Skeletal Muscle最新文献

{"title":"Large MAF transcription factors reawaken evolutionarily dormant fast-glycolytic type IIb myofibers in human skeletal muscle.","authors":"Shunya Sadaki, Ryosuke Tsuji, Takuto Hayashi, Masato Watanabe, Ryoto Iwai, Gu Wenchao, Ekaterina A Semenova, Rinat I Sultanov, Andrey V Zhelankin, Edward V Generozov, Ildus I Ahmetov, Iori Sakakibara, Koichi Ojima, Hidetoshi Sakurai, Masafumi Muratani, Takashi Kudo, Satoru Takahashi, Ryo Fujita","doi":"10.1186/s13395-025-00391-5","DOIUrl":"10.1186/s13395-025-00391-5","url":null,"abstract":"<p><strong>Background: </strong>Small mammals such as mice rely on type IIb myofibers, which express the fast-contracting myosin heavy chain isoform Myh4, to achieve rapid movements. In contrast, larger mammals, including humans, have lost MYH4 expression. Thus, they favor slower-contracting myofiber types. However, the mechanisms underlying this evolutionary shift remain unclear. We recently identified the large Maf transcription factor family (Mafa, Mafb, and Maf) as key regulators of type IIb myofiber specification in mice. In this study, we investigate whether large MAFs play a conserved role in the induction of MYH4 expression and glycolytic metabolism in human and bovine skeletal muscle.</p><p><strong>Methods: </strong>We performed adenovirus-mediated overexpression of large MAFs in iPSC-derived human myotubes and primary bovine myotubes. We subsequently quantified MYH4 expression using RT-qPCR, RNA sequencing (RNA-seq), and LC-MS/MS analysis. Glycolytic capacity was assessed using a flux analyzer and metabolic gene expression profiling. Additionally, RNA-seq analysis of human muscle biopsy samples was conducted to determine the correlations between large MAFs and the expression of MYH4 and other myosin genes, as well as their association with fast fiber composition and athletic training.</p><p><strong>Results: </strong>Overexpression of large MAFs in human and bovine myotubes robustly induced MYH4 expression, with mRNA levels increasing by 100- to 1000-fold. LC-MS/MS analysis provided clear evidence of MYH4 protein expression in human myotubes, where it was previously undetectable. RNA-seq and flux analyzer data revealed that large MAFs significantly enhanced glycolytic capacity by upregulating the expression of key genes involved in glucose metabolism. Moreover, RNA-seq analysis of human muscle biopsy samples revealed a positive correlation between MAFA, MAF, and MYH4 expression. Furthermore, MAFA and MAF expression levels were elevated in power-trained individuals, accompanied by increased expression of MYH4 and other fast myosin genes.</p><p><strong>Conclusions: </strong>Our findings establish large MAF transcription factors as key regulators of MYH4 expression and glycolytic metabolism in human skeletal muscle. This discovery provides novel insights into the evolutionary loss of type IIb myofibers in larger mammals and suggests potential strategies for enhancing muscle performance and mitigating fast-twitch fiber loss associated with aging and muscle degeneration.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":"15 1","pages":"19"},"PeriodicalIF":4.4,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12296675/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144718389","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":"Abnormalities in the genioglossus muscle and its neuromuscular synapse in leptin-deficient male mice.","authors":"Srujith Medharametla, Garrett Borger, Shashir Gaonkar, Isabel Martinez-Pena Y Valenzuela","doi":"10.1186/s13395-025-00387-1","DOIUrl":"10.1186/s13395-025-00387-1","url":null,"abstract":"<p><strong>Background: </strong>The genioglossus (GG) muscle, the largest upper airway dilator muscle, plays a crucial role in maintaining pharyngeal airway patency. It is innervated by hypoglossal motoneurons, and its tone is often reduced in patients with obstructive sleep apnea (OSA), leading to tongue collapse and airway obstruction during sleep. Although the mechanisms underlying this disorder are not fully understood, the neuromuscular junction (NMJ) of the GG muscle, essential for communication between motor neurons and skeletal muscle, has largely been overlooked.</p><p><strong>Methods: </strong>In this study, we explored whether obesity impacts the NMJ of the GG muscle. Using the leptin-deficient obese mouse model, Lep^ob/ob, which exhibits pharyngeal collapsibility and hypoventilation, we analyzed the GG muscle and its NMJ in both male and female mice. We conducted morphological and histochemical studies of the GG muscle; quantitative fluorescence imaging to assess the density and dynamics of nicotinic acetylcholine receptors (nAChRs) at the NMJ; high-resolution confocal microscopy to evaluate structural changes in the pre- and postsynaptic apparatus; and transmission electron microscopy for ultrastructural analysis. Additionally, we examined the diaphragm (DIA) and sternomastoid (ST) muscles for comparative analysis.