Skeletal Muscle最新文献

{"title":"Fully-automated segmentation of muscle and inter-/intra-muscular fat from magnetic resonance images of calves and thighs: an open-source workflow in Python.","authors":"Kenneth Tam, Si Wen Liu, Sarah Costa, Eva Szabo, Shannon Reitsma, Hana Gillick, Jonathan D Adachi, Andy Kin On Wong","doi":"10.1186/s13395-024-00365-z","DOIUrl":"10.1186/s13395-024-00365-z","url":null,"abstract":"<p><strong>Background: </strong>INTER- and INTRAmuscular fat (IMF) is elevated in high metabolic states and can promote inflammation. While magnetic resonance imaging (MRI) excels in depicting IMF, the lack of reproducible tools prevents the ability to measure change and track intervention success.</p><p><strong>Methods: </strong>We detail an open-source fully-automated iterative threshold-seeking algorithm (ITSA) for segmenting IMF from T1-weighted MRI of the calf and thigh within three cohorts (CaMos Hamilton (N = 54), AMBERS (N = 280), OAI (N = 105)) selecting adults 45-85 years of age. Within the CaMos Hamilton cohort, same-day and 1-year repeated images (N = 38) were used to evaluate short- and long-term precision error with root mean square coefficients of variation; and to validate against semi-automated segmentation methods using linear regression. The effect of algorithmic improvements to fat ascertainment using 3D connectivity and partial volume correction rules on analytical precision was investigated. Robustness and versatility of the algorithm was demonstrated by application to different MR sequences/magnetic strength and to calf versus thigh scans.</p><p><strong>Results: </strong>Among 439 adults (319 female(89%), age: 71.6 ± 7.6 yrs, BMI: 28.06 ± 4.87 kg/m², IMF%: 10.91 ± 4.57%), fully-automated ITSA performed well across MR sequences and anatomies from three cohorts. Applying both 3D connectivity and partial volume fat correction improved precision from 4.99% to 2.21% test-retest error. Validation against semi-automated methods showed R² from 0.92 to 0.98 with fully-automated ITSA routinely yielding more conservative computations of IMF volumes. Quality control shows 7% of cases requiring manual correction, primarily due to IMF merging with subcutaneous fat. A full workflow described methods to export tags for manual correction.</p><p><strong>Conclusions: </strong>The greatest challenge in segmenting IMF from MRI is in selecting a dynamic threshold that consistently performs across repeated imaging. Fully-automated ITSA achieved this, demonstrated low short- and long-term precision error, conducive of use within RCTs.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":"14 1","pages":"37"},"PeriodicalIF":5.3,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11674188/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142897126","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":"Mll4 in skeletal muscle fibers maintains muscle stem cells.","authors":"Yea-Eun Kim, Sang-Hyeon Hann, Young-Woo Jo, Kyusang Yoo, Ji-Hoon Kim, Jae W Lee, Young-Yun Kong","doi":"10.1186/s13395-024-00369-9","DOIUrl":"10.1186/s13395-024-00369-9","url":null,"abstract":"<p><strong>Background: </strong>Muscle stem cells (MuSCs) undergo numerous state transitions throughout life, which are critical for supporting normal muscle growth and regeneration. Epigenetic modifications in skeletal muscle play a significant role in influencing the niche and cellular states of MuSCs. Mixed-lineage leukemia 4 (Mll4) is a histone methyltransferase critical for activating the transcription of various target genes and is highly expressed in skeletal muscle. This raises the question of whether Mll4 has a regulatory function in modulating the state transitions of MuSCs, warranting further investigation.</p><p><strong>Methods: </strong>To assess if myofiber-expressed Mll4, a histone methyltransferase, contributes to the maintenance of MuSCs, we crossed MCK^Cre/+ or HSA^MerCreMer/+ mice to Mll4^f/f mice to generate myofiber-specific Mll4-deleted mice. Investigations were conducted using 8-week-old and 4-week-old MCK^Cre/+;Mll4^f/f mice, and adult HSA^MerCreMer/+;Mll4^f/f mice between the ages of 3 months and 6 months.