RARE DISEASE
Centronuclear myopathy
Centronuclear myopathy
Centronuclear myopathy
Synonyms: CNM
Synonyms: CNM
Synonyms: CNM
Drug discovery
2
drugs
With orphan designations
Overview
Centronuclear Myopathy (CNM) is a rare genetic neuromuscular disorder characterized by skeletal muscle weakness, atrophy, and displaced nuclei in muscle fibers. Symptoms range from mild hypotonia to severe respiratory and motor impairment, with variable onset (birth to adulthood). Associated features include ptosis, scoliosis, cardiomyopathy, and neuropathy. Caused by mutations in DNM2, BIN1, TTN, or MTM1 genes, inheritance patterns include autosomal dominant, recessive, or X-linked forms [2][4].
Burden
High mortality in severe X-linked forms (30% survival in infancy) [12][20]; chronic disability in milder forms.
Respiratory failure, prolonged ventilator dependence, and recurrent infections drive healthcare costs [4][12].
Limited epidemiological data and heterogeneity hinder targeted interventions [2][4].
Categories: rare genetic diseases, rare neurological diseases
Research Papers
162 drug discovery papers about Centronuclear myopathy, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
162 drug discovery papers about Centronuclear myopathy, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-05-27 | Beyond Membrane Remodeling: Organelle Crosstalk and Convergent Pathology in Centronuclear Myopathy.
Centronuclear myopathy (CNM) is a genetically heterogenous congenital myopathy traditionally classified as a membrane remodeling disorder. Emerging evidence reveals that centronuclear myopathy mutations converge upon common cellular dysfunction extending beyond membrane trafficking. This review proposes a unified model positioning CNM as a disorder of impaired organelle communication and structural crosstalk. We focus on how mutations in Myotubularin1 (MTM1) and gain-of-function mutations in Dynamin 2 (DNM2) disrupt the triad architecture, leading to aberrant calcium handling, mitochondrial dysfunction, imbalanced reactive oxygen species (ROS) production, and defective autophagy. These dysfunctions are not isolated but form a pathological feedback loop that compromises muscle integrity and regeneration. By identifying shared mechanisms across CNM types, this review positions the disorder as the convergence of organelle stress and cytoskeletal network failure. This perspective reveals novel therapeutic strategies based on the principle that targeting a central pathological node may alleviate systemic dysfunction. However, given the complexity of the organelle feedback loop, a comprehensive, multi-target approach may ultimately be required to achieve full phenotypic rescue across all affected tissues.
2025-12-29 | Tamoxifen treatment fails to improve muscle dysfunction in a model of recessive RYR1-linked centronuclear myopathy.
Centronuclear myopathies (CNMs) are rare congenital muscle disorders with no effective treatment. Previous studies showed that tamoxifen improved muscle function in mice modeling CNMs caused by variants in MTM1, BIN1 and DNM2. Here, we investigated whether tamoxifen administration improves muscle function and pathology in the severe recessive Ryr1TM/indel mouse model of RYR1-related CNM. Contractile performance, histological analyses and protein levels were assessed in Ryr1TM/indel mice and control littermates (wild type) treated with either a tamoxifen-enriched diet (65 mg/kg of food) or a control diet for 5 weeks, beginning at 3 weeks of age. Ryr1TM/indel mice displayed muscle weakness, reduced myofiber size and a high number of fibers with nuclei in abnormal position, regardless of the treatment. Force production during repeated contractions was reduced in tamoxifen-treated Ryr1TM/indel mice compared to that in untreated Ryr1TM/indel mice. The levels of CNM proteins (DNM2 and BIN1) were unchanged following the treatment. Tamoxifen did not improve muscle dysfunction, atrophy or histological hallmarks in Ryr1TM/indel mice. Our data indicate that tamoxifen supplementation is not beneficial and may negatively impact muscle function in this model of CNM, suggesting limited therapeutic value for patients with RYR1 mutations.
2025-11-28 | Integrative Multi-Omics and Network Analyses Reveal Pathogenic and Protective Pathways in Centronuclear Myopathies
Centronuclear and myotubular myopathies (CNMs) are rare, inherited muscle disorders characterized by muscle atrophy, weakness, and altered muscle fiber structure, primarily caused by mutations in MTM1, DNM2, or BIN1. The molecular mechanisms driving CNM are only partially understood, and no curative therapies are available. To elucidate molecular pathways involved in CNMs, we present an integrative multi-omics analysis across several CNM mouse models untreated or treated with pre-clinical strategies, combining transcriptomic, proteomic, and metabolomic datasets with curated interaction, metabolic, tissue, and phenotype knowledge using network-based approaches. Weighted Gene Co-expression Network Analysis (WGCNA) identified gene modules commonly altered in three CNM genetic forms. Modules correlated with improved muscle function were enriched for processes such as muscle contraction, RNA metabolism, and oxidative phosphorylation, whereas modules linked to disease severity were enriched for immune response, innervation, vascularization, and fatty acid oxidation. We further integrated transcriptomic, proteomic, and metabolomic data from the Mtm1−/y mouse model with public knowledge bases into a multilayer network, and explored it using a random walk with restart approach. These analyses highlighted metabolites closely connected to CNM phenotypes, some of which may represent candidates for nutritional or pharmacological modulation. Our findings illustrate how integrative multi-omics and network analyses reveal both pathogenic and protective pathways in CNM and provide a foundation for identifying novel therapeutic opportunities.
2025-11-04 | DREAMS: Drug REpurposing with Artificial Intelligence for Muscular Disorders
Rare diseases affect over 300 million people worldwide, yet only 6% currently have an approved treatment option. Given these numbers, and the pharmaceutical industry’s traditional “one drug, one disease” paradigm, it is crucial to develop disruptive approaches that accelerate drug discovery while reducing development time and costs. To address this challenge, the DREAMS project aims to identify repurposable treatments for multiple rare diseases by targeting shared pathological phenotypes. Our approach is built on four key pillars: (i) disease modeling using patient-derived pluripotent stem cells to identify common pathological phenotypes; (ii) phenotypic screening to identify compounds that rescue these molecular and cellular dysfunctions; (iii) artificial intelligence-based target deconvolution to understand mechanisms of action, predict therapeutic targets, and propose new disease indications; and (iv) innovative clinical trial methodologies designed to address groups of diseases rather than single conditions. Importantly, DREAMS is deeply patient-centric, with patient representatives actively involved in the design of the clinical trial to ensure that the research aligns with patients’ needs and priorities. To develop this approach, DREAMS specifically focuses on rare neuromuscular disorders that share a key pathological mechanism: impaired autophagy in striated muscle tissue. Five genetic diseases were selected based on their clinical relevance and preclinical evidence demonstrating that autophagy rescue can be beneficial: dynamin 2-related centronuclear myopathy, Duchenne muscular dystrophy, LMNA-related Emery–Dreifuss muscular dystrophy type 2, glycogen storage disease type II (Pompe disease), and Danon disease. By focusing on shared mechanisms rather than disease-specific mutations, DREAMS establishes a scalable and reusable platform for drug discovery that can be applied to additional rare diseases with overlapping pathophysiological features.
2025-05-21 | Combining dynamin 2 myopathy and neuropathy mutations rescues both phenotypes.