</p><p><strong>Results: </strong>Our results show that the GG muscle and its NMJs exhibit significant alterations in Lep^ob/ob male mice, while the ST and DIA muscles remain unaffected. Lep^ob/ob males displayed altered GG muscle morphology, changes in synapse structure, and reduced postsynaptic AChR density compared to both controls and Lep^ob/ob females. Additionally, AChR turnover and the morphology of the presynaptic apparatus were impaired in Lep^ob/ob male mice. In contrast, Lep^ob/ob females exhibited NMJs similar to those of wild-type mice.</p><p><strong>Conclusions: </strong>These findings suggest that the GG muscle is particularly susceptible to degeneration in obesity induced by leptin deficiency, with distinct alterations observed in both the muscle and the NMJ. This specificity underscores the complex impact of obesity on NMJ health and highlights the need for further investigation into muscle-specific responses to obesity-related stress. Additionally, the degeneration of the GG muscle appears to reflect a sex-specific impact of obesity on neuromuscular integrity and may contribute to the pathogenesis of OSA.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":"15 1","pages":"18"},"PeriodicalIF":5.3,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12228284/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144565128","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":"Identifying kinematic biomarkers of the dystrophic phenotype in a zebrafish model of Duchenne muscular dystrophy.","authors":"Jeffrey J Widrick, Matthias R Lambert, Felipe de Souza Leite, Youngsook Lucy Jung, Junseok Park, James R Conner, Eunjung Alice Lee, Alan H Beggs, Louis M Kunkel","doi":"10.1186/s13395-025-00382-6","DOIUrl":"10.1186/s13395-025-00382-6","url":null,"abstract":"<p><strong>Background: </strong>Dystrophin-deficient zebrafish larvae are a small, genetically tractable vertebrate model of Duchenne muscular dystrophy that is well suited for early-stage therapeutic development. However, current approaches for evaluating their mobility, a physiologically relevant therapeutic outcome, yield data of low resolution and high variability that provides minimal insight into potential mechanisms responsible for their abnormal locomotion.</p><p><strong>Methods: </strong>To address these issues, we used high speed videography and deep learning-based markerless motion capture to quantify escape response (ER) swimming kinematics of two dystrophic zebrafish strains (sapje and sapje-like). Each ER was partitioned into an initiating C-start, a subsequent power stroke, and a final burst of undulatory swimming activity.</p><p><strong>Results: </strong>Markerless motion capture provided repeatable, high precision estimates of swimming kinematics. Random forest and support vector machine prediction models identified overall ER distance and peak speed, the instantaneous speed conferred by the power stroke, and the average speed and distance covered during burst swimming as the most predictive biomarkers for differentiating dystrophic from wild-type larvae. For each of these predictors, mutant and wild-type larvae differed markedly with effect sizes ranging from 2.4 to 3.7 standard deviations. To identify mechanisms underlying these performance deficits, we evaluated the amplitude and frequency of propulsive tail movements. There was little evidence that tail stroke amplitude was affected by the absence of dystrophin. Instead, temporal aspects of tail kinematics, including tail maximal angular velocity during the C-start and power stroke and tail stroke frequency during burst swimming, were slowed in mutants. In fact, tail kinematics were as effective as direct, non-survival in vitro assessments of tail muscle contractility in differentiating mutant from wild-type larvae.</p><p><strong>Conclusions: </strong>ER kinematics can be used as precise and physiologically relevant biomarkers of the dystrophic phenotype, may serve as non-lethal proxies for skeletal muscle dysfunction, and reveal new insights into why mobility is impaired in the absence of dystrophin. The approach outlined here opens new possibilities for the design and interpretation of studies using zebrafish to model movement disorders.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":"15 1","pages":"17"},"PeriodicalIF":5.3,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12180146/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144336841","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":"Extensive striated muscle damage in a rat model of Duchenne muscular dystrophy with Dmd exons 10-17 duplication.","authors":"Jean-Daniel Masson, Valentina Taglietti, François Ruby, Hiroya Ono, Nadir Mouri, Alan Jorge, Laurent Guillaud, Laurent Tiret, Frederic Relaix","doi":"10.1186/s13395-025-00386-2","DOIUrl":"10.1186/s13395-025-00386-2","url":null,"abstract":"<p><strong>Background: </strong>Duchenne muscular dystrophy (DMD) mainly affects young boys with out-of-frame mutations in the DMD gene, leading to dystrophin deficiency. This loss disrupts the assembly of the sarcolemmal dystrophin-associated glycoprotein complex, resulting in membrane fragility and damage during muscle contraction-relaxation cycles. Consequently, patients experience progressive muscle weakness, loss of ambulation and cardiorespiratory failure. Gene therapy represents one of the most promising therapeutic approaches, requiring rigorous preclinical validation of candidate strategies. While several preclinical models of dystrophin deficiency mimic point mutations or exon deletions, no existing rat model accurately replicates DMD gene duplications, which account for approximately 10% of DMD cases.