Skeletal Muscle最新文献

{"title":"Muscle degeneration in aging Drosophila flies: the role of mechanical stress.","authors":"Maria Chechenova, Lilla McLendon, Bracey Dallas, Hannah Stratton, Kaveh Kiani, Erik Gerberich, Alesia Alekseyenko, Natasya Tamba, SooBin An, Lizzet Castillo, Emily Czajkowski, Christina Talley, Austin Brown, Anton L Bryantsev","doi":"10.1186/s13395-024-00352-4","DOIUrl":"10.1186/s13395-024-00352-4","url":null,"abstract":"<p><p>Muscle wasting is a universal hallmark of aging which is displayed by a wide range of organisms, although the causes and mechanisms of this phenomenon are not fully understood. We used Drosophila to characterize the phenomenon of spontaneous muscle fiber degeneration (SMFD) during aging. We found that SMFD occurs across diverse types of somatic muscles, progresses with chronological age, and positively correlates with functional muscle decline. Data from vital dyes and morphological markers imply that degenerative fibers most likely die by necrosis. Mechanistically, SMFD is driven by the damage resulting from muscle contractions, and the nervous system may play a significant role in this process. Our quantitative model of SMFD assessment can be useful in identifying and validating novel genetic factors that influence aging-related muscle wasting.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11334408/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142009291","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":"Pilot investigations into the mechanistic basis for adverse effects of glucocorticoids in dysferlinopathy.","authors":"Erin M Lloyd, Rachael C Crew, Vanessa R Haynes, Robert B White, Peter J Mark, Connie Jackaman, John M Papadimitriou, Gavin J Pinniger, Robyn M Murphy, Matthew J Watt, Miranda D Grounds","doi":"10.1186/s13395-024-00350-6","DOIUrl":"10.1186/s13395-024-00350-6","url":null,"abstract":"<p><strong>Background: </strong>Dysferlinopathies are a clinically heterogeneous group of muscular dystrophies caused by gene mutations resulting in deficiency of the membrane-associated protein dysferlin. They manifest post-growth and are characterised by muscle wasting (primarily in the limb and limb-gridle muscles), inflammation, and replacement of myofibres with adipose tissue. The precise pathomechanism for dysferlinopathy is currently unclear; as such there are no treatments currently available. Glucocorticoids (GCs) are widely used to reduce inflammation and treat muscular dystrophies, but when administered to patients with dysferlinopathy, they have unexpected adverse effects, with accelerated loss of muscle strength.</p><p><strong>Methods: </strong>To investigate the mechanistic basis for the adverse effects of GCs in dysferlinopathy, the potent GC dexamethasone (Dex) was administered for 4-5 weeks (0.5-0.75 µg/mL in drinking water) to dysferlin-deficient BLA/J and normal wild-type (WT) male mice, sampled at 5 (Study 1) or 10 months (Study 2) of age. A wide range of analyses were conducted. Metabolism- and immune-related gene expression was assessed in psoas muscles at both ages and in quadriceps at 10 months of age. For the 10-month-old mice, quadriceps and psoas muscle histology was assessed. Additionally, we investigated the impact of Dex on the predominantly slow and fast-twitch soleus and extensor digitorum longus (EDL) muscles (respectively) in terms of contractile function, myofibre-type composition, and levels of proteins related to contractile function and metabolism, plus glycogen.</p><p><strong>Results: </strong>At both ages, many complement-related genes were highly expressed in BLA/J muscles, and WT mice were generally more responsive to Dex than BLA/J. The effects of Dex on BLA/J mice included (i) increased expression of inflammasome-related genes in muscles (at 5 months) and (ii) exacerbated histopathology of quadriceps and psoas muscles at 10 months. A novel observation was pronounced staining for glycogen in many myofibres of the damaged quadriceps muscles, with large pale vacuolated myofibres, suggesting possible myofibre death by oncosis.</p><p><strong>Conclusion: </strong>These pilot studies provide a new focus for further investigation into the adverse effects of GCs on dysferlinopathic muscles.