Mutations within a single gene can lead to diverse human genetic diseases affecting highly specialized tissues. Notably, dominant mutations in the DNM2 gene, encoding the mechanoenzyme dynamin, lead to distinct neuromuscular disorders: centronuclear myopathy (CNM) and Charcot-Marie-Tooth neuropathy (CMT). CNM is characterized by myofiber structural anomalies while CMT presents peripheral nerve defects, both culminating in muscle weakness and atrophy. Despite their shared genetic origin, the mechanisms driving these diseases remain elusive, and no cure is available. Here, we present in vitro assays underlining opposing effects of DNM2 mutations, gain-of-function in CNM and loss-of-function in CMT. In vivo, we explored the potential compensatory effects of CNM and CMT mutations by breeding Dnm2S619L/+ CNM with Dnm2K562E/+ CMT mouse models. Dnm2S619L/K562E offspring exhibit strongly improved motor coordination and muscle strength and mass, compared to single-mutant littermates. Dnm2S619L/K562E mice present normalized muscle structure and nerve fiber organization. This study reveals that two distinct disease-causing mutations within the DNM2 gene compensate each other in vivo, leading to corrections of most individual phenotypes. The inverse modulation of DNM2 activity emerges as a promising therapeutic strategy to address CNM and CMT diseases.
gene therapies
2025-12-16 | Comparative analysis of viral and development of non-viral muscle-targeted gene delivery systems with application to BIN1-related Centronuclear Myopathy
Analyse comparative des approches virales et développement de systèmes de délivrance génique non viraux ciblant le muscle, avec application à la myopathie centronucléaire liée à BIN1 Les myopathies centronucléaires (CNM) sont des maladies musculaires génétiques rares affectant la structure et la fonction du muscle squelettique. Cette thèse visait à développer des systèmes de délivrance génique spécifiquement ciblés vers le muscle squelettique par des approches virales ou non virales, avec un focus particulier sur la CNM liée à BIN1 (CNM-BIN1). L’analyse comparative d’AAV myotropiques dérivées de l’AAV9 a identifié MyoAAV4A comme le vecteur le plus performant pour la transduction du muscle et du coeur, tout en dé-ciblant le foie. En parallèle, des nanoparticules lipidiques fonctionnalisées avec le peptide MyomP1 (MyomP1-LNPs) ont été développées afin d’obtenir un ciblage musculaire actif et une réduction de la captation hépatique, offrant ainsi une alternative non virale prometteuse. L’utilisation du vecteur optimisé MyoAAV4A pour la thérapie de remplacement du gène BIN1 a permis de restaurer la structure et la fonction musculaires chez des souris CNM-BIN1, même après l’apparition de la maladie, en corrigeant les caractéristiques clés de la CNM telles que la faiblesse et l’atrophie musculaires, grâce à la restauration du réseau des tubules T et des protéines impliquées dans le couplage excitation-contraction. Dans l’ensemble, ce travail propose des plateformes virales et non virales efficaces pour la thérapie génique ciblée du muscle et ouvre de nouvelles perspectives thérapeutiques pour les CNM liées à BIN1 et, plus largement, pour d’autres maladies musculaires génétiques.
2025-09-05 | CRISPR/Cas13-mediated Dynamin 2 reduction therapy in a canine model of DNM2 -related centronuclear myopathy
Abstract We determined the potential of CRISPR/Cas13 technology as a therapeutic approach for centronuclear myopathies (CNMs) by reducing the expression of a single protein, DNM2. CNMs are severe congenital rare muscle disorders that result in muscle hypotrophy and weakness, with no cure. CNMs frequently result from mutations in either BIN1 , MTM1 , or DNM2 genes, with DNM2 being a key GTPase that plays a pivotal role in muscle membrane interactions with MTM1 and BIN1. Previous studies indicate that reducing DNM2 transcript expression by half could correct CNM phenotypes regardless the genetic forms, paving the way for a broad-spectrum CNM-therapy. We evaluated CRISPR/Cas13X.1-mediated DNM2 transcript knockdown, as a therapeutic application in a unique naturally-occurring canine CNM model harboring the DNM2 R465W /+ mutation, the most frequent pathogenic variant in patients. We show that in vivo intramuscular AAV-mediated CRISPR/Cas13X.1 injections, led to a reduction in DNM2 transcript and protein levels at one and two months post-treatment. Our results demonstrate the feasibility of CRISPR/Cas13-based therapy for CNM in a large animal model, paving the way for advancing this approach towards clinical trials.
2025-07-26 | Gene replacement therapy for centronuclear myopathy: A breakthrough in complex genetic muscle disease
Centronuclear myopathy (CNM) is a congenital myopathy characterized by muscle weakness accompanied by abnormal positioning of cell structures in skeletal muscle fibers. For decades, CNM has been considered essentially untreatable, with pathological mechanisms not fully understood and no effective therapeutic interventions available. In this issue of Molecular Therapy, Ji and colleagues demonstrated that adeno-associated virus (AAV)-mediated bridging integrator 1 (BIN1) gene replacement can prevent and reverse disease phenotypes in a mouse model of BIN1-related CNM.
2025-06-26 | Centronuclear myopathy in a Labrador Retriever presenting for evaluation of a ‘bunny‐hopping’ gait
Abstract A 3‐year‐old female neutered Labrador Retriever presented with a chronic history of ‘bunny‐hopping’ gait, presumed secondary to hip dysplasia. They exhibited moderate exercise intolerance, developing a stiff, short‐strided gait and collapsing into sternal recumbency after a brief period of exercise. Physical examination identified crepitus upon abduction of the left hip. Neurological examination at rest identified absent patellar reflexes, with repeat examination at the time of collapse identifying concurrently reduced withdrawal reflexes in all limbs that spontaneously resolved over a short period of time. A neuromuscular localisation was made. A conscious thoracic radiograph and clinical pathology (including measurement of creatine kinase and aspartate aminotransferase), were normal. An electrodiagnostic study identified spontaneous activity on electromyography coupled with normal nerve conduction studies and repetitive nerve stimulation, consistent with a myopathy. Genetic testing identified a homozygous mutation of the protein tyrosine phosphatase‐like A (PTPLA) gene, causative of centronuclear myopathy.
2025-05-01 | BIN1 gene replacement reverses BIN1-related centronuclear myopathy.
Centronuclear myopathies (CNMs) are severe genetic disorders characterized by generalized muscle weakness associated with organelle mispositioning in myofibers. Most CNM cases are caused by mutations in proteins involved in membrane remodeling, including amphiphysin 2 (BIN1). There is no treatment, and the pathological mechanisms are not understood. Here, we aimed to cure the Bin1-CNM mouse model (Bin1mck-/-) via an adeno-associated virus (AAV)-based gene replacement strategy. Early systemic exogenous BIN1 expression efficiently prevented disease progression. Moreover, BIN1 expression after disease onset reversed all disease signs 4 weeks after treatment, including motor defects, muscle weakness, muscle and myofiber hypotrophy, kyphosis, nuclei and mitochondria misposition, and altered T-tubules network. We then validated the most efficient construct combining a myotropic AAV serotype with the muscle BIN1 isoform. The rescue correlated with the normalization of autophagy and excitation-contraction coupling markers. Cellular and in vivo investigations revealed that different BIN1 natural isoforms shared similar beneficial effects. Artificial constructs coding for separated protein domains rescued different CNM hallmarks. Only the muscle-specific BIN1 isoform combined the different cellular functions of BIN1 on membrane tubulation and dynamin (DNM2) regulation necessary for a full rescue. Overall, this study validates BIN1 gene replacement as a promising strategy to cure BIN1-related CNM.
proteins
2026-09-11 | Genetic and Pharmacologic Inhibition of Myostatin Restores Muscle Mass in a Dynamin 2-Related Centronuclear Myopathy Mouse Model.
Autosomal dominant centronuclear myopathy (ADCNM), most commonly caused by mutations in the dynamin 2 (DNM2) gene, is a rare congenital myopathy characterized by progressive muscle weakness and atrophy. Myostatin, a key negative regulator of skeletal muscle mass, has shown therapeutic potential in several models of neuromuscular diseases. We hypothesized that inhibiting myostatin could counteract muscle deconditioning in ADCNM and evaluated the therapeutic potential of both genetic and pharmacological myostatin inhibition strategies in a mouse model of ADCNM. Knockin-dnm2R465W/+ (KI) mice were first crossed with knockout-myostatin mice (KO) to generate double mutant (KIKO) mice carrying both the R465W missense mutation and the myostatin gene deletion. In a second experiment, KI mice received intraperitoneal injections of a soluble activin type IIB receptor fused to IgG1 Fc fragment (sActRIIB-Fc) at 5 mg kg-1 twice weekly starting at 4 weeks of age for 4 weeks. Muscle structure, molecular pathways and functional analysis were performed in tibialis anterior muscle. MRI and immunohistochemical analyses showed that KI mice exhibited impaired postnatal muscle growth between 1 and 2 months of age, resulting in persistent muscle hypotrophy (-15%, p < 0.05). This defect was associated with a significant reduction in the number of satellite cells (-53%, p < 0.001 at 1 month and -68%, p < 0.01 at 2 months), the central accumulation of dense NADH-TR staining in more than 20% of muscle fibres, an upregulation of atrophy-related E3 ligases mRNA (Trim63 + 50%, p < 0.001 and +87%, p < 0.001; Fbxo32 + 39% p < 0.05 and +95%, p < 0.001 at 1 and 2 months of age, respectively) and impaired autophagy. Genetic deletion of myostatin in KIKO mice fully restored muscle mass and normalized muscle function to wild-type conditions. Pharmacological inhibition with sActRIIB-Fc also robustly restored muscle mass to wild-type values, primarily via activation of the Akt-mTOR pathway. However, this anabolic effect was transient, as muscle mass returned to baseline 5 weeks after treatment cessation. Importantly, despite increased muscle mass, sActRIIB-Fc treatment did not improve muscle force and key pathological features, including defects in proteostasis, mitochondrial organization and excitation-contraction coupling. These findings establish the proof of concept that myostatin inhibition counteracts skeletal muscle growth defect in ADCNM, which may be combined with other drugs to better address the multifactorial nature of muscle weakness in ADCNM.
