RARE DISEASE
Myofibrillar myopathy
Myofibrillar myopathy
Myofibrillar myopathy
Synonyms: MFM
Synonyms: MFM
Synonyms: MFM
Drug discovery
1
drug
With orphan designation
Overview
Myofibrillar myopathy (MFM) is a rare, genetically heterogeneous group of neuromuscular disorders characterized by progressive skeletal muscle weakness, cardiomyopathy, and pathological Z-disc disintegration with protein aggregates. Onset ranges from infancy to late adulthood, typically manifesting as distal or proximal weakness. Cardiac involvement (arrhythmias, cardiomyopathy) and respiratory insufficiency are major complications. Diagnosis relies on muscle biopsy showing desmin-positive aggregates and genetic testing (mutations in DES, MYOT, BAG3, and others) [1][9][16].
Burden
Progressive disability (30% require wheelchairs), high cardiovascular morbidity/mortality (60% pacemaker dependence), and respiratory failure.
Lifespan may normalize with early cardiac/respiratory intervention, but quality of life is significantly impacted by chronic disability and care needs [1][6][19].
Categories: rare genetic diseases, rare neurological diseases
Research Papers
149 drug discovery papers about Myofibrillar myopathy, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
149 drug discovery papers about Myofibrillar myopathy, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
cell therapies
2025-05-04 | Generation and characterization of a human induced pluripotent stem cell (iPSC) line from a patient with BAG3 P209L myofibrillar myopathy-6.
Bag3 is important for protein homeostasis in mechanically stressed muscle proteins as member of the chaperone-assisted selective autophagy (CASA) complex. Patients with BAG3P209L myofibrillar myopathy-6 (MFM6) carry a point mutation (p.P209L; c.626C>T) in the BAG3 gene and display clinical features such as restrictive cardiomyopathy, skeletal muscle dystrophy and polyneuropathy. To obtain a representative MFM6-model, biopsies from a female BAG3P209L-patient were used to generate a human induced pluripotent stem cell (iPSC) line. For quality control, germ layer differentiation and pluripotency analyses were conducted. This iPSC allows us to characterize the pathophysiology of MFM6 and develop innovative experimental therapeutic strategies.
2024-01-27 | Generation of two hiPSCs lines of two patients carrying truncating mutations in the dimerization domain of filamin C
Here we introduce the human induced pluripotent stem cell lines (hiPSCs), HIMRi004-A and HIMRi005-A from dermal fibroblasts of a 48-year-old female (HIMRi004-A) carrying missense mutation that translate to the first described filamin C isoform p.W2710X and from a 56-year-old female (HIMRi005-A) carrying a recently described mutation in the same domain p.Y2704X. Both lines are generated via lentiviral expression of OCT4, SOX2, KLF4 and c-MYC. The lines display a typical embryonic stem cell-like morphology, express pluripotency markers, retain a normal karyotype (46, XX) and have the differentiation capacity in all three germ layers. The two lines can be used to elucidate the pathomechanisms of FLNC myofibrillar myopathies and to develop novel therapeutic options.
2023-11-06 | Generation of a human iPSC line (HIMRi001-A) from a patient with filaminopathy.
Here we introduce the human induced pluripotent stem cell (hiPSC) line HIMRi001-A generated from cultured dermal fibroblasts of a 60-year-old male patient with a myofibrillar myopathy, carrying a heterozygous c.4984C > T [p.Q1662X] mutation in the filamin C (FLNC)-gene, via lentiviral expression of OCT4, SOX2, KLF4 and c-MYC. HIMRi001-A displays typical embryonic stem cell-like morphology, carries the c.4984C > T FLNC gene mutation, expressed several pluripotent stem cell makers, retained normal karyotype (46, XY) and holds the potential to differentiate in all three germ layers. We postulate that HIMRi001-A can be used for the elucidation of FLNC-associated pathomechanisms and for developing new therapeutic options.
2006-05-24 | Human macrophages rescue myoblasts and myotubes from apoptosis through a set of adhesion molecular systems
The mechanisms underlying stromal cell supportive functions are incompletely understood but probably implicate a mixture of cytokines, matrix components and cell adhesion molecules. Skeletal muscle uses recruited macrophages to support post-injury regeneration. We and others have previously shown that macrophages secrete mitogenic factors for myogenic cells. Here, we focused on macrophage-elicited survival signals. We demonstrated that: (1) macrophage influx is temporally correlated with the disappearance of TUNEL-positive apoptotic myogenic cells during post-injury muscle regeneration in mice; (2) direct cell-cell contacts between human macrophages and myogenic cells rescue myogenic cells from apoptosis, as assessed by decreased annexin V labelling and caspase-3 activity, and by increased DIOC-6 staining, Bcl-2 expression and phosphorylation of Akt and ERK1/2 survival pathways; (3) four pro-survival cell-cell adhesion molecular systems detected by DNA macroarray are expressed by macrophages and myogenic cells in vitro and in vivo - VCAM-1-VLA-4, ICAM-1-LFA-1, PECAM-1-PECAM-1 and CX3CL1-CX3CR1; (4) macrophages deliver anti-apoptotic signals through all four adhesion systems, as assessed by functional analyses with blocking antibodies; and (5) macrophages more strongly rescue differentiated myotubes, which must achieve adhesion-induced stabilisation of their structure to survive. Macrophages could secure these cells until they establish final association with the matrix.
1982-10-01 | Beneficial effects of transplanting normal limb‐bud mesenchyme into dystrophic mouse muscles
A new technique is being developed to remedy muscle weakness of hereditary myopathies. Mesenchymal cells dissected from limb-buds of day-12 normal mouse embryos were transplanted into the right solei of 20-day-old normal or dystrophic C56BL/6J-dy2J mice. Host and donors were immunocompatible. Unoperated left solei served as controls. Sham control solei receiving similar surgical treatment but no mesenchyme transplant did not differ from contralateral, unoperated solei. Six to seven months postoperatively the test solei (8 normal and 15 dystrophic) exhibited greater cross-sectional area, total fiber number, and twitch and tetanus tensions than their contralateral controls. Test dystrophic solei contained more normal-appearing and less abnormal-appearing fibers than their controls. Their mean fiber resting potential was intermediate between those of normal and dystrophic controls. There is no difference in twitch time course between test and control solei. The results indicate that such transplantation improves the structure and function of the dystrophic muscles.