</p><p><strong>Methods: </strong>Using CRISPR/Cas9 genome editing, we generated a ~ 125 kbp duplication encompassing exons 10-17 of the Dmd gene in Sprague Dawley rats. To characterise disease progression in these rats, we assessed biochemical, histological and functional biomarkers at 6 and 10 months of age, comparing them to their healthy littermates.</p><p><strong>Results: </strong>We established the R-DMDdup10-17 line. The microstructure of limb, diaphragm and cardiac muscles of R-DMDdup10-17 (DMD) rats exhibited dystrophic changes at 6 and 10 months, including loss of myofibres and fibrosis. These alterations led to a significant body mass reduction, muscle weakness (including diaphragm deficiency) and cardiac electrical defects. Premature lethality was observed between 10 and 13 months.</p><p><strong>Conclusion: </strong>Duplication of the Dmd genomic region encompassing exons 10 to 17 in rats results in dystrophin deficiency, severe striated muscle dystrophy, and premature death. The R-DMDdup10-17 line represents the first reported genetic model of a severe and early lethal duplication variant in the Dmd gene. It provides a critical tool for assessing targeted gene therapies aimed to correct such mutations.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":"15 1","pages":"16"},"PeriodicalIF":5.3,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12147255/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144258927","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":"Contrasting Becker and Duchenne muscular dystrophy serum biomarker candidates by using data independent acquisition LC-MS/MS.","authors":"Camilla Johansson, Esther J Schrama, David Kotol, Andreas Hober, Zaïda Koeks, Nienke M van de Velde, Jan J G M Verschuuren, Erik H Niks, Fredrik Edfors, Pietro Spitali, Cristina Al-Khalili Szigyarto","doi":"10.1186/s13395-025-00385-3","DOIUrl":"10.1186/s13395-025-00385-3","url":null,"abstract":"<p><strong>Background: </strong>Becker muscular dystrophy (BMD) is a rare and heterogeneous form of dystrophinopathy caused by expression of altered dystrophin proteins, as a consequence of in-frame genetic mutations. The majority of the BMD biomarker studies employ targeted approaches and focus on translating findings from Duchenne Muscular Dystrophy (DMD), a more severe disease form with clinical similarities but caused by out-of-frame mutations in the dystrophin gene. Importantly, DMD therapies assume that disease progression can be slowed by promoting the expression of truncated dystrophin comparable to what occurs in BMD patients. In this study, we explore similarities and differences in protein trajectories over time between BMD and DMD serum, and explore proteins related to motor function performance.</p><p><strong>Methods: </strong>Serum samples collected from 34 BMD patients, in a prospective longitudinal 3-year study, and 19 DMD patients, were analyzed by using Data Independent Acquisition Tandem Mass Spectrometry (DIA-MS). Subsequent normalization, linear mixed effects model was employed to identify proteins associated with physical tests and dystrophin expression in skeletal muscle. Analysis was also performed to explore the discrepancy between DMD and BMD biomarker abundance trajectories over time.</p><p><strong>Results: </strong>Linear mixed effects models identified 20 proteins with altered longitudinal signatures between DMD and BMD, including creatine kinase M-type (CKM) pyruvate kinase (PKM), fibrinogen gamma chain (FGG), lactate dehydrogenase B (LDHB) and alpha-2-macroglobulin (A2M). Furthermore, several proteins related to innate immune response were associated with motor function in BMD patients. In particular, A2M displayed an altered time-dependent decline in relation to dystrophin expression in the tibialis anterior muscle.</p><p><strong>Conclusions: </strong>Our study revealed differences in the serum proteome between BMD and DMD, which comprises proteins involved in the immune response, extracellular matrix organization and hemostasis but not muscle leakage proteins significantly associated with disease progression in DMD. If further evaluated and validated, these biomarker candidates may offer means to monitor disease progression in BMD patients. A2M is of particular interest due to its association with dystrophin expression in BMD muscle and higher abundance in DMD patients in comparison to BMD. If validated, A2M could be used as a pharmacodynamic biomarker in therapeutic clinical trials aiming to restore dystrophin expression.