancement of IMNM precision medicine therapies.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":" ","pages":"8"},"PeriodicalIF":3.9,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12882220/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145597182","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":"FLASH: innovative integrated enzymatic-fluorescent labeling for automated muscle fiber typing, metabolic and morphometric analysis.","authors":"Maxime Di Gallo, Thomas Guilbert, Doriane Pereira, Zoé Cepella, Raphaël Braud-Mussi, Edgar Jauliac, Gaspard Macaux, Florian Alexis Britto, Thierry Launay","doi":"10.1186/s13395-025-00401-6","DOIUrl":"10.1186/s13395-025-00401-6","url":null,"abstract":"<p><strong>Background: </strong>Skeletal muscle is a dynamic tissue capable of structural and metabolic remodeling in response to physiological and pathological stimuli. These adaptations are central to understanding the mechanisms underlying conditions such as genetic myopathies, cancer, aging, and recovery from injury. Muscle fiber characterization-assessing fiber type, size, and metabolic profile-is essential for such studies. However, conventional histological methods often rely on serial tissue sections and multiple staining protocols, which are time-consuming, require significant biological material, and introduce methodological bias.</p><p><strong>Methods: </strong>We developed FLASH (Fluorescence-based Labeling for Assessing Skeletal muscle Histology), a novel methodology combining enzymatic (SDH or GPDH) and quadruple fluorescent labeling (Laminin, MYH4, MYH2, MYH7) on a single muscle section. The resulting images were analyzed using a custom macro in Fiji/ImageJ, integrating the Cellpose segmentation algorithm. This automated pipeline detects individual muscle fibers, quantifies their cross-sectional area (CSA), identifies fiber types based on myosin isoform expression, and measures enzymatic staining intensity. Batch analysis was implemented to process entire image folders automatically. Validation was performed by comparing automated fiber detection with expert manual segmentation using correlation analysis and Bland-Altman plots.</p><p><strong>Results: </strong>The FLASH method allowed simultaneous assessment of both contractile and metabolic properties within individual fibers on the same section, removing the need for serial cuts. The automated image analysis achieved high accuracy in fiber detection (r > 0.95 compared to manual annotation) and produced consistent CSA and fiber-type quantification, even under suboptimal staining conditions. The macro enabled significant time savings by automating the complete analysis workflow, including ROI generation and Excel data export for each image.</p><p><strong>Conclusions: </strong>FLASH provides an efficient and robust tool for high-throughput skeletal muscle histology. By combining enzymatic and fluorescent co-labeling with machine learning-based image analysis, this method improves reproductibility, reduces experimental complexity, and minimizes user bias. FLASH is particularly well-suited for large-scale or longitudinal studies investigating muscle adaptation in health and disease.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":"15 1","pages":"32"},"PeriodicalIF":3.9,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12639953/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145574304","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":"Pirfenidone treatment improves ischemic muscle function in mice with chronic kidney disease.","authors":"Nicholas Balestrieri, Gengfu Dong, Terence E Ryan","doi":"10.1186/s13395-025-00402-5","DOIUrl":"10.1186/s13395-025-00402-5","url":null,"abstract":"<p><p>Chronic kidney disease (CKD) and peripheral artery disease (PAD) frequently coexist and synergistically exacerbate skeletal muscle dysfunction, contributing to limb function impairment and increased risk of amputation and mortality. Both diseases independently promote fibrotic remodeling in muscle, suggesting that anti-fibrotic therapies may improve muscle health in this high-risk population. We tested whether targeting the fibrotic niche with batimastat, a matrix metalloprotease inhibitor, or pirfenidone, an approved anti-fibrotic medication, would improve ischemic limb function in a mouse model of CKD and PAD. Male mice (n = 21) were fed an adenine diet to induce CKD and subsequently underwent surgical femoral artery ligation to induce hindlimb ischemia, an experimental model of PAD. Pirfenidone significantly improved ischemic muscle absolute force (P < 0.0001) and specific force (P = 0.0027), and increased time-tension integral during a muscle fatigue test (P < 0.0001), while batimastat significantly reduced these parameters compared to placebo. Surprisingly, neither treatment altered muscle fibrosis, perfusion recovery, capillary density, or myofiber regeneration, indicating that functional improvements with pirfenidone occurred independently of structural remodeling. These findings suggest that pirfenidone preserves muscle strength and quality and may have therapeutic potential to improve limb function in patients with CKD and PAD. Further investigation is warranted to define pirfenidone's mechanism of action in skeletal muscle and evaluate its efficacy in the clinical setting.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":"15 1","pages":"31"},"PeriodicalIF":3.9,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12625154/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145542354","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}