proteins
2023-06-01 | Skeletal Muscle-Specific Bis Depletion Leads to Muscle Dysfunction and Early Death Accompanied by Impairment in Protein Quality Control
Bcl-2-interacting cell death suppressor (BIS), also called BAG3, plays a role in physiological functions such as anti-apoptosis, cell proliferation, autophagy, and senescence. Whole-body Bis-knockout (KO) mice exhibit early lethality accompanied by abnormalities in cardiac and skeletal muscles, suggesting the critical role of BIS in these muscles. In this study, we generated skeletal muscle-specific Bis-knockout (Bis-SMKO) mice for the first time. Bis-SMKO mice exhibit growth retardation, kyphosis, a lack of peripheral fat, and respiratory failure, ultimately leading to early death. Regenerating fibers and increased intensity in cleaved PARP1 immunostaining were observed in the diaphragm of Bis-SMKO mice, indicating considerable muscle degeneration. Through electron microscopy analysis, we observed myofibrillar disruption, degenerated mitochondria, and autophagic vacuoles in the Bis-SMKO diaphragm. Specifically, autophagy was impaired, and heat shock proteins (HSPs), such as HSPB5 and HSP70, and z-disk proteins, including filamin C and desmin, accumulated in Bis-SMKO skeletal muscles. We also found metabolic impairments, including decreased ATP levels and lactate dehydrogenase (LDH) and creatine kinase (CK) activities in the diaphragm of Bis-SMKO mice. Our findings highlight that BIS is critical for protein homeostasis and energy metabolism in skeletal muscles, suggesting that Bis-SMKO mice could be used as a therapeutic strategy for myopathies and to elucidate the molecular function of BIS in skeletal muscle physiology.
2019-05-03 | HspB1 phosphorylation regulates its intramolecular dynamics and mechanosensitive molecular chaperone interaction with filamin C
Mechanical force-induced conformational changes in proteins underpin a variety of physiological functions, typified in muscle contractile machinery. Mutations in the actin-binding protein filamin C (FLNC) are linked to musculoskeletal pathologies characterized by altered biomechanical properties and sometimes aggregates. HspB1, an abundant molecular chaperone, is prevalent in striated muscle where it is phosphorylated in response to cues including mechanical stress. We report the interaction and up-regulation of both proteins in three mouse models of biomechanical stress, with HspB1 being phosphorylated and FLNC being localized to load-bearing sites. We show how phosphorylation leads to increased exposure of the residues surrounding the HspB1 phosphosite, facilitating their binding to a compact multidomain region of FLNC proposed to have mechanosensing functions. Steered unfolding of FLNC reveals that its extension trajectory is modulated by the phosphorylated region of HspB1. This may represent a posttranslationally regulated chaperone-client protection mechanism targeting over-extension during mechanical stress.
2019-03-20 | Fibroblast growth factor 21 controls mitophagy and muscle mass
Abstract Background Skeletal muscle is a plastic tissue that adapts to changes in exercise, nutrition, and stress by secreting myokines and myometabolites. These muscle‐secreted factors have autocrine, paracrine, and endocrine effects, contributing to whole body homeostasis. Muscle dysfunction in aging sarcopenia, cancer cachexia, and diabetes is tightly correlated with the disruption of the physiological homeostasis at the whole body level. The expression levels of the myokine fibroblast growth factor 21 (FGF21) are very low in normal healthy muscles. However, fasting, ER stress, mitochondrial myopathies, and metabolic disorders induce its release from muscles. Although our understanding of the systemic effects of muscle‐derived FGF21 is exponentially increasing, the direct contribution of FGF21 to muscle function has not been investigated yet. Methods Muscle‐specific FGF21 knockout mice were generated to investigate the consequences of FGF21 deletion concerning skeletal muscle mass and force. To identify the mechanisms underlying FGF21‐dependent adaptations in skeletal muscle during starvation, the study was performed on muscles collected from both fed and fasted adult mice. In vivo overexpression of FGF21 was performed in skeletal muscle to assess whether FGF21 is sufficient per se to induce muscle atrophy. Results We show that FGF21 does not contribute to muscle homeostasis in basal conditions in terms of fibre type distribution, fibre size, and muscle force. In contrast, FGF21 is required for fasting‐induced muscle atrophy and weakness. The mass of isolated muscles from control‐fasted mice was reduced by 15–25% ( P < 0.05) compared with fed control mice. FGF21‐null muscles, however, were significantly protected from muscle loss and weakness during fasting. Such important protection is due to the maintenance of protein synthesis rate in knockout muscles during fasting compared with a 70% reduction in control‐fasted muscles ( P < 0.01), together with a significant reduction of the mitophagy flux via the regulation of the mitochondrial protein Bnip3. The contribution of FGF21 to the atrophy programme was supported by in vivo FGF21 overexpression in muscles, which was sufficient to induce autophagy and muscle loss by 15% ( P < 0.05). Bnip3 inhibition protected against FGF21‐dependent muscle wasting in adult animals ( P < 0.05). Conclusions FGF21 is a novel player in the regulation of muscle mass that requires the mitophagy protein Bnip3.
2016-05-20 | The Human 343delT HSPB5 Chaperone Associated with Early-onset Skeletal Myopathy Causes Defects in Protein Solubility
Mutations of HSPB5 (also known as CRYAB or αB-crystallin), a bona fide heat shock protein and molecular chaperone encoded by the HSPB5 (crystallin, alpha B) gene, are linked to multisystem disorders featuring variable combinations of cataracts, cardiomyopathy, and skeletal myopathy. This study aimed to investigate the pathological mechanisms involved in an early-onset myofibrillar myopathy manifesting in a child harboring a homozygous recessive mutation in HSPB5, 343delT. To study HSPB5 343delT protein dynamics, we utilize model cell culture systems including induced pluripotent stem cells derived from the 343delT patient (343delT/343delT) along with isogenic, heterozygous, gene-corrected control cells (WT KI/343delT) and BHK21 cells, a cell line lacking endogenous HSPB5 expression. 343delT/343delT and WT KI/343delT-induced pluripotent stem cell-derived skeletal myotubes and cardiomyocytes did not express detectable levels of 343delT protein, contributable to the extreme insolubility of the mutant protein. Overexpression of HSPB5 343delT resulted in insoluble mutant protein aggregates and induction of a cellular stress response. Co-expression of 343delT with WT prevented visible aggregation of 343delT and improved its solubility. Additionally, in vitro refolding of 343delT in the presence of WT rescued its solubility. We demonstrate an interaction between WT and 343delT both in vitro and within cells. These data support a loss-of-function model for the myopathy observed in the patient because the insoluble mutant would be unavailable to perform normal functions of HSPB5, although additional gain-of-function effects of the mutant protein cannot be excluded. Additionally, our data highlight the solubilization of 343delT by WT, concordant with the recessive inheritance of the disease and absence of symptoms in carrier individuals.