2023-09-18 | Speg interactions that regulate the stability of excitation-contraction coupling protein complexes in triads and dyads.
Here we show that striated muscle preferentially expressed protein kinase α (Spegα) maintains cardiac function in hearts with Spegβ deficiency. Speg is required for stability of excitation-contraction coupling (ECC) complexes and interacts with esterase D (Esd), Cardiomyopathy-Associated Protein 5 (Cmya5), and Fibronectin Type III and SPRY Domain Containing 2 (Fsd2) in cardiac and skeletal muscle. Mice with a sequence encoding a V5/HA tag inserted into the first exon of the Speg gene (HA-Speg mice) display a >90% decrease in Spegβ but Spegα is expressed at ~50% of normal levels. Mice deficient in both Spegα and Speg β (Speg KO mice) develop a severe dilated cardiomyopathy and muscle weakness and atrophy, but HA-Speg mice display mild muscle weakness with no cardiac involvement. Spegα in HA-Speg mice suppresses Ca2+ leak, proteolytic cleavage of Jph2, and disruption of transverse tubules. Despite it's low levels, HA-Spegβ immunoprecipitation identified Esd, Cmya5 and Fsd2 as Spegβ binding partners that localize to triads and dyads to stabilize ECC complexes. This study suggests that Spegα and Spegβ display functional redundancy, identifies Esd, Cmya5 and Fsd2 as components of both cardiac dyads and skeletal muscle triads and lays the groundwork for the identification of new therapeutic targets for centronuclear myopathy.
2022-03-16 | BIN1 modulation in vivo rescues dynamin-related myopathy.
The mechanoenzyme dynamin 2 (DNM2) is crucial for intracellular organization and trafficking. DNM2 is mutated in dominant centronuclear myopathy (DNM2-CNM), a muscle disease characterized by defects in organelle positioning in myofibers. It remains unclear how the in vivo functions of DNM2 are regulated in muscle. Moreover, there is no therapy for DNM2-CNM to date. Here, we overexpressed human amphiphysin 2 (BIN1), a membrane remodeling protein mutated in other CNM forms, in Dnm2RW/+ and Dnm2RW/RW mice modeling mild and severe DNM2-CNM, through transgenesis or with adeno-associated virus (AAV). Increasing BIN1 improved muscle atrophy and main histopathological features of Dnm2RW/+ mice and rescued the perinatal lethality and survival of Dnm2RW/RW mice. In vitro experiments showed that BIN1 binds and recruits DNM2 to membrane tubules, and that the BIN1-DNM2 complex regulates tubules fission. Overall, BIN1 is a potential therapeutic target for dominant centronuclear myopathy linked to DNM2 mutations.
2018-07-03 | [Myonuclear domain and microtubule proteome during skeletal muscle maturation].
In the normal course of muscle fiber development, myonuclei actively position and adapt a precise localization in mature fibers, shaping MyoNuclear Domains (MNDs). Myonuclei positioning in fibers appears to be essential for muscle function as defects in MNDs settings are always associated with dysfunction (i.e., centronuclear myopathy, sarcopenia). Previous studies have shown that myonuclei positioning in fibers is reversible, suggesting that in pathologies presenting MNDs impairment, myonuclei could be re-addressed to the "correct" position in fibers and this could benefit to muscle function. Cytoskeleton networks, and particularly microtubules, have been implicated in early nuclei localization in myotubes. As the microtubule network is completely redesigned during muscle maturation, we hypothesized that "microtubules associated proteomes" would change between immature and mature fibers and contribute to a microtubule-dependent process resulting in MNDs setting and maintenance in mature fibers. We performed an in vitro biochemical approach to isolate microtubules partners in immature (myotubes) and mature myofibers. Using mass-spectrometry identification, we selected 244 candidates, differentially associated/expressed with microtubules during myofiber maturation and potentially controlling MNDs settings. We are currently conducting a siRNA screen approach on these candidates to decipher their respective implication in early and late phases of MNDs establishment, using an unbiased assay developed by our team allowing statistical analysis of MNDs regarding myonuclei content. This approach will lead to the identification of new pathways related to nuclear positioning and MNDs setting in normal condition and in myopathies associated to MNDs impairment such as CNMs.
2015-10-01 | Amphiphysin 2 Orchestrates Nucleus Positioning and Shape by Linking the Nuclear Envelope to the Actin and Microtubule Cytoskeleton
Nucleus positioning is key for intracellular organization, cell differentiation, and organ development and is affected in many diseases, including myopathies due to alteration in amphiphysin-2 (BIN1). The actin and microtubule cytoskeletons are essential for nucleus positioning, but their crosstalk in this process is sparsely characterized. Here, we report that impairment of amphiphysin/BIN1 in Caenorhabditis elegans, mammalian cells, or muscles from patients with centronuclear myopathy alters nuclear position and shape. We show that AMPH-1/BIN1 binds to nesprin and actin, as well as to the microtubule-binding protein CLIP170 in both species. Expression of the microtubule-anchoring CAP-GLY domain of CLIP170 fused to the nuclear-envelope-anchoring KASH domain of nesprin rescues nuclear positioning defects of amph-1 mutants. Amphiphysins thus play a central role in linking the nuclear envelope with the actin and microtubule cytoskeletons. We propose that BIN1 has a direct and evolutionarily conserved role in nuclear positioning, altered in myopathies.
oligonucleotides
2021-10-08 | Differential physiological roles for BIN1 isoforms in skeletal muscle development, function and regeneration.
Skeletal muscle development and regeneration are tightly regulated processes. How the intracellular organization of muscle fibers is achieved during these steps is unclear. Here, we focus on the cellular and physiological roles of amphiphysin 2 (BIN1), a membrane remodeling protein mutated in both congenital and adult centronuclear myopathies (CNM), that is ubiquitously expressed and has skeletal muscle-specific isoforms. We created and characterized constitutive muscle-specific and inducible Bin1 homozygous and heterozygous knockout mice targeting either ubiquitous or muscle-specific isoforms. Constitutive Bin1-deficient mice died at birth from lack of feeding due to a skeletal muscle defect. T-tubules and other organelles were misplaced and altered, supporting a general early role for BIN1 in intracellular organization, in addition to membrane remodeling. Although restricted deletion of Bin1 in unchallenged adult muscles had no impact, the forced switch from the muscle-specific isoforms to the ubiquitous isoforms through deletion of the in-frame muscle-specific exon delayed muscle regeneration. Thus, ubiquitous BIN1 function is necessary for muscle development and function, whereas its muscle-specific isoforms fine tune muscle regeneration in adulthood, supporting that BIN1 CNM with congenital onset are due to developmental defects, whereas later onset may be due to regeneration defects.
2021-01-13 | The intragenic microRNA miR199A1 in the dynamin 2 gene contributes to the pathology of X-linked centronuclear myopathy.
Mutations in the myotubularin 1 (MTM1) gene can cause the fatal disease X-linked centronuclear myopathy (XLCNM), but the underlying mechanism is incompletely understood. In this report, using an Mtm1-/y disease model, we found that expression of the intragenic microRNA miR-199a-1 is up-regulated along with that of its host gene, dynamin 2 (Dnm2), in XLCNM skeletal muscle. To assess the role of miR-199a-1 in XLCNM, we crossed miR-199a-1-/- with Mtm1-/y mice and found that the resultant miR-199a-1-Mtm1 double-knockout mice display markers of improved health, as evidenced by lifespans prolonged by 30% and improved muscle strength and histology. Mechanistic analyses showed that miR-199a-1 directly targets nonmuscle myosin IIA (NM IIA) expression and, hence, inhibits muscle postnatal development as well as muscle maturation. Further analysis revealed that increased expression and phosphorylation of signal transducer and activator of transcription 3 (STAT3) up-regulates Dnm2/miR-199a-1 expression in XLCNM muscle. Our results suggest that miR-199a-1 has a critical role in XLCNM pathology and imply that this microRNA could be targeted in therapies to manage XLCNM.