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11312411/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141913890","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":"Age-related differences in the loss and recovery of serial sarcomere number following disuse atrophy in rats.","authors":"Avery Hinks, Geoffrey A Power","doi":"10.1186/s13395-024-00351-5","DOIUrl":"10.1186/s13395-024-00351-5","url":null,"abstract":"<p><strong>Background: </strong>Older adults exhibit a slower recovery of muscle mass following disuse atrophy than young adults. At a smaller scale, muscle fibre cross-sectional area (i.e., sarcomeres in parallel) exhibits this same pattern. Less is known, however, about age-related differences in the recovery of muscle fibre length, driven by increases in serial sarcomere number (SSN), following disuse. The purpose of this study was to investigate age-related differences in SSN adaptations and muscle mechanical function during and following muscle immobilization. We hypothesized that older adult rats would experience a similar magnitude of SSN loss during immobilization, however, take longer to recover SSN than young following cast removal, which would limit the recovery of muscle mechanical function.</p><p><strong>Methods: </strong>We casted the plantar flexors of young (8 months) and old (32 months) male rats in a shortened position for 2 weeks, and assessed recovery during 4 weeks of voluntary ambulation. Following sacrifice, legs were fixed in formalin for measurement of soleus SSN and physiological cross-sectional area (PCSA) with the un-casted soleus acting as a control. Ultrasonographic measurements of pennation angle (PA) and muscle thickness (MT) were conducted weekly. In-vivo active and passive torque-angle relationships were constructed pre-cast, post-cast, and following 4 weeks of recovery.</p><p><strong>Results: </strong>From pre- to post-cast, young and older adult rats experienced similar decreases in SSN (-20%, P < 0.001), muscle wet weight (-25%, P < 0.001), MT (-30%), PA (-15%, P < 0.001), and maximum isometric torque (-40%, P < 0.001), but there was a greater increase in passive torque in older (+ 180%, P < 0.001) compared to young adult rats (+ 68%, P = 0.006). Following cast removal, young exhibited quicker recovery of SSN and MT than old, but SSN recovered sooner than PA and MT in both young and old. PCSA nearly recovered and active torque fully recovered in young adult rats, whereas in older adult rats these remained unrecovered at ∼ 75%.</p><p><strong>Conclusions: </strong>This study showed that older adult rats retain a better ability to recover longitudinal compared to parallel muscle morphology following cast removal, making SSN a highly adaptable target for improving muscle function in elderly populations early on during rehabilitation.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11295870/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141879350","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":"AAV-NRIP gene therapy ameliorates motor neuron degeneration and muscle atrophy in ALS model mice.","authors":"Hsin-Hsiung Chen, Hsin-Tung Yeo, Yun-Hsin Huang, Li-Kai Tsai, Hsing-Jung Lai, Yeou-Ping Tsao, Show-Li Chen","doi":"10.1186/s13395-024-00349-z","DOIUrl":"10.1186/s13395-024-00349-z","url":null,"abstract":"<p><strong>Background: </strong>Amyotrophic lateral sclerosis (ALS) is characterized by progressive motor neuron (MN) degeneration, leading to neuromuscular junction (NMJ) dismantling and severe muscle atrophy. The nuclear receptor interaction protein (NRIP) functions as a multifunctional protein. It directly interacts with calmodulin or α-actinin 2, serving as a calcium sensor for muscle contraction and maintaining sarcomere integrity. Additionally, NRIP binds with the acetylcholine receptor (AChR) for NMJ stabilization. Loss of NRIP in muscles results in progressive motor neuron degeneration with abnormal NMJ architecture, resembling ALS phenotypes. Therefore, we hypothesize that NRIP could be a therapeutic factor for ALS.</p><p><strong>Methods: </strong>We used SOD1 G93A mice, expressing human SOD1 with the ALS-linked G93A mutation, as an ALS model. An adeno-associated virus vector encoding the human NRIP gene (AAV-NRIP) was generated and injected into the muscles of SOD1 G93A mice at 60 days of age, before disease onset. Pathological and behavioral changes were measured to evaluate the therapeutic effects of AAV-NRIP on the disease progression of SOD1 G93A mice.