</p><p><strong>Results: </strong>During postnatal myogenesis, Mll4 deleted muscles were observed with increased number of cycling MuSCs that proceeded to a differentiation state, leading to MuSC deprivation. This phenomenon occurred independently of gender. When Mll4 was ablated in adult muscles using the inducible method, adult MuSCs lost their quiescence and differentiated into myoblasts, also causing the depletion of MuSCs. Such roles of Mll4 in myofibers coincided with decreased expression levels of distinct Notch ligands: Jag1 and Dll1 in pubertal and Jag2 and Dll4 in adult muscles.</p><p><strong>Conclusions: </strong>Our study suggests that Mll4 is crucial for maintaining MuSCs in both pubertal and adult muscles, which may be accomplished through the modulation of distinct Notch ligand expressions in myofibers. These findings offer new insights into the role of myofiber-expressed Mll4 as a master regulator of MuSCs, highlighting its significance not only in developmental myogenesis but also in adult muscle, irrespective of sex.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":"14 1","pages":"35"},"PeriodicalIF":5.3,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11665228/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142877900","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":"Comparative lipidomic and metabolomic profiling of mdx and severe mdx-apolipoprotein e-null mice.","authors":"Ram B Khattri, Abhinandan Batra, Zoe White, David Hammers, Terence E Ryan, Elisabeth R Barton, Pascal Bernatchez, Glenn A Walter","doi":"10.1186/s13395-024-00368-w","DOIUrl":"10.1186/s13395-024-00368-w","url":null,"abstract":"<p><p>Despite its notoriously mild phenotype, the dystrophin-deficient mdx mouse is the most common model of Duchenne muscular dystrophy (DMD). By mimicking a human DMD-associated metabolic comorbidity, hyperlipidemia, in mdx mice by inactivating the apolipoprotein E gene (mdx-ApoE) we previously reported severe myofiber damage exacerbation via histology with large fibro-fatty infiltrates and phenotype humanization with ambulation dysfunction when fed a cholesterol- and triglyceride-rich Western diet (mdx-ApoE^W). Herein, we performed comparative lipidomic and metabolomic analyses of muscle, liver and serum samples from mdx and mdx-ApoE^W mice using solution and high-resolution-magic angle spinning (HR-MAS) ¹H-NMR spectroscopy. Compared to mdx and regular chow-fed mdx-ApoE mice, we observed an order of magnitude increase in lipid deposition in gastrocnemius muscle of mdx-ApoE^W mice including 11-fold elevations in -CH₃ and -CH₂ lipids, along with pronounced elevations in serum cholesterol, fatty acid, triglyceride and phospholipids. Hepatic lipids were also elevated but did not correlate with the extent of muscle lipid infiltration or differences in serum lipids. This study provides the first lipometabolomic signature of severe mdx lesions exacerbated by high circulating lipids and lends credence to claims that the liver, the main regulator of whole-body lipoprotein metabolism, may play only a minor role in this process.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":"14 1","pages":"36"},"PeriodicalIF":5.3,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11664822/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142882889","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":"Wnt7a is required for regeneration of dystrophic skeletal muscle.","authors":"Uxia Gurriaran-Rodriguez, Kasun Kodippili, David Datzkiw, Ehsan Javandoost, Fan Xiao, Maria Teresa Rejas, Michael A Rudnicki","doi":"10.1186/s13395-024-00367-x","DOIUrl":"10.1186/s13395-024-00367-x","url":null,"abstract":"<p><p>Intramuscular injection of Wnt7a has been shown to accelerate and augment skeletal muscle regeneration and to ameliorate dystrophic progression in mdx muscle, a model for Duchenne muscular dystrophy (DMD). Here, we assessed muscle regeneration and function in wild type (WT) and mdx mice where Wnt7a was deleted in muscle using a conditional Wnt7a floxed allele and a Myf5-Cre driver. We found that both WT and mdx mice lacking Wnt7a in muscle, exhibited marked deficiencies in muscle regeneration at 21 d following cardiotoxin (CTX) induced injury. Unlike WT, deletion of Wnt7a in mdx resulted in decreased force generation prior to CTX injury. However, both WT and mdx muscle lacking Wnt7a displayed decreased force generation following CTX injection. Notably the regeneration deficit in mdx mice was rescued by a single tail vein injection of extracellular vesicles containing Wnt7a (Wnt7a-EVs). Therefore, we conclude that the regenerative capacity of muscle in mdx mice is highly dependant on the upregulation of endogenous Wnt7a following injury, and that systemic delivery of Wnt7a-EVs represents a therapeutic strategy for treating DMD.