2019-04-25 | EDTP/MTMR14: A novel target for improved survivorship to prolonged anoxia and cellular protein aggregates
Drosophila egg-derived tyrosine phosphatase (EDTP), a lipid phosphatase that removes 3-position phosphate at the inositol ring, has dual functions in oogenesis and muscle performance in adults. A mammalian homologous gene MTMR14, which encodes the myotubularin-related protein 14, negatively regulates autophagy. Mutation of EDTP/MTMR14, however, causes at least three deleterious consequences: (1) the lethality in early embryogenesis in Drosophila; (2) a "jumpy" phenotype with apparently impaired motor functions; and (3) an association with a rare genetic disorder called centronuclear myopathy. The potential benefit of EDTP/MTMR14 downregulation is likely masked by the lethality or severe muscle defects due to ubiquitous loss of this gene. Here we show that flies carrying a heterozygous EDTP mutation had increased survivorship to prolonged anoxia; tissue-specific downregulation of EDTP in non-muscle tissues, particularly motoneurons, extended lifespan and improved survivorship to beta-amyloid peptides (Aβ42) and polyglutamine protein aggregates. These data highlight the significance of selective downregulation of EDTP in non-muscles for beneficial consequences. MTMR14 expression was evident in the hippocampus and cortex in C57BL/6 J and APP/PS1 mice. Compared with C57BL/6 J mice, APP/PS1 mice had reduced MTMR14 in the cortex. Hippocampal expression of MTMR14 was increased and plateaued at 9-17 months compared with 2-6 months in C57BL/6 J mice. Additionally, MTMR14 was inducible by Aβ42 in the rat primarily hippocampal neurons and mouse Neuro2a neuroblasts. We demonstrate a novel approach of tissue-specific downregulation of the disease-associated gene EDTP/MTMR14 for extended lifespan and improved survivorship to cellular protein aggregates. This approach could be extended from insects to mammals.
2018-11-23 | Differential physiological role of BIN1 isoforms in skeletal muscle development, function and regeneration
Abstract Skeletal muscle development and regeneration are tightly regulated processes. How the intracellular organization of muscle fibers is achieved during these steps is unclear. Here we focus on the cellular and physiological roles of amphiphysin 2 (BIN1), a membrane remodeling protein mutated in both congenital and adult centronuclear myopathies, that is ubiquitously expressed and has skeletal muscle-specific isoforms. We created and characterized constitutive, muscle-specific and inducible Bin1 homozygous and heterozygous knockout mice targeting either ubiquitous or muscle-specific isoforms. Constitutive Bin1 -deficient mice died at birth from lack of feeding due to a skeletal muscle defect. T-tubules and other organelles were misplaced and altered, supporting a general early role of BIN1 on intracellular organization in addition to membrane remodeling. Whereas restricted deletion of Bin1 in unchallenged adult muscles had no impact, the forced switch from the muscle-specific isoforms to the ubiquitous isoforms through deletion of the in-frame muscle–specific exon delayed muscle regeneration. Thus, BIN1 ubiquitous function is necessary for muscle development and function while its muscle-specific isoforms fine-tune muscle regeneration in adulthood, supporting that BIN1 centronuclear myopathy with congenital onset are due to developmental defects while later onset may be due to regeneration defects.
2016-09-13 | Reprogramming the Dynamin 2 mRNA by Spliceosome-mediated RNA Trans-splicing
Dynamin 2 (DNM2) is a large GTPase, ubiquitously expressed, involved in membrane trafficking and regulation of actin and microtubule cytoskeletons. DNM2 mutations cause autosomal dominant centronuclear myopathy which is a rare congenital myopathy characterized by skeletal muscle weakness and histopathological features including nuclear centralization in absence of regeneration. No curative treatment is currently available for the DNM2-related autosomal dominant centronuclear myopathy. In order to develop therapeutic strategy, we evaluated here the potential of Spliceosome-Mediated RNA Trans-splicing technology to reprogram the Dnm2-mRNA in vitro and in vivo in mice. We show that classical 3'-trans-splicing strategy cannot be considered as accurate therapeutic strategy regarding toxicity of the pre-trans-splicing molecules leading to low rate of trans-splicing in vivo. Thus, we tested alternative strategies devoted to prevent this toxicity and enhance frequency of trans-splicing events. We succeeded to overcome the toxicity through a 5'-trans-splicing strategy which also allows detection of trans-splicing events at mRNA and protein levels in vitro and in vivo. These results suggest that the Spliceosome-Mediated RNA Trans-splicing strategy may be used to reprogram mutated Dnm2-mRNA but highlight the potential toxicity linked to the molecular tools which have to be carefully investigated during preclinical development.
other
2026-05-08 | DNM2 lipid binding drives centronuclear myopathy and represents a potential therapeutic target.
Centronuclear myopathies (CNMs) are rare congenital disorders characterized by muscle weakness, fiber hypotrophy, and organelle mislocalization. Most cases arise from mutations in MTM1 or DNM2, encoding myotubularin and dynamin-2, respectively. DNM2 is a GTPase that binds lipids, oligomerizes around membranes, and mediates fission. We previously showed that DNM2 levels are elevated in MTM1-CNM patients and Mtm1-/y mice, and that normalizing DNM2 rescues disease phenotypes. However, the specific DNM2 functions driving pathology remain unclear. Here, we expressed AAV-delivered WT and DNM2 mutants in WT and Mtm1-/y mouse muscles to disrupt specific DNM2 molecular functions. In WT mice, overexpression of WT DNM2 and most mutants induced CNM-like phenotypes, including reduced force, fiber hypotrophy, and centralized nuclei, consistent with gain-of-function mechanisms. The lipid-binding-defective mutant K562E did not induce disease-like phenotype. In Mtm1-/y mice, K562E mutant markedly improved muscle force, mass, and fiber size, while others failed to rescue. Therefore, we generated Mtm1-/y Dnm2K562E/+ mice, which showed full rescue of survival, motor function, and muscle force, with improved muscle mass, fiber size, and organelle positioning despite persistently elevated DNM2 levels. This study reveals that DNM2 lipid binding, not protein abundance or GTPase activity, drives pathology, and represents the most rational therapeutic target for DNM2 therapy in MTM1-CNM.
2025-11-10 | Ca2+, ROS, IL-6, and p38 MAPK signaling loops underlying alterations in myotube formation induced by a severe MH/CCD mutation in RyR1.
Mutations in the gene encoding the skeletal muscle ryanodine receptor (RyR1) can result in muscle diseases, termed RyR1-related myopathies (RyR1-RM). Examples include malignant hyperthermia (MH), central core disease (CCD), and centronuclear myopathy (CNM). The muscles involved often have more (and mispositioned) nuclei than normal. A subset of the corresponding mutant proteins shows an overactive or leaky sarcoplasmic reticulum (SR) channel behavior that depletes the SR Ca2+ content and increases the level of cytosolic Ca2+. In addition, two remarkable effects of these RyR1 variants have been reported in cultured myogenic cells: enhanced expression of interleukin-6 (IL-6) and stimulation of myoblast fusion (myonuclei accretion). Here, we have investigated whether the latter effect is due to a possible IL-6-dependent autocrine loop. Toward this goal, we analyzed the impact of the overactive Y523S mutant compared with the wild-type RyR1 after expression in C2C12 cells. The results show that this mutation indeed drastically promotes myoblast fusion up to ∼300%. Moreover, this action depends on the sequential activation of SR Ca2+ release, store-operated Ca2+ channels, reactive oxygen species (ROS, cytosolic and mitochondrial), calpain, and calcineurin. In addition, a neutralizing antibody directed against IL-6 and a p38 inhibitor completely suppressed the stimulation of myoblast fusion. Furthermore, in RyR1-expressing cells, myotube formation was promoted by either exogenous IL-6 or conditioned medium obtained from the Y523S-expressing cells. These findings suggest an autocrine mechanism involving the interplay between Ca2+, ROS, IL-6, and p38 signaling pathways in controlling myonuclei density, which could be essential to explain the pathogenesis of RyR1-RM.NEW & NOTEWORTHY Overactive RyR1 mutant proteins are associated with muscle disease; interestingly, they increase the number of myonuclei when expressed in C2C12 cells. We discovered that this alteration depends on a Ca2+/ROS loop, which recruits calpain and calcineurin to stimulate the production of IL-6 and the subsequent autocrine activation of p38. Thus, disease-causing RyR1 mutations require an IL-6 autocrine system to alter myonuclear density. This novel mechanism could be critical to understanding the pathogenesis of congenital myopathies.
small molecules
2026-05-27 | Beyond Membrane Remodeling: Organelle Crosstalk and Convergent Pathology in Centronuclear Myopathy.