2015-05-11 | Rescue of αB Crystallin (HSPB5) Mutants Associated Protein Aggregation by Co-Expression of HSPB5 Partners
HSPB5 (also called αB-crystallin) is a ubiquitously expressed small heat shock protein. Mutations in HSPB5 have been found to cause cataract, but are also associated with a subgroup of myofibrillar myopathies. Cells expressing each of these HSPB5 mutants are characterized by the appearance of protein aggregates of primarily the mutant HSPB5. Like several members of the HSPB family, HSPB5 can form both homo-oligomeric and hetero-oligomeric complexes. Previous studies showed that co-expression of HSPB1 and HSPB8 can prevent the aggregation associated with the HSPB5 (R120G) mutant in cardiomyocytes and in transgenic mice. In this study, we systematically compared the effect of co-expression of each of the members of the human HSPB family (HSPB1-10) on the aggregation of three different HSPB5 mutants (R120G, 450 Δ A, 464 Δ CT). Of all members, co-expression of HSPB1, HSPB4 and HSPB5 itself, most effectively prevent the aggregation of these 3 HSPB5 mutants. HSPB6 and HSPB8 were also active but less, whilst the other 5 HSPB members were ineffective. Co-expression of Hsp70 did not reduce the aggregation of the HSPB5 mutants, suggesting that aggregate formation is most likely not related to a toxic gain of function of the mutants per se, but rather related to a loss of chaperone function of the oligomeric complexes containing the HSPB5 mutants (dominant negative effects). Our data suggest that the rescue of aggregation associated with the HSPB5 mutants is due to competitive incorporation of its partners into hetero-oligomers hereby negating the dominant negative effects of the mutant on the functioning of the hetero-oligomer.
small molecules
2026-07-06 | Unmasking Supervillin : SVIL haploinsufficiency causes hypertrophic cardiomyopathy by impairing mechanotransduction and cellular energetics
Abstract Background Rare heterozygous loss-of-function (LoF) variants in SVIL , encoding the Z-disk and costameric protein supervillin, have recently been identified as a cause of hypertrophic cardiomyopathy (HCM). Although supervillin is implicated in actin-dependent mechanotransduction, the mechanisms linking SVIL deficiency to cardiomyopathy remain poorly understood. Homozygous LoF cause a novel skeletal Myofibrillar Myopathy-10 (MFM-10) while heterozygous LoF cause HCM without skeletal myopathy. In this study we use a human model system to disentangle the LoF pathomechanism of the scaffolding protein supervillin in cardiomyocytes and its clinical implications. Methods Using CRISPR/Cas-9 we engineered a representative pathogenic LoF variant Q255X into an isogenic induced pluripotent stem cell (iPSC) line creating the heterozygous SVIL Q255X/+ and homozygous SVIL Q255X/Q255X cell lines. These lines were differentiated into iPSC-derived cardiomyocytes (iPSC-CMs) and cellular phenotypes were assessed using bulk RNA-sequencing, LC-MS proteomics, electrophysiological and calcium handling analyses, contractility measurements, sarcomere organization analysis, Seahorse metabolic flux assay, and pharmacological intervention with mavacamten. Results The Q255X variant resulted in SVIL haploinsufficiency at both RNA and protein levels with no evidence of a truncated protein. Compared with isogenic controls, SVIL Q255X/+ iPSC-CMs demonstrated action potential shortening, calcium transient elongation, sarcomeric disorganization and hypertrophy, and impaired mitochondrial respiration. Multi-omic analyses of SVIL Q255X/+ iPSC-CMs showed a profile of cellular stress and inflammation, hypertrophic and pro-fibrotic signalling, and a pseudohypoxic state driven by decreased respiration and a HIF-induced glycolytic shift. These abnormalities were not present in SVIL Q255X/Q255X cardiomyocytes, consistent with a relatively limited cardiac phenotype reported in homozygous variant carriers. Mavacamten improved sarcomeric disorganization and hypertrophy in SVIL Q255X/+ cells but did not rescue energetic compromise. Conclusions Pathogenic heterozygous SVIL LoF produces a distinct cellular phenotype characterized by impaired mechanotransduction, mitochondrial dysfunction, and maladaptive metabolic remodelling that promotes hypertrophic and pro-fibrotic signalling. These findings define a mechanistic basis for SVIL -associated cardiomyopathy and identify metabolic dysfunction as a potential therapeutic target beyond sarcomere-directed therapy. Clinical Perspective What Is New? SVIL haploinsufficiency causes HCM through a mechanism distinct from canonical sarcomeric disease, characterized by impaired mechanotransduction, mitochondrial dysfunction, and pseudohypoxia-driven metabolic remodeling. Heterozygous SVIL loss of function produces a substantially more severe cardiomyocyte phenotype than homozygous loss of function, providing a mechanistic explanation for the predominance of cardiac disease in heterozygous variant carriers. Mavacamten improves sarcomeric organization but does not restore impaired mitochondrial respiration, demonstrating that energetic dysfunction persists despite sarcomere-directed therapy. What Are the Clinical Implications? Our findings give functional evidence to support SVIL as a clinically relevant HCM disease gene and its inclusion in clinical genetic testing panels. These findings establish SVIL -associated cardiomyopathy as a mechanistically distinct form of HCM and offer insight into the pathomechanism of Z-disk and costameric HCM The persistence of mitochondrial dysfunction despite myosin inhibition suggests that drugs targeting mitochondrial bioenergetics may be a therapeutic strategy in patients with SVIL -associated cardiomyopathy.
2026-04-17 | Cure MFM13 and Drug Repurposing Strategies for Myofibrillar Myopathy Type 13
Myofibrillar Myopathy type 13 with Rimmed Vacuoles (MFM13), (OMIM#621078) is an ultra-rare disease caused by a frameshift mutation in the HSPB8 gene. This mutation produces an abnormal HSPB8 protein with an elongated C-terminal tail, leading to toxic gain-of-function, promoting protein aggregation and autophagy impartment with muscle weakness phenotype. Currently, there are no approved treatments, and awareness of the disease remains limited. To address this critical gap, Cure MFM13 was established, as the first and only charitable initiative dedicated exclusively to this disease. Our mission is to improve the lives of all individuals affected by MFM13 by accelerating therapeutic development, advocating for patients, and building a global and empowered community. We are currently focused on drug repurposing screening. We have developed several cellular models, including patient-derived fibroblasts and iPSCs. Because selecting the most appropriate cell model is critical to repurposing project success, we conducted extensive research on the use of C2C12 murine myoblasts and primary human myoblasts in studies of autophagy and muscle-related diseases. In addition, we are generating multiple research tools for the scientific community. Since the mutant HSPB8 protein differs structurally from the wild-type form, we developed a mutation-specific antibody targeting the frameshift variant (c.515dupC). To further accelerate progress, we are developing mouse model which next will be under investigation at a Czech Centre for Phenogenomics (CCP) in preparation for future preclinical testing. At this stage, key questions remain: What is the most appropriate model for drug repurposing, considering that MFM13 is a slow-progressing, adult-onset, autophagy and muscle-related disease? Which assays best show the efficacy of candidate small molecules? And strategically, where to find collaborators and where to look for additional funding?