</p><p><strong>Results: </strong>SOD1 G93A mice exhibited lower NRIP expression than wild-type mice in both the spinal cord and skeletal muscle tissues. Forced NRIP expression through AAV-NRIP intramuscular injection was observed in skeletal muscles and retrogradely transduced into the spinal cord. AAV-NRIP gene therapy enhanced movement distance and rearing frequencies in SOD1 G93A mice. Moreover, AAV-NRIP increased myofiber size and slow myosin expression, ameliorated NMJ degeneration and axon terminal denervation at NMJ, and increased the number of α-motor neurons (α-MNs) and compound muscle action potential (CMAP) in SOD1 G93A mice.</p><p><strong>Conclusions: </strong>AAV-NRIP gene therapy ameliorates muscle atrophy, motor neuron degeneration, and axon terminal denervation at NMJ, leading to increased NMJ transmission and improved motor functions in SOD1 G93A mice. Collectively, AAV-NRIP could be a potential therapeutic drug for ALS.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11267858/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141752637","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":"ASM is a therapeutic target in dermatomyositis by regulating the differentiation of naive CD4 + T cells into Th17 and Treg subsets.","authors":"Yuehong Chen, Huan Liu, Zhongling Luo, Jiaqian Zhang, Min Dong, Geng Yin, Qibing Xie","doi":"10.1186/s13395-024-00347-1","DOIUrl":"10.1186/s13395-024-00347-1","url":null,"abstract":"<p><strong>Background: </strong>This study aims to investigate the involvement of acid sphingomyelinase (ASM) in the pathology of dermatomyositis (DM), making it a potential therapeutic target for DM.</p><p><strong>Methods: </strong>Patients with DM and healthy controls (HCs) were included to assess the serum level and activity of ASM, and to explore the associations between ASM and clinical indicators. Subsequently, a myositis mouse model was established using ASM gene knockout and wild-type mice to study the significant role of ASM in the pathology and to assess the treatment effect of amitriptyline, an ASM inhibitor. Additionally, we investigated the potential treatment mechanism by targeting ASM both in vivo and in vitro.</p><p><strong>Results: </strong>A total of 58 DM patients along with 30 HCs were included. The ASM levels were found to be significantly higher in DM patients compared to HCs, with median (quartile) values of 2.63 (1.80-4.94) ng/mL and 1.64 (1.47-1.96) ng/mL respectively. The activity of ASM in the serum of DM patients was significantly higher than that in HCs. Furthermore, the serum levels of ASM showed correlations with disease activity and muscle enzyme levels. Knockout of ASM or treatment with amitriptyline improved the severity of the disease, rebalanced the CD4 T cell subsets Th17 and Treg, and reduced the production of their secreted cytokines. Subsequent investigations revealed that targeting ASM could regulate the expression of relevant transcription factors and key regulatory proteins.</p><p><strong>Conclusion: </strong>ASM is involved in the pathology of DM by regulating the differentiation of naive CD4 + T cells and can be a potential treatment target.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11256435/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141724463","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":"Skeletal muscle vulnerability in a child with Pitt-Hopkins syndrome.","authors":"Celine Chiu, Alma Küchler, Christel Depienne, Corinna Preuße, Adela Della Marina, Andre Reis, Frank J Kaiser, Kay Nolte, Andreas Hentschel, Ulrike Schara-Schmidt, Heike Kölbel, Andreas Roos","doi":"10.1186/s13395-024-00348-0","DOIUrl":"10.1186/s13395-024-00348-0","url":null,"abstract":"<p><strong>Background: </strong>TCF4 acts as a transcription factor that binds to the immunoglobulin enhancer Mu-E5/KE5 motif. Dominant variants in TCF4 are associated with the manifestation of Pitt-Hopkins syndrome, a rare disease characterized by severe mental retardation, certain features of facial dysmorphism and, in many cases, with abnormalities in respiratory rhythm (episodes of paroxysmal tachypnea and hyperventilation, followed by apnea and cyanosis). Frequently, patients also develop epilepsy, microcephaly, and postnatal short stature. Although TCF4 is expressed in skeletal muscle and TCF4 seems to play a role in myogenesis as demonstrated in mice, potential myopathological findings taking place upon the presence of dominant TCF4 variants are thus far not described in human skeletal muscle.