Centronuclear myopathy (CNM) is a genetically heterogenous congenital myopathy traditionally classified as a membrane remodeling disorder. Emerging evidence reveals that centronuclear myopathy mutations converge upon common cellular dysfunction extending beyond membrane trafficking. This review proposes a unified model positioning CNM as a disorder of impaired organelle communication and structural crosstalk. We focus on how mutations in Myotubularin1 (MTM1) and gain-of-function mutations in Dynamin 2 (DNM2) disrupt the triad architecture, leading to aberrant calcium handling, mitochondrial dysfunction, imbalanced reactive oxygen species (ROS) production, and defective autophagy. These dysfunctions are not isolated but form a pathological feedback loop that compromises muscle integrity and regeneration. By identifying shared mechanisms across CNM types, this review positions the disorder as the convergence of organelle stress and cytoskeletal network failure. This perspective reveals novel therapeutic strategies based on the principle that targeting a central pathological node may alleviate systemic dysfunction. However, given the complexity of the organelle feedback loop, a comprehensive, multi-target approach may ultimately be required to achieve full phenotypic rescue across all affected tissues.
2025-12-29 | Tamoxifen treatment fails to improve muscle dysfunction in a model of recessive RYR1-linked centronuclear myopathy.
Centronuclear myopathies (CNMs) are rare congenital muscle disorders with no effective treatment. Previous studies showed that tamoxifen improved muscle function in mice modeling CNMs caused by variants in MTM1, BIN1 and DNM2. Here, we investigated whether tamoxifen administration improves muscle function and pathology in the severe recessive Ryr1TM/indel mouse model of RYR1-related CNM. Contractile performance, histological analyses and protein levels were assessed in Ryr1TM/indel mice and control littermates (wild type) treated with either a tamoxifen-enriched diet (65 mg/kg of food) or a control diet for 5 weeks, beginning at 3 weeks of age. Ryr1TM/indel mice displayed muscle weakness, reduced myofiber size and a high number of fibers with nuclei in abnormal position, regardless of the treatment. Force production during repeated contractions was reduced in tamoxifen-treated Ryr1TM/indel mice compared to that in untreated Ryr1TM/indel mice. The levels of CNM proteins (DNM2 and BIN1) were unchanged following the treatment. Tamoxifen did not improve muscle dysfunction, atrophy or histological hallmarks in Ryr1TM/indel mice. Our data indicate that tamoxifen supplementation is not beneficial and may negatively impact muscle function in this model of CNM, suggesting limited therapeutic value for patients with RYR1 mutations.
2025-11-28 | Integrative Multi-Omics and Network Analyses Reveal Pathogenic and Protective Pathways in Centronuclear Myopathies
Centronuclear and myotubular myopathies (CNMs) are rare, inherited muscle disorders characterized by muscle atrophy, weakness, and altered muscle fiber structure, primarily caused by mutations in MTM1, DNM2, or BIN1. The molecular mechanisms driving CNM are only partially understood, and no curative therapies are available. To elucidate molecular pathways involved in CNMs, we present an integrative multi-omics analysis across several CNM mouse models untreated or treated with pre-clinical strategies, combining transcriptomic, proteomic, and metabolomic datasets with curated interaction, metabolic, tissue, and phenotype knowledge using network-based approaches. Weighted Gene Co-expression Network Analysis (WGCNA) identified gene modules commonly altered in three CNM genetic forms. Modules correlated with improved muscle function were enriched for processes such as muscle contraction, RNA metabolism, and oxidative phosphorylation, whereas modules linked to disease severity were enriched for immune response, innervation, vascularization, and fatty acid oxidation. We further integrated transcriptomic, proteomic, and metabolomic data from the Mtm1−/y mouse model with public knowledge bases into a multilayer network, and explored it using a random walk with restart approach. These analyses highlighted metabolites closely connected to CNM phenotypes, some of which may represent candidates for nutritional or pharmacological modulation. Our findings illustrate how integrative multi-omics and network analyses reveal both pathogenic and protective pathways in CNM and provide a foundation for identifying novel therapeutic opportunities.
2025-11-04 | DREAMS: Drug REpurposing with Artificial Intelligence for Muscular Disorders
Rare diseases affect over 300 million people worldwide, yet only 6% currently have an approved treatment option. Given these numbers, and the pharmaceutical industry’s traditional “one drug, one disease” paradigm, it is crucial to develop disruptive approaches that accelerate drug discovery while reducing development time and costs. To address this challenge, the DREAMS project aims to identify repurposable treatments for multiple rare diseases by targeting shared pathological phenotypes. Our approach is built on four key pillars: (i) disease modeling using patient-derived pluripotent stem cells to identify common pathological phenotypes; (ii) phenotypic screening to identify compounds that rescue these molecular and cellular dysfunctions; (iii) artificial intelligence-based target deconvolution to understand mechanisms of action, predict therapeutic targets, and propose new disease indications; and (iv) innovative clinical trial methodologies designed to address groups of diseases rather than single conditions. Importantly, DREAMS is deeply patient-centric, with patient representatives actively involved in the design of the clinical trial to ensure that the research aligns with patients’ needs and priorities. To develop this approach, DREAMS specifically focuses on rare neuromuscular disorders that share a key pathological mechanism: impaired autophagy in striated muscle tissue. Five genetic diseases were selected based on their clinical relevance and preclinical evidence demonstrating that autophagy rescue can be beneficial: dynamin 2-related centronuclear myopathy, Duchenne muscular dystrophy, LMNA-related Emery–Dreifuss muscular dystrophy type 2, glycogen storage disease type II (Pompe disease), and Danon disease. By focusing on shared mechanisms rather than disease-specific mutations, DREAMS establishes a scalable and reusable platform for drug discovery that can be applied to additional rare diseases with overlapping pathophysiological features.
2025-05-21 | Combining dynamin 2 myopathy and neuropathy mutations rescues both phenotypes.
Mutations within a single gene can lead to diverse human genetic diseases affecting highly specialized tissues. Notably, dominant mutations in the DNM2 gene, encoding the mechanoenzyme dynamin, lead to distinct neuromuscular disorders: centronuclear myopathy (CNM) and Charcot-Marie-Tooth neuropathy (CMT). CNM is characterized by myofiber structural anomalies while CMT presents peripheral nerve defects, both culminating in muscle weakness and atrophy. Despite their shared genetic origin, the mechanisms driving these diseases remain elusive, and no cure is available. Here, we present in vitro assays underlining opposing effects of DNM2 mutations, gain-of-function in CNM and loss-of-function in CMT. In vivo, we explored the potential compensatory effects of CNM and CMT mutations by breeding Dnm2S619L/+ CNM with Dnm2K562E/+ CMT mouse models. Dnm2S619L/K562E offspring exhibit strongly improved motor coordination and muscle strength and mass, compared to single-mutant littermates. Dnm2S619L/K562E mice present normalized muscle structure and nerve fiber organization. This study reveals that two distinct disease-causing mutations within the DNM2 gene compensate each other in vivo, leading to corrections of most individual phenotypes. The inverse modulation of DNM2 activity emerges as a promising therapeutic strategy to address CNM and CMT diseases.
gene therapies
2025-12-16 | Comparative analysis of viral and development of non-viral muscle-targeted gene delivery systems with application to BIN1-related Centronuclear Myopathy
Analyse comparative des approches virales et développement de systèmes de délivrance génique non viraux ciblant le muscle, avec application à la myopathie centronucléaire liée à BIN1 Les myopathies centronucléaires (CNM) sont des maladies musculaires génétiques rares affectant la structure et la fonction du muscle squelettique. Cette thèse visait à développer des systèmes de délivrance génique spécifiquement ciblés vers le muscle squelettique par des approches virales ou non virales, avec un focus particulier sur la CNM liée à BIN1 (CNM-BIN1). L’analyse comparative d’AAV myotropiques dérivées de l’AAV9 a identifié MyoAAV4A comme le vecteur le plus performant pour la transduction du muscle et du coeur, tout en dé-ciblant le foie. En parallèle, des nanoparticules lipidiques fonctionnalisées avec le peptide MyomP1 (MyomP1-LNPs) ont été développées afin d’obtenir un ciblage musculaire actif et une réduction de la captation hépatique, offrant ainsi une alternative non virale prometteuse. L’utilisation du vecteur optimisé MyoAAV4A pour la thérapie de remplacement du gène BIN1 a permis de restaurer la structure et la fonction musculaires chez des souris CNM-BIN1, même après l’apparition de la maladie, en corrigeant les caractéristiques clés de la CNM telles que la faiblesse et l’atrophie musculaires, grâce à la restauration du réseau des tubules T et des protéines impliquées dans le couplage excitation-contraction. Dans l’ensemble, ce travail propose des plateformes virales et non virales efficaces pour la thérapie génique ciblée du muscle et ouvre de nouvelles perspectives thérapeutiques pour les CNM liées à BIN1 et, plus largement, pour d’autres maladies musculaires génétiques.
