Skeletal Muscle最新文献

{"title":"Functional and structural pathologies in skeletal muscle of a rat model of Duchenne muscular dystrophy.","authors":"Young Il Lee, Cora C Hart, C Spencer Henley-Beasley, Jeffrey S Herr, Eli Zerpa, Elisabeth R Barton, David W Hammers, H Lee Sweeney","doi":"10.1186/s13395-026-00419-4","DOIUrl":"10.1186/s13395-026-00419-4","url":null,"abstract":"<p><strong>Background: </strong>Duchenne muscular dystrophy (DMD) is a lethal pediatric degenerative muscle disease for which there is no cure. Robust preclinical models that recapitulate major clinical features of DMD are required to investigate efficacy of potential DMD therapeutics. Rat models of DMD have emerged as promising small animal models to accomplish this; however, there have been no comprehensive studies investigating the functional skeletal muscle decrements associated with the modeling of DMD in rats.</p><p><strong>Methods: </strong>CRISPR/Cas9 gene editing was used to generate a dystrophin-deficient Sprague-Dawley muscular dystrophy rat (MDR). Biochemical and immunofluorescent analyses were performed to confirm loss of dystrophin in striated muscles of this rat model. In situ and ex vivo muscle function was assessed in wild-type (WT) and MDR muscles at 3, 6, and 12 months of age, followed by histopathological analyses.</p><p><strong>Results: </strong>MDR muscle tissues exhibited loss of full-length dystrophin and reduced content of other dystrophin glycoprotein complex members. MDR extensor digitorum longus (EDL) muscles and diaphragms displayed pronounced and progressive muscle weakness beginning at 3 months of age, compared to WT littermates. EDLs also exhibit susceptibility to eccentric contraction-induced damage. Functional deficits in soleus muscles were less severe and were associated with a right shift in force-frequency relationship. MDR muscles display progressive histopathology including degenerative lesions, fibrosis, regenerative foci, and modest adipose deposition.</p><p><strong>Conclusions: </strong>MDR is a preclinical model of DMD that exhibits many translational features of the human disease, including a large dynamic range of muscle decrements, that has high utility for the evaluation of potential therapeutics for DMD.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13040700/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147309889","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":"FGF2 rescues denervation-induced muscle atrophy in Ambystoma mexicanum.","authors":"Haruki Nakayama, Ayaka Ohashi, Sakiya Yamamoto, Saya Furukawa, Akira Satoh","doi":"10.1186/s13395-026-00413-w","DOIUrl":"10.1186/s13395-026-00413-w","url":null,"abstract":"<p><p>BACKGROUND: Denervation occurs as a consequence of disease or injury and is typically accompanied by skeletal muscle atrophy. Although the relationship between nerves and muscle atrophy has been studied, the direct molecular contributions of nerves remain unclear. METHODS: We used the axolotl (Ambystoma mexicanum), a vertebrate with robust regenerative capacity and optically accessible musculature, to investigate the role of nerve-derived signals in muscle maintenance. RESULTS: Forelimb denervation produced significant muscle atrophy in axolotls. Quantitative imaging showed that reduced muscle fiber size—rather than fiber loss—underlies this atrophy. To investigate the molecular basis of denervation-induced atrophy, we focused on fibroblast growth factor 2 (FGF2), a nerve-derived factor previously implicated in axolotl limb regeneration. Electroporation of FGF2 into denervated muscles significantly preserved muscle fiber size compared with controls. Conversely, pharmacological inhibition of FGF signaling with SU5402 reduced fiber size, supporting a requirement for FGF signaling in maintaining muscle mass. CONCLUSIONS: These findings demonstrate that FGF2 is sufficient to mitigate denervation-induced muscle atrophy and support a requirement for FGF signaling in the maintenance of muscle mass. Together with the neural expression of Fgf2, our data support a model in which nerve-derived FGF2 contributes to muscle maintenance. This work positions the axolotl as a tractable model for dissecting neuromuscular signaling and identifies FGF2 as a promising therapeutic candidate for neuromuscular atrophy. Understanding this mechanism may inform strategies to preserve muscle mass after nerve injury or in neurodegenerative diseases.