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":"14 1","pages":"34"},"PeriodicalIF":5.3,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11656582/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142865510","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":"Intramuscular fatty infiltration and its correlation with muscle composition and function in hip osteoarthritis.","authors":"Tatiane Gorski, Nicola C Casartelli, Gillian Fitzgerald, Astrid M H Horstman, Evi Masschelein, Kalliopi J Essers, Nicola A Maffiuletti, Reto Sutter, Michael Leunig, Katrien De Bock","doi":"10.1186/s13395-024-00364-0","DOIUrl":"10.1186/s13395-024-00364-0","url":null,"abstract":"<p><strong>Background: </strong>Hip osteoarthritis patients display higher levels of fatty infiltration (FI) in the gluteus minimus (GM) compared to other hip muscles. We investigated specific histological factors such as fiber type composition and collagen deposition, and functional outcomes like muscle strength and activation associated with FI in these patients.</p><p><strong>Methods: </strong>In twelve men (67 ± 6 y) undergoing total hip replacement (THR), hip and knee muscle strength and activation (electromyography, EMG) were assessed bilaterally. Magnetic resonance imaging (MRI) was used to compare the relative FI area and muscle cross sectional area (CSA) of the GM, rectus femoris (RF), tensor fascia latae (TFL) and vastus lateralis (VL). Adipocyte content, fiber type composition, grouping, fiber size, centrally nucleated fiber frequency, collagen deposition, satellite cell density and capillarization were assessed in intraoperative biopsies of the four muscles. Differences between GM and other muscles were assessed with repeated-measures one-way ANOVA followed by Dunnett's post-hoc test. Pearson coefficients were calculated for the correlations between FI measurements and the other histological and functional parameters.</p><p><strong>Results: </strong>Strength was lower in the affected limb. Knee extensor weakness was accompanied by lower VL muscle activation. Muscle CSA and FI did not differ between sides. In the affected limb, GM displayed larger relative FI area (MRI) compared to RF and VL. Biopsy adipocyte content was higher in GM than RF and TFL. Compared to the other hip muscles, GM displayed higher type 1 fiber content while its type 2X fiber content was lower. Fiber grouping levels were higher in GM than the other muscles. Collagen content was higher in GM than TFL and VL.  FI in GM was associated with type 1 (r = 0.43) and type 2X (r = -0.34) fiber content, fiber grouping (r = 0.39), and collagen deposition (r = 0.37). FI in VL was negatively associated with maximal knee extension strength (r = -0.65).</p><p><strong>Conclusions: </strong>In patients undergoing THR, the higher FI levels of GM compared to other hip muscles were associated with fiber type composition and grouping, and with higher collagen deposition. Experimental studies exploring these associations could potentially uncover new targets for the treatment of intramuscular FI and related impairments in muscle function.</p><p><strong>Trial registration: </strong>KEK number: 2016-01852, date of registration: 12-4-2017.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":"14 1","pages":"32"},"PeriodicalIF":5.3,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11657216/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142855139","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":"Regulation of injury-induced skeletal myofiber regeneration by glucose transporter 4 (GLUT4).","authors":"Tyler J Sermersheim, LeAnna J Phillips, Parker L Evans, Barbara B Kahn, Steven S Welc, Carol A Witczak","doi":"10.1186/s13395-024-00366-y","DOIUrl":"10.1186/s13395-024-00366-y","url":null,"abstract":"<p><strong>Background: </strong>Insulin resistance and type 2 diabetes impair cellular regeneration in multiple tissues including skeletal muscle. The molecular basis for this impairment is largely unknown. Glucose uptake via glucose transporter GLUT4 is impaired in insulin resistance. In healthy muscle, acute injury stimulates glucose uptake. Whether decreased glucose uptake via GLUT4 impairs muscle regeneration is presently unknown. The goal of this study was to determine whether GLUT4 regulates muscle glucose uptake and/or regeneration following acute injury.