2025-09-05 | CRISPR/Cas13-mediated Dynamin 2 reduction therapy in a canine model of DNM2 -related centronuclear myopathy
Abstract We determined the potential of CRISPR/Cas13 technology as a therapeutic approach for centronuclear myopathies (CNMs) by reducing the expression of a single protein, DNM2. CNMs are severe congenital rare muscle disorders that result in muscle hypotrophy and weakness, with no cure. CNMs frequently result from mutations in either BIN1 , MTM1 , or DNM2 genes, with DNM2 being a key GTPase that plays a pivotal role in muscle membrane interactions with MTM1 and BIN1. Previous studies indicate that reducing DNM2 transcript expression by half could correct CNM phenotypes regardless the genetic forms, paving the way for a broad-spectrum CNM-therapy. We evaluated CRISPR/Cas13X.1-mediated DNM2 transcript knockdown, as a therapeutic application in a unique naturally-occurring canine CNM model harboring the DNM2 R465W /+ mutation, the most frequent pathogenic variant in patients. We show that in vivo intramuscular AAV-mediated CRISPR/Cas13X.1 injections, led to a reduction in DNM2 transcript and protein levels at one and two months post-treatment. Our results demonstrate the feasibility of CRISPR/Cas13-based therapy for CNM in a large animal model, paving the way for advancing this approach towards clinical trials.
2025-07-26 | Gene replacement therapy for centronuclear myopathy: A breakthrough in complex genetic muscle disease
Centronuclear myopathy (CNM) is a congenital myopathy characterized by muscle weakness accompanied by abnormal positioning of cell structures in skeletal muscle fibers. For decades, CNM has been considered essentially untreatable, with pathological mechanisms not fully understood and no effective therapeutic interventions available. In this issue of Molecular Therapy, Ji and colleagues demonstrated that adeno-associated virus (AAV)-mediated bridging integrator 1 (BIN1) gene replacement can prevent and reverse disease phenotypes in a mouse model of BIN1-related CNM.
2025-06-26 | Centronuclear myopathy in a Labrador Retriever presenting for evaluation of a ‘bunny‐hopping’ gait
Abstract A 3‐year‐old female neutered Labrador Retriever presented with a chronic history of ‘bunny‐hopping’ gait, presumed secondary to hip dysplasia. They exhibited moderate exercise intolerance, developing a stiff, short‐strided gait and collapsing into sternal recumbency after a brief period of exercise. Physical examination identified crepitus upon abduction of the left hip. Neurological examination at rest identified absent patellar reflexes, with repeat examination at the time of collapse identifying concurrently reduced withdrawal reflexes in all limbs that spontaneously resolved over a short period of time. A neuromuscular localisation was made. A conscious thoracic radiograph and clinical pathology (including measurement of creatine kinase and aspartate aminotransferase), were normal. An electrodiagnostic study identified spontaneous activity on electromyography coupled with normal nerve conduction studies and repetitive nerve stimulation, consistent with a myopathy. Genetic testing identified a homozygous mutation of the protein tyrosine phosphatase‐like A (PTPLA) gene, causative of centronuclear myopathy.
2025-05-01 | BIN1 gene replacement reverses BIN1-related centronuclear myopathy.
Centronuclear myopathies (CNMs) are severe genetic disorders characterized by generalized muscle weakness associated with organelle mispositioning in myofibers. Most CNM cases are caused by mutations in proteins involved in membrane remodeling, including amphiphysin 2 (BIN1). There is no treatment, and the pathological mechanisms are not understood. Here, we aimed to cure the Bin1-CNM mouse model (Bin1mck-/-) via an adeno-associated virus (AAV)-based gene replacement strategy. Early systemic exogenous BIN1 expression efficiently prevented disease progression. Moreover, BIN1 expression after disease onset reversed all disease signs 4 weeks after treatment, including motor defects, muscle weakness, muscle and myofiber hypotrophy, kyphosis, nuclei and mitochondria misposition, and altered T-tubules network. We then validated the most efficient construct combining a myotropic AAV serotype with the muscle BIN1 isoform. The rescue correlated with the normalization of autophagy and excitation-contraction coupling markers. Cellular and in vivo investigations revealed that different BIN1 natural isoforms shared similar beneficial effects. Artificial constructs coding for separated protein domains rescued different CNM hallmarks. Only the muscle-specific BIN1 isoform combined the different cellular functions of BIN1 on membrane tubulation and dynamin (DNM2) regulation necessary for a full rescue. Overall, this study validates BIN1 gene replacement as a promising strategy to cure BIN1-related CNM.
proteins
2026-09-11 | Genetic and Pharmacologic Inhibition of Myostatin Restores Muscle Mass in a Dynamin 2-Related Centronuclear Myopathy Mouse Model.
Autosomal dominant centronuclear myopathy (ADCNM), most commonly caused by mutations in the dynamin 2 (DNM2) gene, is a rare congenital myopathy characterized by progressive muscle weakness and atrophy. Myostatin, a key negative regulator of skeletal muscle mass, has shown therapeutic potential in several models of neuromuscular diseases. We hypothesized that inhibiting myostatin could counteract muscle deconditioning in ADCNM and evaluated the therapeutic potential of both genetic and pharmacological myostatin inhibition strategies in a mouse model of ADCNM. Knockin-dnm2R465W/+ (KI) mice were first crossed with knockout-myostatin mice (KO) to generate double mutant (KIKO) mice carrying both the R465W missense mutation and the myostatin gene deletion. In a second experiment, KI mice received intraperitoneal injections of a soluble activin type IIB receptor fused to IgG1 Fc fragment (sActRIIB-Fc) at 5 mg kg-1 twice weekly starting at 4 weeks of age for 4 weeks. Muscle structure, molecular pathways and functional analysis were performed in tibialis anterior muscle. MRI and immunohistochemical analyses showed that KI mice exhibited impaired postnatal muscle growth between 1 and 2 months of age, resulting in persistent muscle hypotrophy (-15%, p < 0.05). This defect was associated with a significant reduction in the number of satellite cells (-53%, p < 0.001 at 1 month and -68%, p < 0.01 at 2 months), the central accumulation of dense NADH-TR staining in more than 20% of muscle fibres, an upregulation of atrophy-related E3 ligases mRNA (Trim63 + 50%, p < 0.001 and +87%, p < 0.001; Fbxo32 + 39% p < 0.05 and +95%, p < 0.001 at 1 and 2 months of age, respectively) and impaired autophagy. Genetic deletion of myostatin in KIKO mice fully restored muscle mass and normalized muscle function to wild-type conditions. Pharmacological inhibition with sActRIIB-Fc also robustly restored muscle mass to wild-type values, primarily via activation of the Akt-mTOR pathway. However, this anabolic effect was transient, as muscle mass returned to baseline 5 weeks after treatment cessation. Importantly, despite increased muscle mass, sActRIIB-Fc treatment did not improve muscle force and key pathological features, including defects in proteostasis, mitochondrial organization and excitation-contraction coupling. These findings establish the proof of concept that myostatin inhibition counteracts skeletal muscle growth defect in ADCNM, which may be combined with other drugs to better address the multifactorial nature of muscle weakness in ADCNM.
2023-09-18 | Speg interactions that regulate the stability of excitation-contraction coupling protein complexes in triads and dyads.