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13032313/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146259139","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":"Unveiling FLNC variants: iPSC-derived myogenic cells as a model to study disease mechanisms.","authors":"Nassam M Daya, Anne Schänzer, Andreas Hentschel, Marie-Cecile Kienitz, Dominik Sellung, Nicolina Suedkamp, Karsten Krause, Jaqueline C Kinold, Leon Volke, Anja Schreiner, Hanna Schlierbach, Christopher Nelke, Felix Kleefeld, Anne-Katrin Guettsches, Holm Zaehres, Tobias Ruck, Lampros Mavrommatis, Andreas Roos, Matthias Vorgerd","doi":"10.1186/s13395-026-00418-5","DOIUrl":"10.1186/s13395-026-00418-5","url":null,"abstract":"<p><strong>Background: </strong>Filaminopathies, caused by pathogenic FLNC variants, are rare neuromuscular disorders characterized by protein aggregation, z-disk pathology and lead to progressive muscle weakness and/or cardiomyopathies.</p><p><strong>Methods: </strong>To address the lack of existing filaminopathy models in skeletal muscle, we developed a patient-specific cellular platform using induced pluripotent stem cells (iPSCs) harboring two truncating filamin C (FLNc) variants (p.Q1662X, p.Y2704X). Employing a developmental human skeletal muscle organoid hSMO model, we enrich for myogenic progenitor cells that are further differentiated into functional myotubes through 2D and 3D approaches (myotubes and musculoids).</p><p><strong>Results: </strong>The 2D myotubes exhibited poor sarcomeric organization and hallmarks of filaminopathies, including protein aggregation and proteostatic dysfunction, marked by elevated aggresome formation and an increased basal autophagic flux. The 3D musculoids revealed ultrastructural abnormalities and enabled the identification of novel disease-associated proteins involved in ER stress and protein folding (e.g. DNAJC10) through proteomic analysis. Proteomic findings were additionally validated in 2D cultures and in corresponding patient-derived muscle biopsies enhancing the model's translational value.</p><p><strong>Conclusions: </strong>Our model is suitable to monitor aspects of filaminopathies' pathogenesis and to investigate possible therapeutic interventions with quantitative readouts.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13063712/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146182318","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 transcriptomic signature of age and sex is not conserved in human primary myotubes.","authors":"Séverine Lamon, Megan Soria, Ross Williams, Annabel Critchlow, Karel Van Belleghem, Andrew Garnham, Akriti Varshney, Traude Beillharz, Danielle Hiam, Mark Ziemann","doi":"10.1186/s13395-026-00416-7","DOIUrl":"10.1186/s13395-026-00416-7","url":null,"abstract":"<p><strong>Background: </strong>Human primary muscle cell (HPMC) lines derived from skeletal muscle biopsies are potentially powerful tools to interrogate the molecular pathways underlying fundamental muscle mechanisms. HPMCs retain their genome in culture, but many endogenous circulating factors are not present in the in vitro environment, or at concentrations that do not mirror physiological levels. To address the assumption that HPMCs are valid models of age and sex-specificity in human muscle research, we examined to what extent differentiated HPMC lines retain their source phenotype in culture.</p><p><strong>Methods: </strong>Biopsies from the vastus lateralis muscle were collected from ten males aged 18-30, ten females aged 18-30 and ten males aged 60-75 recruited from a healthy population. A portion of the muscle was used for the establishment of 30 individual HMPC lines. The remaining sample was immediately snap frozen and stored for further analysis. RNA was extracted from muscle tissue samples and their corresponding, fully differentiated HMPCs and analysed using RNA Sequencing. To compare their transcriptomic signature, principal component analysis (PCA), differential expression analysis, single-cell deconvolution and pathway enrichment analysis were conducted in R.</p><p><strong>Results: </strong>A comparison of the transcriptomic signature of 30 human muscle biopsies and their corresponding differentiated HPMCs indicated a near-complete lack of retention of the genes and pathways differentially regulated in vivo when compared to their in vitro equivalent, with the exception of several genes encoded on the Y-chromosome.