</p><p><strong>Method: </strong>To address the pathological effect of a novel deletion affecting exons 15 and 16 of TCF4 on skeletal muscle, histological and immunofluorescence studies were carried out on a quadriceps biopsy in addition to targeted transcript studies and global proteomic profiling.</p><p><strong>Results: </strong>We report on muscle biopsy findings from a Pitt-Hopkins patient with a novel heterozygous deletion spanning exon 15 and 16 presenting with neuromuscular symptoms. Microscopic characterization of the muscle biopsy revealed moderate fiber type I predominance, imbalance in the proportion of fibroblasts co-expressing Vimentin and CD90, and indicate activation of the complement cascade in TCF4-mutant muscle. Protein dysregulations were unraveled by proteomic profiling. Transcript studies confirmed a mitochondrial vulnerability in muscle and confirmed reduced TCF4 expression.</p><p><strong>Conclusion: </strong>Our combined findings, for the first time, unveil myopathological changes as phenotypical association of Pitt-Hopkins syndrome and thus expand the current clinical knowledge of the disease as well as support data obtained on skeletal muscle of a mouse model.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11256580/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141724464","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":"David J. Glass elected to the U.S. National Academy of Sciences.","authors":"Se-Jin Lee, Bruce Spiegelman, Kevin Campbell","doi":"10.1186/s13395-024-00343-5","DOIUrl":"10.1186/s13395-024-00343-5","url":null,"abstract":"","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11232304/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141564260","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":"Targeted expression of heme oxygenase-1 in satellite cells improves skeletal muscle pathology in dystrophic mice.","authors":"Urszula Florczyk-Soluch, Katarzyna Polak, Sarka Jelinkova, Iwona Bronisz-Budzyńska, Reece Sabo, Subhashini Bolisetty, Anupam Agarwal, Ewa Werner, Alicja Józkowicz, Jacek Stępniewski, Krzysztof Szade, Józef Dulak","doi":"10.1186/s13395-024-00346-2","DOIUrl":"10.1186/s13395-024-00346-2","url":null,"abstract":"<p><strong>Background: </strong>Adult muscle-resident myogenic stem cells, satellite cells (SCs), that play non-redundant role in muscle regeneration, are intrinsically impaired in Duchenne muscular dystrophy (DMD). Previously we revealed that dystrophic SCs express low level of anti-inflammatory and anti-oxidative heme oxygenase-1 (HO-1, HMOX1). Here we assess whether targeted induction of HMOX1 affect SC function and alleviates hallmark symptoms of DMD.</p><p><strong>Methods: </strong>We generated double-transgenic mouse model (mdx;HMOX1^Pax7Ind) that allows tamoxifen (TX)-inducible HMOX1 expression in Pax7 positive cells of dystrophic muscles. Mdx;HMOX1^Pax7Ind and control mdx mice were subjected to 5-day TX injections (75 mg/kg b.w.) followed by acute exercise protocol with high-speed treadmill (12 m/min, 45 min) and downhill running to worsen skeletal muscle phenotype and reveal immediate effects of HO-1 on muscle pathology and SC function.</p><p><strong>Results: </strong>HMOX1 induction caused a drop in SC pool in mdx;HMOX1^Pax7Ind mice (vs. mdx counterparts), while not exaggerating the effect of physical exercise. Upon physical exercise, the proliferation of SCs and activated CD34^- SC subpopulation, was impaired in mdx mice, an effect that was reversed in mdx;HMOX1^Pax7Ind mice, however, both in vehicle- and TX-treated animals. This corresponded to the pattern of HO-1 expression in skeletal muscles. At the tissue level, necrotic events of selective skeletal muscles of mdx mice and associated increase in circulating levels of muscle damage markers were blunted in HO-1 transgenic animals which showed also anti-inflammatory cytokine profile (vs. mdx).</p><p><strong>Conclusions: </strong>Targeted expression of HMOX1 plays protective role in DMD and alleviates dystrophic muscle pathology.