2025-10-15 | Novel truncating Desmin mutation Arg150Stop disrupts structural integrity and cellular homeostasis by formation of persistent aggregate-like structure
Abstract Desminopathies are a heterogeneous group of myofibrillar myopathies defined by the presence of desmin-positive aggregates that compromise cytoskeletal integrity in skeletal and cardiac muscle. Although desmin knockout models and several truncating mutations typically result in a functional null phenotype without inclusion body formation, the molecular consequences of specific stop-gain variants remain poorly understood. In this study, we investigated the pathogenic mechanism of a novel DES nonsense mutation, NM_001927.4:c.448C>T; p.(Arg150Stop), previously identified in an Indian patient with congenital myopathy. This premature stop codon lies within the Linker 1A domain and is predicted to generate a truncated protein lacking the C-terminal tail. To delineate its functional consequences, we used two complementary experimental approaches: transient overexpression of the R150X mutant in skeletal and cardiac myocytes, and a CRISPR/Cas9-engineered homozygous R150X cardiomyocyte line (Des-R150X-CRISPR). Both models consistently revealed the formation of persistent aggregate-like structures, in striking contrast to desmin knockout systems that do not generate inclusions. These aggregate-like structures disrupted actin filament organization, impaired filament bundling, and induced organelle mislocalization. Biochemical analysis indicated that the aggregates were resistant to proteasomal degradation, yet they were partially cleared by autophagy, underscoring a role for protein quality control pathways in modulating disease severity. Importantly, the Des-R150X-CRISPR line demonstrated aggregate-driven pathology at endogenous levels, confirming that this mutation acts through a toxic gain-of-function mechanism rather than simple loss of desmin function. Our findings establish the Arg150Stop variant as a mechanistically distinct truncating mutation that generates aggregation-prone protein rather than a null state. By reproducing hallmark features of desminopathy in a physiologically relevant human cell models, this work not only broadens the known pathogenic spectrum of DES variants but also highlights aggregate formation as a central driver of cellular dysfunction and a promising therapeutic target in desminopathies.
2025-06-09 | Myofibrillar myopathy: towards a mechanism-based definition as a Z-disk-opathy.
Myofibrillar myopathies (MFMs) are traditionally defined by histopathology, but recent genetic discoveries have broadened the spectrum of causative genes beyond Z-disk components. This review aims to address the resulting terminological inconsistency by proposing a refined, mechanism-based definition of MFM centered on its identity as a "Z-disk-opathy." This re-evaluation is timely and relevant for improving diagnostic clarity and guiding future research. The literature increasingly reports MFM-like pathology in conditions caused by mutations in genes not directly encoding Z-disk structural proteins or their interacting chaperones. This review highlights the pathogenic mechanisms distinguishing true MFMs, which involve disruption of Z-disk protein structure or Z-disk protein homeostasis, from "myopathies with MFM pathology" that share histological features but stem from different molecular etiologies. Key themes include the dominant nature of mutations in Z-disk structural proteins and the critical role of chaperone dysfunction in MFM pathogenesis. A refined definition classifying MFM as a "Z-disk-opathy" offers a clearer framework for diagnosis and mechanistic understanding. This distinction has significant implications for clinical practice, facilitating more accurate diagnosis, and for research, by supporting the development of targeted therapeutic strategies aimed at either restoring Z-disk proteostasis or mitigating the effects of aberrant protein accumulation.
2025-04-17 | Mitochondrial dysfunction is driven by imbalanced fission and fusion of mitochondria in myofibrillar myopathy type 5.
Myofibrillar myopathy type 5 (MFM5) is a dominantly inherited myopathy caused by mutations in the FLNC gene. The underlying pathogenic mechanisms of MFM5 remain unclear, and there are currently no effective treatments available. This study hypothesizes that mitochondrial dysfunction plays a key role in the pathogenesis of MFM5, on the basis of the COX-negative fibres observed in MFM5 patients. To test this hypothesis, a zebrafish model was developed to explore the impact of filamin-C on mitochondrial dynamics. These results demonstrated that defects in filamin-C disrupt mitochondrial fission, leading to mitochondrial dysfunction and mitophagy. This hypothesis was further validated through the analysis of skeletal muscle samples from MFM5 patients. These findings suggest that mitochondrial dysfunction caused by imbalanced fission and fusion of mitochondria and mitophagy contributes to MFM5 pathology. Importantly, this study identified potential therapeutic targets for MFM5 treatment, opening avenues for future research aimed at developing targeted interventions.
gene therapies
2026-07-02 | AAV-Delivered RNAi Targeting Mutant LDB3 Prevents and Reverses Myofibrillar Myopathy through Mechanosignaling Restoration.
The autosomal dominant p.Ala165Val mutation in LIM Domain Binding Protein 3 (LDB3) causes myofibrillar myopathy marked by Z-disc disruption, accumulation of filamin-C (FLNc) and chaperone proteins, and progressive muscle weakness. We previously showed that this mutation interferes with the LDB3-protein kinase C alpha (PKCα)-FLNc mechanosensing axis and impairs chaperone-assisted selective autophagy (CASA), establishing a gain-of-function mechanism. In this study, we examined whether mutant allele-specific knockdown could reverse the disease or mitigate disease progression in-vivo. A single intramuscular-injection of an AAV9-delivered microRNA-based shRNA produced substantial knockdown of mutant Ldb3 transcripts and protein in Ldb3 Ala165Val/+ knock-in mice treated either before or after the onset of pathology. Treatment after disease onset reduced filamin-C and CASA protein aggregates and improved muscle strength, whereas early intervention prevented development of molecular and histological features of myopathy. Phosphoproteomic profiling further showed broad remodeling of dysregulated phosphorylation networks, including restoration of PKCα-responsive sites and normalization of altered sarcomeric and cytoskeletal signaling observed in Ldb3 Ala165Val/+ mice. These findings identify disruption of the LDB3-PKCα-FLNc mechanosensing pathway as a central disease driver and suggest that restoring this signaling axis may complement mutant allele-specific RNA interference (RNAi). Overall, our results support RNAi as a promising therapeutic strategy for dominant LDB3-related myofibrillar myopathy.