</p><p><strong>Conclusions: </strong>The diversity of resident cell populations in muscle tissue and the lack of sex- and age-dependent circulating factors in the cellular milieu likely contribute to these observations, which call for caution when using differentiated HPMCs as an experimental model of human muscle sex or age.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12973877/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146132865","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":"TRPV1 manipulating polarization of M1/M2 macrophages to promote skeletal muscle regeneration.","authors":"Jinfang Liu, Na Li, Shuwei Jing, Fangyu Wu, Guoshuai An, Liangliang Wang, Jian Li, Ximei Cao, Junhong Sun","doi":"10.1186/s13395-026-00417-6","DOIUrl":"10.1186/s13395-026-00417-6","url":null,"abstract":"<p><p>BACKGROUND: Skeletal muscle regeneration is a dynamically complex and multistage process in which balanced polarization of M1/M2 macrophages plays a crucial role. M1/M2 macrophages defend against microbial invasion, regulate tissue repair by engulfing pathogens and cellular debris, and secrete a variety of cytokines. However, the precise molecular mechanisms involved in M1/M2 macrophage polarization during skeletal muscle regeneration remain poorly understood. Transient receptor potential vanilloid 1 (TRPV1) is a cation channel implicated in pain perception and inflammation during tissue repair. This study aimed to investigate the role of TRPV1 in cardiotoxin (CTX)-induced skeletal muscle injury and regeneration, focusing on its impact on macrophage polarization and myogenesis. METHODS: Using a CTX-induced muscle injury model in mice, we examined the effects of TRPV1 on skeletal muscle regeneration, macrophage infiltration, and M1/M2 polarization. Mice were pretreated with capsaicin (CAP, a TRPV1 agonist) and capsazepine (CPZ, a TRPV1 antagonist). In vitro, the impact of TRPV1 on RAW264.7 macrophage polarization and myoblast differentiation was evaluated using co-culture experiments. Histological analysis and expression of TRPV1, MyoD, myogenin, CD86, CD206, Arg1, and IL-6 were assessed by Hematoxylin and Eosin staining, Sirius Red staining, immunofluorescence, western blotting, RT-qPCR and enzyme-linked immunosorbent assay. RAW264.7 macrophages were stimulated with LPS /IFN-γ or IL-4/IL-10 before pretreatment with CAP and CPZ and co-cultured with C2C12 myoblasts. Cell Counting Kit-8, immunofluorescence, western blotting, and Giemsa staining were utilized to evaluate macrophage proliferation, polarization and its effects on C2C12 differentiation. RESULTS: The expression of TRPV1 was markedly upregulated following CTX-induced skeletal muscle injury. Activation of TRPV1 by CAP reversed the M1/M2 macrophage imbalance, significantly reduced M1 macrophage infiltration, slightly increased M2 macrophage infiltration, and markedly increased MyoD and myogenin expression, thereby enhancing myogenesis. Additionally, CAP administration dramatically decreased M1-associated marker CD86 while increasing M2-associated marker Arg1 compared with controls or CPZ-treated mice. In vitro, TRPV1 activation inhibited M1 polarization and promoted M2 polarization. Co-culture of C2C12 cells with CAP-pretreated macrophages further implies that enhanced M2 polarization and reduced M1 polarization could be a contributing factor to the facilitation of myoblast differentiation. CONCLUSIONS: Our findings indicate that TRPV1 promotes skeletal muscle regeneration at least in part by modulating M1/M2 macrophage polarization.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12958662/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146107083","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":"FibroTrack: a standalone deep learning platform for automated fibrosis quantification in muscle and cardiac histology.","authors":"Anas Odeh, Rahaf Salem, Maher Abu Saleh, Ariel Shemesh, Polina Stein, Ido Livneh, Peleg Hasson","doi":"10.1186/s13395-026-00415-8","DOIUrl":"10.1186/s13395-026-00415-8","url":null,"abstract":"<p><p>Accurate fibrosis quantification is essential for understanding muscle and cardiac disease, yet current manual and semi‑automated methods remain slow, subjective, and poorly reproducible. We introduce FibroTrack, a standalone deep learning platform with a graphical user interface (GUI) that streamlines fibrosis