</p><p><strong>Methods: </strong>Tibialis anterior and extensor digitorum longus muscles from wild-type, control, or muscle-specific GLUT4 knockout (mG4KO) mice were injected with the myotoxin barium chloride to induce muscle injury. After 3, 5, 7, 10, 14, or 21 days (in wild-type mice), or after 7 or 14 days (in control & mG4KO) mice, muscles were isolated to examine [³H]-2-deoxyglucose uptake, GLUT4 levels, extracellular fluid space, fibrosis, myofiber cross-sectional area, and myofiber centralized nuclei.</p><p><strong>Results: </strong>In wild-type mice, muscle glucose uptake was increased 3, 5, 7, and 10 days post-injury. There was a rapid decrease in GLUT4 protein levels that were restored to baseline at 5-7 days post-injury, followed by a super-compensation at 10-21 days. In mG4KO mice, there were no differences in muscle glucose uptake, extracellular fluid space, muscle fibrosis, myofiber cross-sectional areas, or percentage of centrally nucleated myofibers at 7 days post-injury. In contrast, at 14 days injured muscles from mG4KO mice exhibited decreased glucose uptake, muscle weight, myofiber cross sectional areas, and centrally nucleated myofibers, with no change in extracellular fluid space or fibrosis.</p><p><strong>Conclusions: </strong>Collectively, these findings demonstrate that glucose uptake via GLUT4 regulates skeletal myofiber regeneration following acute injury.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":"14 1","pages":"33"},"PeriodicalIF":5.3,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11656879/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142855143","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":"Fibro-adipogenic progenitor cells in skeletal muscle unloading: metabolic and functional impairments.","authors":"Margarita Sorokina, Danila Bobkov, Natalia Khromova, Natalia Vilchinskaya, Boris Shenkman, Anna Kostareva, Renata Dmitrieva","doi":"10.1186/s13395-024-00362-2","DOIUrl":"10.1186/s13395-024-00362-2","url":null,"abstract":"<p><strong>Background: </strong>Skeletal muscle resident fibro-adipogenic progenitor cells (FAPs) control skeletal muscle regeneration providing a supportive role for muscle stem cells. Altered FAPs characteristics have been shown for a number of pathological conditions, but the influence of temporary functional unloading of healthy skeletal muscle on FAPs remains poorly studied. This work is aimed to investigate how skeletal muscle disuse affects the functionality and metabolism of FAPs.</p><p><strong>Methods: </strong>Hindlimb suspension (HS) rat model employed to investigate muscle response to decreased usage. FAPs were purified from m. soleus functioning muscle (Contr) and after functional unloading for 7 and 14 days (HS7 and HS14). FAPs were expanded in vitro, and tested for: immunophenotype; in vitro expansion rate, and migration activity; ability to differentiate into adipocytes in vitro; metabolic changes. Crosstalk between FAPs and muscle stem cells was estimated by influence of medium conditioned by FAP's on migration and myogenesis of C2C12 myoblasts. To reveal the molecular mechanisms behind unloading-induced alterations in FAP's functionality transcriptome analysis was performed.</p><p><strong>Results: </strong>FAPs isolated from Contr and HS muscles exhibited phenotype of MSC cells. FAPs in vitro expansion rate and migration were altered by functional unloading conditions. All samples of FAPs demonstrated the ability to adipogenic differentiation in vitro, however, HS FAPs formed fat droplets of smaller volume and transcriptome analysis showed fatty acids metabolism and PPAR signaling suppression. Skeletal muscle unloading resulted in metabolic reprogramming of FAPs: decreased spare respiratory capacity, decreased OCR/ECAR ratio detected in both HS7 and HS14 samples point to reduced oxygen consumption, decreased potential for substrate oxidation and a shift to glycolytic metabolism. Furthermore, C2C12 cultures treated with medium conditioned by FAPs showed diverse alterations: while the HS7 FAPs-derived paracrine factors supported the myoblasts fusion, the HS14-derived medium stimulated proliferation of C2C12 myoblasts; these observations were supported by increased expression of cytokines detected by transcriptome analysis.