2026-06-26 | A Novel Variant in the Desmin Gene: Case Report
Desminopathies are rare myofibrillar myopathies caused by variants in the desmin (DES) gene on chromosome 2q35, encoding the protein desmin. These variants, typically autosomal dominant missense, result in diverse clinical phenotypes, including progressive skeletal myopathy and cardiac involvement. Over 180 pathogenic variants and 700 variants of uncertain significance have been reported. We describe a 46-year-old male with progressive distal and proximal muscle weakness since age 30, functional impairment, and intermittent dysphagia. There was no family history or respiratory involvement. Electromyography demonstrated a myopathic pattern, and muscle biopsy revealed desmin- positive aggregates. The patient had a prior syncopal episode with minor chronic electrocardiographic abnormalities, suggesting possible cardiac involvement. Whole exome sequencing identified a novel heterozygous DES variant, c.1327_1328delinsTT, p.(Lys443Leu). The combined clinical, electrophysiological, and histopathological findings strongly support the likely pathogenicity of the identified variant. This case expands the spectrum of DES variants and highlights the importance of multidisciplinary evaluation.
2026-05-15 | Autophagy activation via BAG3 gene therapy improves phenotype in a mouse model of LGMD1A.
Myofibrillar myopathies (MFMs) are a group of protein aggregate diseases characterized by abnormal protein aggregations and myofibrillar disintegration. Myotilinopathy, also named MFM3 or limb-girdle muscular dystrophy type 1A (LGMD1A), is caused by myotilin mutations. Myotilin is degraded by the ubiquitin-proteasome system; however, when this pathway is overloaded under pathophysiological conditions, the protein quality control system leans on the autophagy-lysosome pathway (ALP) to mediate degradation of aggregates. BCL2-associated athanogene 3 (BAG3) protein facilitates aggresome formation and initiates ALP. In this study, we assessed our strategy of reducing the aggregate burden in muscle by overexpressing human BAG3 in TgT57I mice, a model for LGMD1A. Overexpression was achieved by systemic delivery of AAVrh74.tMCK.hBAG3, and outcome measures included functional, histological, and molecular studies. The hBAG3-treated cohort demonstrated increased rotarod duration, treadmill running distance, grip strength, and maximum tetanic response compared to the untreated cohort. Myotilin aggregate burden was significantly decreased, and autophagy levels were normalized in the treated group. As an adaptive response, hBAG3 normalized the endogenous Bag1/Bag3 ratio to that of 3-month-old TgT57I mice. This study provides evidence that our strategy of reducing the aggregate burden in muscle by overexpressing BAG3 may be used as a treatment for protein aggregate myopathies.
2026-04-15 | Profile of Inherited Neuromuscular and Movement Disorders Among Filipinos: A Referral Single-Center Retrospective Study
Background: Neuromuscular and movement disorders comprise a heterogeneous group of acquired and inherited conditions affecting the motor unit and central movement pathways. Genetic data from underserved populations, including Filipinos, remain limited, highlighting the need for population-specific characterization. Objective: To characterize inherited neuromuscular and movement disorders among Filipinos and determine the diagnostic yield and genetic spectrum using next-generation sequencing (NGS). Methods: This referral single-center retrospective study reviewed Filipino patients who underwent genetic testing for suspected inherited neuromuscular and movement disorders. Variants were classified according to the American College of Medical Genetics and Genomics (ACMG) criteria. Results: Among 85 patients, 24 (28.2%) had pathogenic/likely pathogenic variants, 33 (38.8%) had variants of uncertain significance (VUS) and 28 (32.9%) were negative. Confirmed diagnoses included pediatric cases of limb-girdle muscular dystrophy, Duchenne muscular dystrophy, spinal muscular atrophy and GNE-related myopathy, and adult cases with myofibrillar myopathy, spinocerebellar ataxia and amyotrophic lateral sclerosis. Pathogenic variants involved 26 genes, most commonly SMN1. Conclusion: This NGS-based characterization of inherited neuromuscular and movement disorders in Filipinos showed 28% diagnostic yield and a spectrum comparable to other Asian cohorts. The high rate of VUS underscores the need for family segregation studies and careful genotype–phenotype correlation. This study highlights the critical role of genetic testing in accurate diagnosis and targeted management to improve outcomes for patients with these rare disorders.
2026-04-12 | Blockage of autophagy causes severe skeletal muscle disruption in a mouse model for myofibrillar myopathy 6.
Myofibrillar myopathy 6 is a rare, autosomal-dominant neuromuscular disorder caused by an amino acid exchange Pro209Leu in the co-chaperone BAG3, which disrupts muscle protein turnover and causes severe muscle weakness and shortened lifespan. We generated transgenic mice overexpressing the human mutant BAG3P209L-GFP, which rapidly develop skeletal muscle weakness unlike controls expressing BAG3WT-GFP. Here we show that mutant mice exhibit sarcomere breakdown, inflammation, protein aggregates, centralized nuclei and mitochondrial defects in their skeletal muscles, thereby reducing contraction force by ~90%. Omics profiling uncovered impaired protein synthesis, blocked autophagy, impaired mitophagy and loss of sarcomere proteins. Pathway modulation in vitro and in vivo showed autophagy dysfunction as the primary driver for the pathology, while BAG3 knockdown gene therapy markedly restored muscle function in vivo. In summary, this model recapitulates core disease features, revealing how BAG3 aggregates and loss of BAG3 function impair autophagy to drive muscle degeneration.