Here we show that striated muscle preferentially expressed protein kinase α (Spegα) maintains cardiac function in hearts with Spegβ deficiency. Speg is required for stability of excitation-contraction coupling (ECC) complexes and interacts with esterase D (Esd), Cardiomyopathy-Associated Protein 5 (Cmya5), and Fibronectin Type III and SPRY Domain Containing 2 (Fsd2) in cardiac and skeletal muscle. Mice with a sequence encoding a V5/HA tag inserted into the first exon of the Speg gene (HA-Speg mice) display a >90% decrease in Spegβ but Spegα is expressed at ~50% of normal levels. Mice deficient in both Spegα and Speg β (Speg KO mice) develop a severe dilated cardiomyopathy and muscle weakness and atrophy, but HA-Speg mice display mild muscle weakness with no cardiac involvement. Spegα in HA-Speg mice suppresses Ca2+ leak, proteolytic cleavage of Jph2, and disruption of transverse tubules. Despite it's low levels, HA-Spegβ immunoprecipitation identified Esd, Cmya5 and Fsd2 as Spegβ binding partners that localize to triads and dyads to stabilize ECC complexes. This study suggests that Spegα and Spegβ display functional redundancy, identifies Esd, Cmya5 and Fsd2 as components of both cardiac dyads and skeletal muscle triads and lays the groundwork for the identification of new therapeutic targets for centronuclear myopathy.
2022-03-16 | BIN1 modulation in vivo rescues dynamin-related myopathy.
The mechanoenzyme dynamin 2 (DNM2) is crucial for intracellular organization and trafficking. DNM2 is mutated in dominant centronuclear myopathy (DNM2-CNM), a muscle disease characterized by defects in organelle positioning in myofibers. It remains unclear how the in vivo functions of DNM2 are regulated in muscle. Moreover, there is no therapy for DNM2-CNM to date. Here, we overexpressed human amphiphysin 2 (BIN1), a membrane remodeling protein mutated in other CNM forms, in Dnm2RW/+ and Dnm2RW/RW mice modeling mild and severe DNM2-CNM, through transgenesis or with adeno-associated virus (AAV). Increasing BIN1 improved muscle atrophy and main histopathological features of Dnm2RW/+ mice and rescued the perinatal lethality and survival of Dnm2RW/RW mice. In vitro experiments showed that BIN1 binds and recruits DNM2 to membrane tubules, and that the BIN1-DNM2 complex regulates tubules fission. Overall, BIN1 is a potential therapeutic target for dominant centronuclear myopathy linked to DNM2 mutations.
2018-07-03 | [Myonuclear domain and microtubule proteome during skeletal muscle maturation].
In the normal course of muscle fiber development, myonuclei actively position and adapt a precise localization in mature fibers, shaping MyoNuclear Domains (MNDs). Myonuclei positioning in fibers appears to be essential for muscle function as defects in MNDs settings are always associated with dysfunction (i.e., centronuclear myopathy, sarcopenia). Previous studies have shown that myonuclei positioning in fibers is reversible, suggesting that in pathologies presenting MNDs impairment, myonuclei could be re-addressed to the "correct" position in fibers and this could benefit to muscle function. Cytoskeleton networks, and particularly microtubules, have been implicated in early nuclei localization in myotubes. As the microtubule network is completely redesigned during muscle maturation, we hypothesized that "microtubules associated proteomes" would change between immature and mature fibers and contribute to a microtubule-dependent process resulting in MNDs setting and maintenance in mature fibers. We performed an in vitro biochemical approach to isolate microtubules partners in immature (myotubes) and mature myofibers. Using mass-spectrometry identification, we selected 244 candidates, differentially associated/expressed with microtubules during myofiber maturation and potentially controlling MNDs settings. We are currently conducting a siRNA screen approach on these candidates to decipher their respective implication in early and late phases of MNDs establishment, using an unbiased assay developed by our team allowing statistical analysis of MNDs regarding myonuclei content. This approach will lead to the identification of new pathways related to nuclear positioning and MNDs setting in normal condition and in myopathies associated to MNDs impairment such as CNMs.
2015-10-01 | Amphiphysin 2 Orchestrates Nucleus Positioning and Shape by Linking the Nuclear Envelope to the Actin and Microtubule Cytoskeleton
Nucleus positioning is key for intracellular organization, cell differentiation, and organ development and is affected in many diseases, including myopathies due to alteration in amphiphysin-2 (BIN1). The actin and microtubule cytoskeletons are essential for nucleus positioning, but their crosstalk in this process is sparsely characterized. Here, we report that impairment of amphiphysin/BIN1 in Caenorhabditis elegans, mammalian cells, or muscles from patients with centronuclear myopathy alters nuclear position and shape. We show that AMPH-1/BIN1 binds to nesprin and actin, as well as to the microtubule-binding protein CLIP170 in both species. Expression of the microtubule-anchoring CAP-GLY domain of CLIP170 fused to the nuclear-envelope-anchoring KASH domain of nesprin rescues nuclear positioning defects of amph-1 mutants. Amphiphysins thus play a central role in linking the nuclear envelope with the actin and microtubule cytoskeletons. We propose that BIN1 has a direct and evolutionarily conserved role in nuclear positioning, altered in myopathies.
oligonucleotides
2021-10-08 | Differential physiological roles for BIN1 isoforms in skeletal muscle development, function and regeneration.
Skeletal muscle development and regeneration are tightly regulated processes. How the intracellular organization of muscle fibers is achieved during these steps is unclear. Here, we focus on the cellular and physiological roles of amphiphysin 2 (BIN1), a membrane remodeling protein mutated in both congenital and adult centronuclear myopathies (CNM), that is ubiquitously expressed and has skeletal muscle-specific isoforms. We created and characterized constitutive muscle-specific and inducible Bin1 homozygous and heterozygous knockout mice targeting either ubiquitous or muscle-specific isoforms. Constitutive Bin1-deficient mice died at birth from lack of feeding due to a skeletal muscle defect. T-tubules and other organelles were misplaced and altered, supporting a general early role for BIN1 in intracellular organization, in addition to membrane remodeling. Although restricted deletion of Bin1 in unchallenged adult muscles had no impact, the forced switch from the muscle-specific isoforms to the ubiquitous isoforms through deletion of the in-frame muscle-specific exon delayed muscle regeneration. Thus, ubiquitous BIN1 function is necessary for muscle development and function, whereas its muscle-specific isoforms fine tune muscle regeneration in adulthood, supporting that BIN1 CNM with congenital onset are due to developmental defects, whereas later onset may be due to regeneration defects.
2021-01-13 | The intragenic microRNA miR199A1 in the dynamin 2 gene contributes to the pathology of X-linked centronuclear myopathy.
Mutations in the myotubularin 1 (MTM1) gene can cause the fatal disease X-linked centronuclear myopathy (XLCNM), but the underlying mechanism is incompletely understood. In this report, using an Mtm1-/y disease model, we found that expression of the intragenic microRNA miR-199a-1 is up-regulated along with that of its host gene, dynamin 2 (Dnm2), in XLCNM skeletal muscle. To assess the role of miR-199a-1 in XLCNM, we crossed miR-199a-1-/- with Mtm1-/y mice and found that the resultant miR-199a-1-Mtm1 double-knockout mice display markers of improved health, as evidenced by lifespans prolonged by 30% and improved muscle strength and histology. Mechanistic analyses showed that miR-199a-1 directly targets nonmuscle myosin IIA (NM IIA) expression and, hence, inhibits muscle postnatal development as well as muscle maturation. Further analysis revealed that increased expression and phosphorylation of signal transducer and activator of transcription 3 (STAT3) up-regulates Dnm2/miR-199a-1 expression in XLCNM muscle. Our results suggest that miR-199a-1 has a critical role in XLCNM pathology and imply that this microRNA could be targeted in therapies to manage XLCNM.
2019-04-25 | EDTP/MTMR14: A novel target for improved survivorship to prolonged anoxia and cellular protein aggregates
Drosophila egg-derived tyrosine phosphatase (EDTP), a lipid phosphatase that removes 3-position phosphate at the inositol ring, has dual functions in oogenesis and muscle performance in adults. A mammalian homologous gene MTMR14, which encodes the myotubularin-related protein 14, negatively regulates autophagy. Mutation of EDTP/MTMR14, however, causes at least three deleterious consequences: (1) the lethality in early embryogenesis in Drosophila; (2) a "jumpy" phenotype with apparently impaired motor functions; and (3) an association with a rare genetic disorder called centronuclear myopathy. The potential benefit of EDTP/MTMR14 downregulation is likely masked by the lethality or severe muscle defects due to ubiquitous loss of this gene. Here we show that flies carrying a heterozygous EDTP mutation had increased survivorship to prolonged anoxia; tissue-specific downregulation of EDTP in non-muscle tissues, particularly motoneurons, extended lifespan and improved survivorship to beta-amyloid peptides (Aβ42) and polyglutamine protein aggregates. These data highlight the significance of selective downregulation of EDTP in non-muscles for beneficial consequences. MTMR14 expression was evident in the hippocampus and cortex in C57BL/6 J and APP/PS1 mice. Compared with C57BL/6 J mice, APP/PS1 mice had reduced MTMR14 in the cortex. Hippocampal expression of MTMR14 was increased and plateaued at 9-17 months compared with 2-6 months in C57BL/6 J mice. Additionally, MTMR14 was inducible by Aβ42 in the rat primarily hippocampal neurons and mouse Neuro2a neuroblasts. We demonstrate a novel approach of tissue-specific downregulation of the disease-associated gene EDTP/MTMR14 for extended lifespan and improved survivorship to cellular protein aggregates. This approach could be extended from insects to mammals.