</p><p><strong>Conclusion: </strong>the results obtained in this work show that the skeletal muscle functional unloading affects properties of FAPs in time-dependent manner: in atrophying skeletal muscle FAPs act as the sensors for the regulatory signals that may stimulate the metabolic and transcriptional reprogramming to preserve FAPs properties associated with maintenance of skeletal muscle homeostasis during unloading and in course of rehabilitation.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":"14 1","pages":"31"},"PeriodicalIF":5.3,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11622572/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142786952","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":"SIX transcription factors are necessary for the activation of DUX4 expression in facioscapulohumeral muscular dystrophy.","authors":"Amelia Fox, Jonathan Oliva, Rajanikanth Vangipurapu, Francis M Sverdrup","doi":"10.1186/s13395-024-00361-3","DOIUrl":"10.1186/s13395-024-00361-3","url":null,"abstract":"<p><strong>Background: </strong>Facioscapulohumeral muscular dystrophy (FSHD) is a common and progressive muscle wasting disease that is characterized by muscle weakness often first noticed in the face, the shoulder girdle and upper arms before progressing to the lower limb muscles. FSHD is caused by the misexpression of the Double Homeobox 4 (DUX4) transcription factor in skeletal muscle. While epigenetic derepression of D4Z4 macrosatellite repeats underlies DUX4 misexpression, our understanding of the complex transcriptional activation of DUX4 is incomplete.</p><p><strong>Methods: </strong>To identify potential DUX4-regulatory factors, we used small interfering RNAs (siRNAs) to knockdown SIX family transcription factors (SIX1, 2, 4, 5) in patient-derived FSHD1 and FSHD2 myoblasts that were differentiated to form multinucleated myotubes. Quantitative real-time polymerase chain reaction was used to measure changes in DUX4 mRNA, DUX4 target gene expression and myogenic markers. Staining for SIX1 and SIX2 with specific antibodies was performed in FSHD myoblasts and myotubes. To assess reciprocal effects of DUX4 on SIX1, 2, and 4 expression, we utilized a doxycycline-inducible DUX4 myoblast cell line.</p><p><strong>Result: </strong>We show that SIX1, 2 and 4 transcription factors, regulators of embryonic development, muscle differentiation, regeneration and homeostasis, are necessary for myogenic differentiation-dependent DUX4 expression in FSHD muscle cells. Using siRNA, we demonstrate SIX1, SIX2, and SIX4 to be critical factors involved in the induction of DUX4 transcription in differentiating FSHD myotubes in vitro. siRNA dual knockdown of SIX1 and SIX2 resulted in a ~ 98% decrease of DUX4 and DUX4 target genes, suggesting that SIX1 and SIX2 are the most critical in promoting DUX4 expression. Importantly, we show that DUX4 downregulates SIX RNA levels, suggesting negative feedback regulation.</p><p><strong>Conclusions: </strong>In this study, we identified a family of developmental regulators that promote aberrant DUX4 expression in FSHD1 and FSHD2 differentiating muscle cells. Our findings highlight the critical involvement of SIX transcription factors (SIX1, 2, 4) in the pathogenesis of FSHD by serving as necessary factors that function in the promotion of DUX4 expression following epigenetic derepression of the D4Z4 repeats.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":"14 1","pages":"30"},"PeriodicalIF":5.3,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11613756/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142771830","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":"Role and mechanism of myonectin in severe acute pancreatitis: a crosstalk between skeletal muscle and pancreas.","authors":"Xiaowu Dong, Weiwei Luo, Yaodong Wang, Qingtian Zhu, Chenchen Yuan, Weiming Xiao, Weijuan Gong, Guotao Lu, Xiaolei Shi, Jin Li","doi":"10.1186/s13395-024-00363-1","DOIUrl":"10.1186/s13395-024-00363-1","url":null,"abstract":"<p><strong>Background: </strong>Severe acute pancreatitis (SAP) is characterized by high mortality rates and various complications, including skeletal muscle atrophy, which significantly exacerbates its outcomes. Despite its clinical relevance, the mechanistic understanding of the relationship between skeletal muscle and the pancreas in SAP remains limited. Our study aimed to elucidate this \"organ crosstalk\" and its potential implications.