other
2023-10-01 | P164 Development of a myotube model for C-terminal titin studies
Mutations in the extreme C-terminal part of titin cause myopathies with different clinical pictures and modes of inheritance. The most common of these is tibial muscular dystrophy (TMD), a dominant adult-onset distal myopathy. Other diseases caused by C-terminal titin mutations are juvenile-onset recessive distal titinopathy, and the severe recessive limb-girdle muscular dystrophy R10 (LGMDR10). The genotype–phenotype correlation of the mutations is, however, complex and not fully understood. The TMD-causing mutations lead to a secondary proteolytic cleavage of the mutant titin C-terminus, and we believe that the propensity of the mutant protein to this cleavage event may explain the variable effects of the mutations. The large size of titin poses challenges to functional studies on titin mutations in the sarcomeric context. To overcome these limitations, we are developing a novel myotube model, C2C12-CTE (C-Terminal Titin Exchange), based on C2C12 mouse myoblasts. Heterospecific lox sites were introduced flanking the last Ttn exons in C2C12 genome using the Cytosurge CellEDIT technology. Transfection of these C2C12-CTE master cells with the Cre recombinase and a donor plasmid drives replacement of the targeted Ttn region with genetic material from the donor construct through recombinase-mediated cassette exchange (RMCE), allowing quick and economical introduction of modifications such as mutations or tags to C-terminal titin. The recombinant cells are selected using positive (G418 resistance) and negative (ganciclovir sensitivity) selection strategies and used as polyclonal pools for myotube differentiation. We expect this system to provide a valuable tool for characterizing the pathological cleavage of mutant titin and other effects of titinopathy mutations, as well as for other studies on C-terminal titin. Mutations in the extreme C-terminal part of titin cause myopathies with different clinical pictures and modes of inheritance. The most common of these is tibial muscular dystrophy (TMD), a dominant adult-onset distal myopathy. Other diseases caused by C-terminal titin mutations are juvenile-onset recessive distal titinopathy, and the severe recessive limb-girdle muscular dystrophy R10 (LGMDR10). The genotype–phenotype correlation of the mutations is, however, complex and not fully understood. The TMD-causing mutations lead to a secondary proteolytic cleavage of the mutant titin C-terminus, and we believe that the propensity of the mutant protein to this cleavage event may explain the variable effects of the mutations. The large size of titin poses challenges to functional studies on titin mutations in the sarcomeric context. To overcome these limitations, we are developing a novel myotube model, C2C12-CTE (C-Terminal Titin Exchange), based on C2C12 mouse myoblasts. Heterospecific lox sites were introduced flanking the last Ttn exons in C2C12 genome using the Cytosurge CellEDIT technology. Transfection of these C2C12-CTE master cells with the Cre recombinase and a donor plasmid drives replacement of the targeted Ttn region with genetic material from the donor construct through recombinase-mediated cassette exchange (RMCE), allowing quick and economical introduction of modifications such as mutations or tags to C-terminal titin. The recombinant cells are selected using positive (G418 resistance) and negative (ganciclovir sensitivity) selection strategies and used as polyclonal pools for myotube differentiation. We expect this system to provide a valuable tool for characterizing the pathological cleavage of mutant titin and other effects of titinopathy mutations, as well as for other studies on C-terminal titin.
2020-11-02 | Genetic compensation prevents myopathy and heart failure in an in vivo model of Bag3 deficiency
Mutations in the molecular co-chaperone Bcl2-associated athanogene 3 (BAG3) are found to cause dilated cardiomyopathy (DCM), resulting in systolic dysfunction and heart failure, as well as myofibrillar myopathy (MFM), which is characterized by protein aggregation and myofibrillar disintegration in skeletal muscle cells. Here, we generated a CRISPR/Cas9-induced Bag3 knockout zebrafish line and found the complete preservation of heart and skeletal muscle structure and function during embryonic development, in contrast to morpholino-mediated knockdown of Bag3. Intriguingly, genetic compensation, a process of transcriptional adaptation which acts independent of protein feedback loops, was found to prevent heart and skeletal muscle damage in our Bag3 knockout model. Proteomic profiling and quantitative real-time PCR analyses identified Bag2, another member of the Bag protein family, significantly upregulated on a transcript and protein level in bag3-/- mutants. This implied that the decay of bag3 mutant mRNA in homozygous bag3-/- embryos caused the transcriptional upregulation of bag2 expression. We further demonstrated that morpholino-mediated knockdown of Bag2 in bag3-/- embryos evoked severe functional and structural heart and skeletal muscle defects, which are similar to Bag3 morphants. However, Bag2 knockdown in bag3+/+ or bag3+/- embryos did not result in (cardio-)myopathy. Finally, we found that inhibition of the nonsense-mediated mRNA decay (NMD) machinery by knockdown of upf1, an essential NMD factor, caused severe heart and skeletal muscle defects in bag3-/- mutants due to the blockade of transcriptional adaptation of bag2 expression. Our findings provide evidence that genetic compensation might vitally influence the penetrance of disease-causing bag3 mutations in vivo.
2020-01-17 | Ppp1r1b-lncRNA inhibits PRC2 at myogenic regulatory genes to promote cardiac and skeletal muscle development in mouse and human
Long noncoding RNAs (lncRNAs) have emerged as critical epigenetic regulators and play important roles in cardiac development and congenital heart disease. In a previous study, we identified a novel lncRNA, Ppp1r1b, with expression highly correlated with myogenesis. However, the molecular mechanism that underlies Ppp1r1b-lncRNA function in myogenic regulation is unknown. By silencing Ppp1r1b-lncRNA, mouse C2C12 and human skeletal myoblasts failed to develop fully differentiated myotubes. Myogenic differentiation was also impaired in PPP1R1B-lncRNA deficient human-induced pluripotent stem cell-derived cardiomyocytes (hiPSCs-CMs). The expression of myogenic transcription factors, including MyoD, Myogenin, and Tbx5, as well as sarcomere proteins, was significantly suppressed in Ppp1r1b-lncRNA inhibited myoblast cells and neonatal mouse heart. Histone modification analysis revealed increased H3K27 tri-methylation at MyoD1 and Myogenin promoters in GapmeR treated C2C12 cells. Furthermore, Ppp1r1b-lncRNA was found to bind to Ezh2, and chromatin isolation by RNA purification (ChIRP) assay revealed enriched interaction of Ppp1r1b-lncRNA with Myod1 and Tbx5 promoters, suggesting that Ppp1r1b-lncRNA induces transcription of myogenic transcription factors by interacting with the polycomb repressive complex 2 (PRC2) at the chromatin interface. Correspondingly, the silencing of Ppp1r1b-lncRNA increased EZH2 binding at promoter regions of myogenic transcription factors. Therefore, our results suggest that Ppp1r1b-lncRNA promotes myogenic differentiation through competing for PRC2 binding with chromatin of myogenic master regulators during heart and skeletal muscle development.