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11167827/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141311630","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":"Studying intramuscular fat deposition and muscle regeneration: insights from a comparative analysis of mouse strains, injury models, and sex differences","authors":"Alessandra M. Norris, Kiara E. Fierman, Jillian Campbell, Rhea Pitale, Muhammad Shahraj, Daniel Kopinke","doi":"10.1186/s13395-024-00344-4","DOIUrl":"https://doi.org/10.1186/s13395-024-00344-4","url":null,"abstract":"Intramuscular fat (IMAT) infiltration, pathological adipose tissue that accumulates between muscle fibers, is a shared hallmark in a diverse set of diseases including muscular dystrophies and diabetes, spinal cord and rotator cuff injuries, as well as sarcopenia. While the mouse has been an invaluable preclinical model to study skeletal muscle diseases, they are also resistant to IMAT formation. To better understand this pathological feature, an adequate pre-clinical model that recapitulates human disease is necessary. To address this gap, we conducted a comprehensive in-depth comparison between three widely used mouse strains: C57BL/6J, 129S1/SvlmJ and CD1. We evaluated the impact of strain, sex and injury type on IMAT formation, myofiber regeneration and fibrosis. We confirm and extend previous findings that a Glycerol (GLY) injury causes significantly more IMAT and fibrosis compared to Cardiotoxin (CTX). Additionally, females form more IMAT than males after a GLY injury, independent of strain. Of all strains, C57BL/6J mice, both females and males, are the most resistant to IMAT formation. In regard to injury-induced fibrosis, we found that the 129S strain formed the least amount of scar tissue. Surprisingly, C57BL/6J of both sexes demonstrated complete myofiber regeneration, while both CD1 and 129S1/SvlmJ strains still displayed smaller myofibers 21 days post injury. In addition, our data indicate that myofiber regeneration is negatively correlated with IMAT and fibrosis. Combined, our results demonstrate that careful consideration and exploration are needed to determine which injury type, mouse model/strain and sex to utilize as preclinical model especially for modeling IMAT formation.","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141168550","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CaMKIIβ deregulation contributes to neuromuscular junction destabilization in Myotonic Dystrophy type I.","authors":"Denis Falcetta, Sandrine Quirim, Ilaria Cocchiararo, Florent Chabry, Marine Théodore, Adeline Stiefvater, Shuo Lin, Lionel Tintignac, Robert Ivanek, Jochen Kinter, Markus A Rüegg, Michael Sinnreich, Perrine Castets","doi":"10.1186/s13395-024-00345-3","DOIUrl":"10.1186/s13395-024-00345-3","url":null,"abstract":"<p><strong>Background: </strong>Myotonic Dystrophy type I (DM1) is the most common muscular dystrophy in adults. Previous reports have highlighted that neuromuscular junctions (NMJs) deteriorate in skeletal muscle from DM1 patients and mouse models thereof. However, the underlying pathomechanisms and their contribution to muscle dysfunction remain unknown.</p><p><strong>Methods: </strong>We compared changes in NMJs and activity-dependent signalling pathways in HSA^LR and Mbnl1^ΔE3/ΔE3 mice, two established mouse models of DM1.</p><p><strong>Results: </strong>Muscle from DM1 mouse models showed major deregulation of calcium/calmodulin-dependent protein kinases II (CaMKIIs), which are key activity sensors regulating synaptic gene expression and acetylcholine receptor (AChR) recycling at the NMJ. Both mouse models exhibited increased fragmentation of the endplate, which preceded muscle degeneration. Endplate fragmentation was not accompanied by changes in AChR turnover at the NMJ. However, the expression of synaptic genes was up-regulated in mutant innervated muscle, together with an abnormal accumulation of histone deacetylase 4 (HDAC4), a known target of CaMKII. Interestingly, denervation-induced increase in synaptic gene expression and AChR turnover was hampered in DM1 muscle. Importantly, CaMKIIβ/βM overexpression normalized endplate fragmentation and synaptic gene expression in innervated Mbnl1^ΔE3/ΔE3 muscle, but it did not restore denervation-induced synaptic gene up-regulation.</p><p><strong>Conclusions: </strong>Our results indicate that CaMKIIβ-dependent and -independent mechanisms perturb synaptic gene regulation and muscle response to denervation in DM1 mouse models. Changes in these signalling pathways may contribute to NMJ destabilization and muscle dysfunction in DM1 patients.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11106974/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141071587","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}