</p><p><strong>Methods: </strong>We established an SAP mouse model through pancreatic duct ligation (PDL) and evaluated pancreatic necrosis, skeletal muscle atrophy, and myonectin expression levels. Recombinant myonectin protein was administered in vivo and in vitro to assess its effects on acinar cell necrosis. Mechanistic insights were gained through RNA-seq data analysis and experimental validation. Serum samples from AP patients and healthy controls were collected to investigate the correlation between serum myonectin levels and disease severity.</p><p><strong>Results: </strong>The mouse model exhibited severe pancreatic necrosis, skeletal muscle atrophy, and elevated myonectin levels, with myonectin administration exacerbating model severity. We identified iron accumulation-induced ferroptosis as a key pathway contributing to myonectin-mediated acinar cell necrosis. A total of 22 healthy controls and 52 patients with varying degrees of AP were included in the serum samples and clinical data (36.5% females, age 49.79 ± 16.53). Analysis of serum samples revealed significantly higher myonectin levels in AP patients, correlating with disease severity (R = 0.28, P = 0.041).</p><p><strong>Conclusions: </strong>Our findings underscore the significant role of myonectin in SAP progression and its potential as a prognostic marker for disease severity in AP patients. This study contributes to a deeper understanding of the pathophysiology of SAP and highlights potential therapeutic targets for intervention.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":"14 1","pages":"29"},"PeriodicalIF":5.3,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11613728/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142771889","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":"Golodirsen restores DMD transcript imbalance in Duchenne Muscular Dystrophy patient muscle cells.","authors":"Rachele Rossi, Silvia Torelli, Marc Moore, Pierpaolo Ala, Jennifer Morgan, Jyoti Malhotra, Francesco Muntoni","doi":"10.1186/s13395-024-00360-4","DOIUrl":"10.1186/s13395-024-00360-4","url":null,"abstract":"<p><strong>Background: </strong>Antisense oligonucleotides (AON) represent a promising treatment for Duchenne muscular dystrophy (DMD) carrying out-of-frame deletions, but also show limitations. In a completed clinical trial golodirsen, approved by FDA to induce skipping of DMD gene exon 53 in eligible patients, we demonstrated increase in DMD expression and protein production, albeit with inter-patient variability.</p><p><strong>Methods: </strong>Here, we investigate further the golodirsen mechanism of action using myotubes derived from MyoD transfected fibroblasts isolated from DMD patients at the baseline of the clinical trial SRP-4053.</p><p><strong>Results: </strong>We confirm golodirsen's selectivity and efficiency in removing only exon 53. For the first time in human cells, we revealed a significant reduction in the so called DMD \"transcript imbalance\", in golodirsen-treated DMD muscle cultures. The transcript imbalance is a unique DMD phenomenon characterized by non-homogeneous transcript expression along its entire length and responsible for the reduced stability of the transcript. Our in-vivo study also showed that the efficiency of exon skipping did not always correspond to a proportional restoration of the dystrophin protein. Predominant nuclear localization of the DMD transcript, observed in patients and animal models, persists even after exon skipping.</p><p><strong>Conclusion: </strong>All these findings suggest challenges other than AON delivery for high level of protein restoration in DMD, highlighting the importance of investigating the biological mechanisms upstream of protein production to further enhance the efficiency of any AON treatment in this condition.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":"14 1","pages":"28"},"PeriodicalIF":5.3,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11606086/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142755459","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}