2016-04-01 | Myosin heavy chain is stabilized by BCL-2 interacting cell death suppressor (BIS) in skeletal muscle
BCL-2 interacting cell death suppressor (BIS), which is ubiquitously expressed, has important roles in various cellular processes, such as apoptosis, the cellular stress response, migration and invasion and protein quality control. In particular, BIS is highly expressed in skeletal and cardiac muscles, and BIS gene mutations result in human myopathy. In this study, we show that mRNA and protein levels of BIS were markedly increased during skeletal myogenesis in C2C12 cells and mouse satellite cells. BIS knockdown did not prevent the early stage of skeletal myogenesis, but did induce muscle atrophy and a decrease in the diameter of myotubes. BIS knockdown significantly suppressed the expression level of myosin heavy chain (MyHC) without changing the expression levels of myogenic marker proteins, such as Mgn, Cav-3 and MG53. In addition, BIS endogenously interacted with MyHC, and BIS knockdown induced MyHC ubiquitination and degradation. From these data, we conclude that molecular association of MyHC and BIS is necessary for MyHC stabilization in skeletal muscle. The protein known as BCL-2 interacting cell death suppressor (BIS) is essential for the formation and maintenance of skeletal muscle. Mutations in the gene for BIS have previously been linked to muscle dysfunction in humans, but the mechanism of the protein's effect was unclear. Jeong-Hwa Lee and colleagues at The Catholic University of Korea, with co-workers elsewhere in South Korea, used genetic studies on mouse muscle cells to investigate the role of BIS. Their results reveal a direct link between BIS and the heavy chain of the protein myosin, an essential component of muscle fibers. BIS binds to and stabilizes the myosin, protecting it from being degraded by cell turnover processes. Modifying the activity of the gene that codes for BIS might offer a new approach for treating various muscle diseases.
2014-02-18 | Novel excitation-contraction coupling related genes reveal aspects of muscle weakness beyond atrophy—new hopes for treatment of musculoskeletal diseases
Research over the last decade strengthened the understanding that skeletal muscles are not only the major tissue in the body from a volume point of view but also function as a master regulator contributing to optimal organismal health. These new contributions to the available body of knowledge triggered great interest in the roles of skeletal muscle beyond contraction. The World Health Organization, through its Global Burden of Disease (GBD) report, recently raised further awareness about the key importance of skeletal muscles as the GDB reported musculoskeletal (MSK) diseases have become the second greatest cause of disability, with more than 1.7 billion people in the globe affected by a diversity of MSK conditions. Besides their role in MSK disorders, skeletal muscles are also seen as principal metabolic organs with essential contributions to metabolic disorders, especially those linked to physical inactivity. In this review, we have focused on the unique function of new genes/proteins (i.e. MTMR14, MG29, sarcalumenin, KFL15) that during the last few years have helped provide novel insights about muscle function in health and disease, muscle fatigue, muscle metabolism, and muscle aging. Next, we provide an in depth discussion of how these genes/proteins converge into a common function of acting as regulators of intracellular calcium homeostasis. A clear link between dysfunctional calcium homeostasis is established and the special role of store-operated calcium entry is analyzed. The new knowledge that has been generated by the understanding of the roles of previously unknown modulatory genes of the skeletal muscle excitation-contraction coupling (ECC) process brings exciting new possibilities for treatment of MSK diseases, muscle regeneration, and skeletal muscle tissue engineering. The next decade of skeletal muscle and MSK research is bound to bring to fruition applied knowledge that will hopefully offset the current heavy and sad burden of MSK diseases on the
cell therapies
2025-05-04 | Generation and characterization of a human induced pluripotent stem cell (iPSC) line from a patient with BAG3 P209L myofibrillar myopathy-6.
Bag3 is important for protein homeostasis in mechanically stressed muscle proteins as member of the chaperone-assisted selective autophagy (CASA) complex. Patients with BAG3P209L myofibrillar myopathy-6 (MFM6) carry a point mutation (p.P209L; c.626C>T) in the BAG3 gene and display clinical features such as restrictive cardiomyopathy, skeletal muscle dystrophy and polyneuropathy. To obtain a representative MFM6-model, biopsies from a female BAG3P209L-patient were used to generate a human induced pluripotent stem cell (iPSC) line. For quality control, germ layer differentiation and pluripotency analyses were conducted. This iPSC allows us to characterize the pathophysiology of MFM6 and develop innovative experimental therapeutic strategies.
2024-01-27 | Generation of two hiPSCs lines of two patients carrying truncating mutations in the dimerization domain of filamin C
Here we introduce the human induced pluripotent stem cell lines (hiPSCs), HIMRi004-A and HIMRi005-A from dermal fibroblasts of a 48-year-old female (HIMRi004-A) carrying missense mutation that translate to the first described filamin C isoform p.W2710X and from a 56-year-old female (HIMRi005-A) carrying a recently described mutation in the same domain p.Y2704X. Both lines are generated via lentiviral expression of OCT4, SOX2, KLF4 and c-MYC. The lines display a typical embryonic stem cell-like morphology, express pluripotency markers, retain a normal karyotype (46, XX) and have the differentiation capacity in all three germ layers. The two lines can be used to elucidate the pathomechanisms of FLNC myofibrillar myopathies and to develop novel therapeutic options.
2023-11-06 | Generation of a human iPSC line (HIMRi001-A) from a patient with filaminopathy.
Here we introduce the human induced pluripotent stem cell (hiPSC) line HIMRi001-A generated from cultured dermal fibroblasts of a 60-year-old male patient with a myofibrillar myopathy, carrying a heterozygous c.4984C > T [p.Q1662X] mutation in the filamin C (FLNC)-gene, via lentiviral expression of OCT4, SOX2, KLF4 and c-MYC. HIMRi001-A displays typical embryonic stem cell-like morphology, carries the c.4984C > T FLNC gene mutation, expressed several pluripotent stem cell makers, retained normal karyotype (46, XY) and holds the potential to differentiate in all three germ layers. We postulate that HIMRi001-A can be used for the elucidation of FLNC-associated pathomechanisms and for developing new therapeutic options.
2006-05-24 | Human macrophages rescue myoblasts and myotubes from apoptosis through a set of adhesion molecular systems
The mechanisms underlying stromal cell supportive functions are incompletely understood but probably implicate a mixture of cytokines, matrix components and cell adhesion molecules. Skeletal muscle uses recruited macrophages to support post-injury regeneration. We and others have previously shown that macrophages secrete mitogenic factors for myogenic cells. Here, we focused on macrophage-elicited survival signals. We demonstrated that: (1) macrophage influx is temporally correlated with the disappearance of TUNEL-positive apoptotic myogenic cells during post-injury muscle regeneration in mice; (2) direct cell-cell contacts between human macrophages and myogenic cells rescue myogenic cells from apoptosis, as assessed by decreased annexin V labelling and caspase-3 activity, and by increased DIOC-6 staining, Bcl-2 expression and phosphorylation of Akt and ERK1/2 survival pathways; (3) four pro-survival cell-cell adhesion molecular systems detected by DNA macroarray are expressed by macrophages and myogenic cells in vitro and in vivo - VCAM-1-VLA-4, ICAM-1-LFA-1, PECAM-1-PECAM-1 and CX3CL1-CX3CR1; (4) macrophages deliver anti-apoptotic signals through all four adhesion systems, as assessed by functional analyses with blocking antibodies; and (5) macrophages more strongly rescue differentiated myotubes, which must achieve adhesion-induced stabilisation of their structure to survive. Macrophages could secure these cells until they establish final association with the matrix.