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":"15 1","pages":"15"},"PeriodicalIF":5.3,"publicationDate":"2025-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12144774/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144249475","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":"Ephrin-A5 or EphA7 stimulation is anti-proliferative for human rhabdomyosarcoma in vitro.","authors":"Alessandra Cecchini, Lorenzo Ceccon, Steven Calandro, Anna Chen, Jenna K Schwesig, Ddw Cornelison","doi":"10.1186/s13395-025-00384-4","DOIUrl":"10.1186/s13395-025-00384-4","url":null,"abstract":"<p><p>Rhabdomyosarcoma (RMS) is a tumor which resembles skeletal muscle. Current treatments are limited to surgery and non-targeted chemotherapy, highlighting the need for alternative therapies. Differentiation therapy uses molecules that act to shift the tumor cells' phenotype from proliferating to differentiated, which in the case of skeletal muscle includes exit from the cell cycle and potentially fusion into myofibers. We previously identified EphA7 expressed on terminally differentiated myocytes as a potent driver of skeletal muscle differentiation: stimulation of ephrin-A5-expressing myoblasts with EphA7 causes them to undergo rapid, collective differentiation. We therefore tested EphA7 as a candidate molecule for differentiation therapy on human RMS (hRMS) cell lines. Surprisingly, EphA7 had a lesser effect than ephrin-A5, a difference explained by the divergent suite of Ephs and ephrins expressed by hRMS. We show that in hRMS ephrin-A5 binds and signals to EphA8 and EphA7 binds and signals to ephrin-A2, and that Fc chimeras of both molecules are potent inhibitors of hRMS proliferation. These results identify key differences between hRMS and normal muscle cells and support further research into Eph: ephrin signaling as potential differentiation therapies.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":"15 1","pages":"14"},"PeriodicalIF":5.3,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12107885/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144162168","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":"GsMTx4-blocked PIEZO1 channel promotes myogenic differentiation and alleviates myofiber damage in Duchenne muscular dystrophy.","authors":"Wengang Wang, Mingyang Huang, Xiusheng Huang, Ke Ma, Ming Luo, Ningning Yang","doi":"10.1186/s13395-025-00383-5","DOIUrl":"10.1186/s13395-025-00383-5","url":null,"abstract":"<p><strong>Background: </strong>Duchenne muscular dystrophy (DMD) is a debilitating disease characterized by progressive muscle-wasting and a lack of effective therapy. Although the application of GsMTx4 has been shown to reduce muscle mass loss in dystrophic mice, the mechanism of action remains unclear.</p><p><strong>Methods: </strong>We employed single-nucleus RNA sequencing data to scrutinize the expression of mechanosensitive channels in skeletal muscle. The upregulation of PIEZO1 and its precise localization were corroborated in DMD patients, mdx mice, and activated satellite cells. To delve into the role of the GsMTx4-blocked PIEZO1 channel in the myogenic program, we conducted comprehensive in vitro and in vivo studies encompassing the proliferation of satellite cells, differentiation of myoblasts, and calcium influx into myofibers. Utilizing both a PIEZO1 channel inhibitor, GsMTx4, and a PIEZO1 channel agonist, Yoda1, we explored the PIEZO1 channel's impact on satellite cell proliferation and myogenic differentiation. Additionally, we explored the protective effect of the PIEZO1 channel on myofiber calcium influx using mdx mouse models and isolated single myofibers.</p><p><strong>Results: </strong>PIEZO1 was upregulated in the muscle of DMD patients and was predominantly expressed in satellite cells and upregulated during satellite cell proliferation. Treatment with GsMTx4 increased the cross-sectional areas of myofibers and reduced the proportion of centrally nucleated fibers in mdx mice. GsMTx4 inhibited satellite cell proliferation while promoting myogenic differentiation. During myogenic differentiation, the YAP nuclear-cytoplasmic ratio increased in cells treated with GsMTx4 and showed a significant correlation with the nuclear localization of MyoG. In myofibers, GsMTx4 significantly reduced the level of p-CaMKII/CaMKII in muscle and calcium load.</p><p><strong>Conclusions: </strong>PIEZO1 upregulation in DMD could potentially stem from an elevated proportion of proliferating satellite cells triggered by sarcolemma damage and muscle necrosis. The inhibition of the PIEZO1 channel by GsMTx4 plays a beneficial role in fostering myogenic differentiation and mitigating myofiber damage. The PIEZO1 channel emerges as a promising therapeutic target for addressing DMD.