analysis across Sirius Red (SR), Masson's Trichrome (MT), and immunohistochemistry (IHC) stainings. FibroTrack uniquely integrates LAB (lightness, green-red, blue-yellow) color space normalization with a You Only Look Once version 11 (YOLOv11) segmentation model trained on 2,034 histological images. This approach achieved 99.5% mask precision for muscle segmentation and demonstrated excellent concordance with blinded pathologists (Spearman correlation, r = 0.87-0.96). Automated outputs include segmented images and structured spreadsheets, ensuring high reproducibility and scalability. By combining advanced color analysis with state‑of‑the‑art segmentation in an accessible tool, FibroTrack provides a novel, accurate, and clinically relevant solution for high‑throughput fibrosis quantification in both preclinical research and pathology practice.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12973923/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146053638","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 contribution of skeletal muscle interstitial cells to myogenesis.","authors":"Fayez Issa, Frédéric Relaix, Joana Esteves de Lima","doi":"10.1186/s13395-026-00414-9","DOIUrl":"10.1186/s13395-026-00414-9","url":null,"abstract":"<p><p>The developmental origin of skeletal muscle cell lineages has been extensively studied in the last 50 years. PAX3 + /PAX7 + myogenic progenitors are the foundation for skeletal muscle development and give rise to muscle satellite cells that support skeletal muscle postnatal growth, homeostasis and regeneration. Research into muscle connective tissue interstitial cells established their supportive role in muscle patterning during development and regeneration. With recent advances in mouse genetic lineage tracing, single cell transcriptomics and specific antibodies, the origin and the contribution of non-myogenic interstitial populations to the myogenic lineage have been reexamined. Growing evidence suggests that subpopulations of muscle interstitial cells actively contribute to myogenesis and fuse with myofibers during development, postnatal growth, and regeneration. In this review, we focus on the recent research advances that highlighted the direct contribution of interstitial cells, particularly connective tissue cells, to skeletal muscle growth and repair. We stress the importance of further investigating the mechanisms by which interstitial cells contribute to a myogenic fate in both physiological and pathological conditions.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12952177/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146019543","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":"ASB5 is a specific marker for muscle satellite cells but dispensable for skeletal muscle development and regeneration.","authors":"Muhammad Asif, Stephanie N Oprescu, Renjie Shang, Zheng Zhang, Feng Yue, Pengpeng Bi, Shihuan Kuang","doi":"10.1186/s13395-025-00409-y","DOIUrl":"10.1186/s13395-025-00409-y","url":null,"abstract":"<p><strong>Background: </strong>Skeletal muscle plays a crucial role in human life, contributing to posture, movement, nutrient storage, and body temperature regulation. Development and regeneration of skeletal muscles rely on embryonic myogenic progenitors and postnatal satellite cells (MuSCs), respectively. Identification of new molecular markers and elucidating their functions in MuSCs will provide better understanding of muscle development and regeneration.</p><p><strong>Methods: </strong>We surveyed single cell RNA-seq (scRNA-seq) data (Tabula Muris and GSE150366) to identify ASB5 (Ankyrin repeat and Suppressor of cytokine signaling Box containing 5) as a marker of MuSCs. We also used CRISPR-CAS9 genome editing and oviduct electroporation to generate a germline knockout (KO) mouse line of Asb5. We then analyzed the muscle growth and regeneration of the KO mice. We further analyzed proliferation and differentiation of MuSCs attached on myofibers. We finally performed Realtime PCR (qPCR) to examine how Asb5 KO affects gene expression in the skeletal muscle.