2018-11-23 | Differential physiological role of BIN1 isoforms in skeletal muscle development, function and regeneration
Abstract Skeletal muscle development and regeneration are tightly regulated processes. How the intracellular organization of muscle fibers is achieved during these steps is unclear. Here we focus on the cellular and physiological roles of amphiphysin 2 (BIN1), a membrane remodeling protein mutated in both congenital and adult centronuclear myopathies, that is ubiquitously expressed and has skeletal muscle-specific isoforms. We created and characterized constitutive, muscle-specific and inducible Bin1 homozygous and heterozygous knockout mice targeting either ubiquitous or muscle-specific isoforms. Constitutive Bin1 -deficient mice died at birth from lack of feeding due to a skeletal muscle defect. T-tubules and other organelles were misplaced and altered, supporting a general early role of BIN1 on intracellular organization in addition to membrane remodeling. Whereas restricted deletion of Bin1 in unchallenged adult muscles had no impact, the forced switch from the muscle-specific isoforms to the ubiquitous isoforms through deletion of the in-frame muscle–specific exon delayed muscle regeneration. Thus, BIN1 ubiquitous function is necessary for muscle development and function while its muscle-specific isoforms fine-tune muscle regeneration in adulthood, supporting that BIN1 centronuclear myopathy with congenital onset are due to developmental defects while later onset may be due to regeneration defects.
2016-09-13 | Reprogramming the Dynamin 2 mRNA by Spliceosome-mediated RNA Trans-splicing
Dynamin 2 (DNM2) is a large GTPase, ubiquitously expressed, involved in membrane trafficking and regulation of actin and microtubule cytoskeletons. DNM2 mutations cause autosomal dominant centronuclear myopathy which is a rare congenital myopathy characterized by skeletal muscle weakness and histopathological features including nuclear centralization in absence of regeneration. No curative treatment is currently available for the DNM2-related autosomal dominant centronuclear myopathy. In order to develop therapeutic strategy, we evaluated here the potential of Spliceosome-Mediated RNA Trans-splicing technology to reprogram the Dnm2-mRNA in vitro and in vivo in mice. We show that classical 3'-trans-splicing strategy cannot be considered as accurate therapeutic strategy regarding toxicity of the pre-trans-splicing molecules leading to low rate of trans-splicing in vivo. Thus, we tested alternative strategies devoted to prevent this toxicity and enhance frequency of trans-splicing events. We succeeded to overcome the toxicity through a 5'-trans-splicing strategy which also allows detection of trans-splicing events at mRNA and protein levels in vitro and in vivo. These results suggest that the Spliceosome-Mediated RNA Trans-splicing strategy may be used to reprogram mutated Dnm2-mRNA but highlight the potential toxicity linked to the molecular tools which have to be carefully investigated during preclinical development.
other
2026-05-08 | DNM2 lipid binding drives centronuclear myopathy and represents a potential therapeutic target.
Centronuclear myopathies (CNMs) are rare congenital disorders characterized by muscle weakness, fiber hypotrophy, and organelle mislocalization. Most cases arise from mutations in MTM1 or DNM2, encoding myotubularin and dynamin-2, respectively. DNM2 is a GTPase that binds lipids, oligomerizes around membranes, and mediates fission. We previously showed that DNM2 levels are elevated in MTM1-CNM patients and Mtm1-/y mice, and that normalizing DNM2 rescues disease phenotypes. However, the specific DNM2 functions driving pathology remain unclear. Here, we expressed AAV-delivered WT and DNM2 mutants in WT and Mtm1-/y mouse muscles to disrupt specific DNM2 molecular functions. In WT mice, overexpression of WT DNM2 and most mutants induced CNM-like phenotypes, including reduced force, fiber hypotrophy, and centralized nuclei, consistent with gain-of-function mechanisms. The lipid-binding-defective mutant K562E did not induce disease-like phenotype. In Mtm1-/y mice, K562E mutant markedly improved muscle force, mass, and fiber size, while others failed to rescue. Therefore, we generated Mtm1-/y Dnm2K562E/+ mice, which showed full rescue of survival, motor function, and muscle force, with improved muscle mass, fiber size, and organelle positioning despite persistently elevated DNM2 levels. This study reveals that DNM2 lipid binding, not protein abundance or GTPase activity, drives pathology, and represents the most rational therapeutic target for DNM2 therapy in MTM1-CNM.
2025-11-10 | Ca2+, ROS, IL-6, and p38 MAPK signaling loops underlying alterations in myotube formation induced by a severe MH/CCD mutation in RyR1.
Mutations in the gene encoding the skeletal muscle ryanodine receptor (RyR1) can result in muscle diseases, termed RyR1-related myopathies (RyR1-RM). Examples include malignant hyperthermia (MH), central core disease (CCD), and centronuclear myopathy (CNM). The muscles involved often have more (and mispositioned) nuclei than normal. A subset of the corresponding mutant proteins shows an overactive or leaky sarcoplasmic reticulum (SR) channel behavior that depletes the SR Ca2+ content and increases the level of cytosolic Ca2+. In addition, two remarkable effects of these RyR1 variants have been reported in cultured myogenic cells: enhanced expression of interleukin-6 (IL-6) and stimulation of myoblast fusion (myonuclei accretion). Here, we have investigated whether the latter effect is due to a possible IL-6-dependent autocrine loop. Toward this goal, we analyzed the impact of the overactive Y523S mutant compared with the wild-type RyR1 after expression in C2C12 cells. The results show that this mutation indeed drastically promotes myoblast fusion up to ∼300%. Moreover, this action depends on the sequential activation of SR Ca2+ release, store-operated Ca2+ channels, reactive oxygen species (ROS, cytosolic and mitochondrial), calpain, and calcineurin. In addition, a neutralizing antibody directed against IL-6 and a p38 inhibitor completely suppressed the stimulation of myoblast fusion. Furthermore, in RyR1-expressing cells, myotube formation was promoted by either exogenous IL-6 or conditioned medium obtained from the Y523S-expressing cells. These findings suggest an autocrine mechanism involving the interplay between Ca2+, ROS, IL-6, and p38 signaling pathways in controlling myonuclei density, which could be essential to explain the pathogenesis of RyR1-RM.NEW & NOTEWORTHY Overactive RyR1 mutant proteins are associated with muscle disease; interestingly, they increase the number of myonuclei when expressed in C2C12 cells. We discovered that this alteration depends on a Ca2+/ROS loop, which recruits calpain and calcineurin to stimulate the production of IL-6 and the subsequent autocrine activation of p38. Thus, disease-causing RyR1 mutations require an IL-6 autocrine system to alter myonuclear density. This novel mechanism could be critical to understanding the pathogenesis of congenital myopathies.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
2 orphan drug designations for Centronuclear myopathy.
2 orphan drug designations for Centronuclear myopathy.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
5¿-cEtG-sp-cEt5MeU-sp-cEt5MeU-sp-dT-sp-dA-sp-dT-sp-dT-sp-dA-sp-dT-sp-dA-sp-dG-sp-dG-sp-dG-sp-cEt5MeC-sp-cEt5MeU-sp-cEt5MeU-3¿ | oligonucleotides | FDA | Dynacure SAS | |
5'-cEtG-sp-cEt5MeU-sp-cEt5MeU-sp-dT-sp-dA-sp-dT-sp-dT-sp-dA-sp-dT-sp-dA-sp-dG-sp-dG-sp-dG-sp-cEt5MeC-sp-cEt5MeU-sp-cEt5MeU-3' | oligonucleotides | EMA | Dynacure S.A.S. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.