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":"15 1","pages":"13"},"PeriodicalIF":5.3,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12076844/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144031497","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":"Forskolin treatment enhances muscle regeneration and shows therapeutic potential with limitations in Duchenne muscular dystrophy.","authors":"Andreea Iuliana Cojocaru, Kaouthar Kefi, Jean-Daniel Masson, Laurent Tiret, Frederic Relaix, Valentina Taglietti","doi":"10.1186/s13395-025-00381-7","DOIUrl":"https://doi.org/10.1186/s13395-025-00381-7","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":"15 1","pages":"12"},"PeriodicalIF":5.3,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12057055/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144038777","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":"Pharmacology and macrophage modulation of HPGDS inhibitor PK007 demonstrate reduced disease severity in DMD-affected muscles of the mdx mouse model.","authors":"Sai Yarlagadda, Chynna-Loren Sheremeta, Sang Won Cheung, Alison Cuffe, Miranda D Grounds, Mark L Smythe, Peter G Noakes","doi":"10.1186/s13395-025-00379-1","DOIUrl":"https://doi.org/10.1186/s13395-025-00379-1","url":null,"abstract":"<p><strong>Background: </strong>Duchenne Muscular Dystrophy (DMD) is an X-linked disease characterised by chronic inflammation, progressive muscle damage, and muscle loss. Typically, initial symptoms affect lower limb muscles, including the gastrocnemius (GA), tibialis anterior (TA), and extensor digitorum longus (EDL). During the acute phase of DMD, particularly in boys aged 2-8 years, muscle damage resulting in necrosis (myonecrosis) involves a complex immune-inflammatory response. Prostaglandin D2 (PGD2) is recognised for enhancing pro-inflammatory chemokine and interleukin signalling and recruiting infiltrating immune cells such as pro-inflammatory macrophages, exacerbating myonecrosis.</p><p><strong>Methods: </strong>To reduce levels of PGD2, a novel hematopoietic prostaglandin D2 synthase (HPGDS) inhibitor, PK007, was characterised (i) for potency and pharmacokinetic profiles and then tested in the mdx mouse model of DMD during the acute early onset of disease progression. Juvenile mdx and wild type (WT) C57Bl/10Scsn mice were orally treated with PK007 and control vehicle solution for 10 days, from postnatal day 18 to 28. This builds upon a previous study with PK007 with (ii) additional analyses of disease progression assessed for muscle grip strength, metabolic and locomotor activity, myonecrosis in a wide range of muscles (3 from hindlimb, diaphragm, heart, and tongue), macrophage infiltration and pro-inflammatory cytokines (TNF-α, IL-1β and iNOS).</p><p><strong>Results: </strong>PK007 exhibited high potency (17.23 ± 12 nM), a long half-life (3.0 ± 0.3 h), and good oral bioavailability (81%). Treatment with PK007 decreased serum PGD2 levels (33.36%) in mdx mice compared to control (vehicle-treated) mdx mice. In mdx mice (compared with controls), PK007 enhanced grip strength (69.05% increase) and improved locomotor activity (69.05% increase). Histological analysis revealed a significant reduction in the total myonecrotic area in PK007-treated GA (49.75%), TA (73.87%), EDL (60.31%), diaphragm (48.02%), and tongue (37.93%) muscles of mdx mice (compared with controls). Additionally, PK007 decreased macrophage cell area by 55.56% in GA and 47.83% in EDL muscles. Further expression of pro-inflammatory cytokines and enzymes such as TNF-α, IL-1β and iNOS were significantly reduced in PK007 treated mice. These results demonstrate that PK007 significantly reduces the inflammatory response, protects muscles from necrosis and increases strength in juvenile mdx mice.</p><p><strong>Conclusion: </strong>This study lays a strong foundation for progressing the use of HPDGS inhibitors such as PK007, which specifically inhibit PGD2 and reduce inflammation, as a viable therapeutic approach for DMD. This approach protects dystrophic muscles from necrosis and reduces the severity of this debilitating disease, improving outcomes and quality of life.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":"15 1","pages":"11"},"PeriodicalIF":5.3,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12020277/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144007522","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: OBSCN undergoes extensive alternative splicing during human cardiac and skeletal muscle development.","authors":"Ali Oghabian, Per Harald Jonson, Swethaa Natraj Gayathri, Mridul Johari, Ella Nippala, David Gomez Andres, Francina Munell, Jessica Camacho Soriano, Maria Angeles Sanchez Duran, Juha Sinisalo, Heli Tolppanen, Johanna Tolva, Peter Hackman, Marco Savarese, Bjarne Udd","doi":"10.1186/s13395-025-00380-8","DOIUrl":"10.1186/s13395-025-00380-8","url":null,"abstract":"","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":"15 1","pages":"10"},"PeriodicalIF":5.3,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11974123/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143804147","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}