</p><p><strong>Results: </strong>Analysis of data publicly available at Tabula Muris identified Asb5 as a specific marker of MuSCs. Further analysis of scRNA-seq data on FACS-purified MuSCs at various regeneration time points revealed that Asb5 is highly expressed in MuSCs and their progenies across various stages of muscle regeneration. We then generated a novel Asb5 KO mouse line through CRISPR-Cas9 deletion of Exon 4. The Asb5-KO mice were born normally and exhibited normal postnatal growth. In addition, Asb5-KO MuSCs proliferated, differentiated and self-renewed normally on myofiber explants. Furthermore, the skeletal muscles of Asb5-KO mice regenerated normally after acute injury. qPCR analysis showed that Asb5 KO reduces the expression levels of Tnfa (Tumor Necrosis Factor Alpha) in the skeletal muscles.</p><p><strong>Conclusion: </strong>These data together identify ASB5 as an abundantly expressed and specific marker of MuSCs and myogenic progenitors. However, Asb5 loss-of-function has no effects on embryonic development and postnatal growth of skeletal muscles, or behavior and regenerative functions of MuSCs under normal physiological conditions.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12990408/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145999042","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":"Correction: The rise of rat models for Duchenne muscular dystrophy and therapeutic evaluations.","authors":"Frederic Relaix, Peggy Lafuste, Valentina Taglietti, Laurent Tiret","doi":"10.1186/s13395-025-00410-5","DOIUrl":"10.1186/s13395-025-00410-5","url":null,"abstract":"","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":"16 1","pages":"3"},"PeriodicalIF":3.9,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12794255/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145960134","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":"Humidity impacts volatile anesthetic and heat responses of malignant hyperthermia susceptible mice.","authors":"Miao He, Sheila Riazi, Luuk R van den Bersselaar, Gunilla Islander, Robyn Gillies, Anna Hellblom, Nicol C Voermans, Sultan Temurziev, Heinz Jungbluth, Robert T Dirksen","doi":"10.1186/s13395-025-00411-4","DOIUrl":"10.1186/s13395-025-00411-4","url":null,"abstract":"<p><strong>Background: </strong>Malignant Hyperthermia (MH) is characterized by life-threatening whole-body hyperthermic reactions triggered by volatile anesthetics in susceptible individuals. MH susceptibility (MHS) and exertional heat stroke (EHS) are linked to mutations in the type I ryanodine receptor (RYR1). However, the discordance between the estimated prevalence of RYR1 MHS mutations in the general population (1:625-1,075) and the occurrence of MH episodes during anesthesia (1:100,000) suggests additional factors beyond genetics.</p><p><strong>Methods: </strong>Using an established MHS mouse model (Y524S or YS mice), 10-12-week-old WT and YS mice were exercised on a treadmill (20° incline, 15 m/min, 60 min) and/or exposed to heat (15 min at 37℃) or 2% isoflurane either in a low or high humid environment. A second cohort of 10-12-week-old WT and YS mice were exposed to 2% isoflurane under a low or high humid environment. Vehicle or dantrolene (4 mg/kg) was administered during isoflurane exposure once the rectal temperature reached 39℃. Rectal temperature was continuously monitored under all conditions. In addition, historical humidity and temperature data were collected from dates on which MHS individuals either experienced or did not experience a defined MH episode.</p><p><strong>Results: </strong>In young, but not older, YS male mice, survival rates significantly decreased during heat challenge (HR Dry/Humid = 0.1621, P = 0.018) and isoflurane exposure in a humid environment (HR Dry/Humid = 0.2273, P = 0.035). Dantrolene improved survival (HR DMSO/Dantrolene ranging from 4.959 to 8.667 in all conditions) and slowed the rate of core temperature increase in young YS mice regardless of humidity. Humidity was similarly associated with increased MH occurrence (AUC = 0.8104, P = 0.0026) in male MHS patients.</p><p><strong>Conclusions: </strong>Absolute humidity was associated with worsened outcomes during heat and isoflurane exposure in male MHS mice and an increase in MH occurrence in male MHS patients. These results support maintaining humidity levels within operating suites at lower levels of current guidelines, especially where dantrolene is not available.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":" ","pages":"10"},"PeriodicalIF":3.9,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12911050/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145946336","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}