1982-10-01 | Beneficial effects of transplanting normal limb‐bud mesenchyme into dystrophic mouse muscles
A new technique is being developed to remedy muscle weakness of hereditary myopathies. Mesenchymal cells dissected from limb-buds of day-12 normal mouse embryos were transplanted into the right solei of 20-day-old normal or dystrophic C56BL/6J-dy2J mice. Host and donors were immunocompatible. Unoperated left solei served as controls. Sham control solei receiving similar surgical treatment but no mesenchyme transplant did not differ from contralateral, unoperated solei. Six to seven months postoperatively the test solei (8 normal and 15 dystrophic) exhibited greater cross-sectional area, total fiber number, and twitch and tetanus tensions than their contralateral controls. Test dystrophic solei contained more normal-appearing and less abnormal-appearing fibers than their controls. Their mean fiber resting potential was intermediate between those of normal and dystrophic controls. There is no difference in twitch time course between test and control solei. The results indicate that such transplantation improves the structure and function of the dystrophic muscles.
proteins
2023-06-01 | Skeletal Muscle-Specific Bis Depletion Leads to Muscle Dysfunction and Early Death Accompanied by Impairment in Protein Quality Control
Bcl-2-interacting cell death suppressor (BIS), also called BAG3, plays a role in physiological functions such as anti-apoptosis, cell proliferation, autophagy, and senescence. Whole-body Bis-knockout (KO) mice exhibit early lethality accompanied by abnormalities in cardiac and skeletal muscles, suggesting the critical role of BIS in these muscles. In this study, we generated skeletal muscle-specific Bis-knockout (Bis-SMKO) mice for the first time. Bis-SMKO mice exhibit growth retardation, kyphosis, a lack of peripheral fat, and respiratory failure, ultimately leading to early death. Regenerating fibers and increased intensity in cleaved PARP1 immunostaining were observed in the diaphragm of Bis-SMKO mice, indicating considerable muscle degeneration. Through electron microscopy analysis, we observed myofibrillar disruption, degenerated mitochondria, and autophagic vacuoles in the Bis-SMKO diaphragm. Specifically, autophagy was impaired, and heat shock proteins (HSPs), such as HSPB5 and HSP70, and z-disk proteins, including filamin C and desmin, accumulated in Bis-SMKO skeletal muscles. We also found metabolic impairments, including decreased ATP levels and lactate dehydrogenase (LDH) and creatine kinase (CK) activities in the diaphragm of Bis-SMKO mice. Our findings highlight that BIS is critical for protein homeostasis and energy metabolism in skeletal muscles, suggesting that Bis-SMKO mice could be used as a therapeutic strategy for myopathies and to elucidate the molecular function of BIS in skeletal muscle physiology.
2019-05-03 | HspB1 phosphorylation regulates its intramolecular dynamics and mechanosensitive molecular chaperone interaction with filamin C
Mechanical force-induced conformational changes in proteins underpin a variety of physiological functions, typified in muscle contractile machinery. Mutations in the actin-binding protein filamin C (FLNC) are linked to musculoskeletal pathologies characterized by altered biomechanical properties and sometimes aggregates. HspB1, an abundant molecular chaperone, is prevalent in striated muscle where it is phosphorylated in response to cues including mechanical stress. We report the interaction and up-regulation of both proteins in three mouse models of biomechanical stress, with HspB1 being phosphorylated and FLNC being localized to load-bearing sites. We show how phosphorylation leads to increased exposure of the residues surrounding the HspB1 phosphosite, facilitating their binding to a compact multidomain region of FLNC proposed to have mechanosensing functions. Steered unfolding of FLNC reveals that its extension trajectory is modulated by the phosphorylated region of HspB1. This may represent a posttranslationally regulated chaperone-client protection mechanism targeting over-extension during mechanical stress.
2019-03-20 | Fibroblast growth factor 21 controls mitophagy and muscle mass
Abstract Background Skeletal muscle is a plastic tissue that adapts to changes in exercise, nutrition, and stress by secreting myokines and myometabolites. These muscle‐secreted factors have autocrine, paracrine, and endocrine effects, contributing to whole body homeostasis. Muscle dysfunction in aging sarcopenia, cancer cachexia, and diabetes is tightly correlated with the disruption of the physiological homeostasis at the whole body level. The expression levels of the myokine fibroblast growth factor 21 (FGF21) are very low in normal healthy muscles. However, fasting, ER stress, mitochondrial myopathies, and metabolic disorders induce its release from muscles. Although our understanding of the systemic effects of muscle‐derived FGF21 is exponentially increasing, the direct contribution of FGF21 to muscle function has not been investigated yet. Methods Muscle‐specific FGF21 knockout mice were generated to investigate the consequences of FGF21 deletion concerning skeletal muscle mass and force. To identify the mechanisms underlying FGF21‐dependent adaptations in skeletal muscle during starvation, the study was performed on muscles collected from both fed and fasted adult mice. In vivo overexpression of FGF21 was performed in skeletal muscle to assess whether FGF21 is sufficient per se to induce muscle atrophy. Results We show that FGF21 does not contribute to muscle homeostasis in basal conditions in terms of fibre type distribution, fibre size, and muscle force. In contrast, FGF21 is required for fasting‐induced muscle atrophy and weakness. The mass of isolated muscles from control‐fasted mice was reduced by 15–25% ( P < 0.05) compared with fed control mice. FGF21‐null muscles, however, were significantly protected from muscle loss and weakness during fasting. Such important protection is due to the maintenance of protein synthesis rate in knockout muscles during fasting compared with a 70% reduction in control‐fasted muscles ( P < 0.01), together with a significant reduction of the mitophagy flux via the regulation of the mitochondrial protein Bnip3. The contribution of FGF21 to the atrophy programme was supported by in vivo FGF21 overexpression in muscles, which was sufficient to induce autophagy and muscle loss by 15% ( P < 0.05). Bnip3 inhibition protected against FGF21‐dependent muscle wasting in adult animals ( P < 0.05). Conclusions FGF21 is a novel player in the regulation of muscle mass that requires the mitophagy protein Bnip3.
2016-05-20 | The Human 343delT HSPB5 Chaperone Associated with Early-onset Skeletal Myopathy Causes Defects in Protein Solubility
Mutations of HSPB5 (also known as CRYAB or αB-crystallin), a bona fide heat shock protein and molecular chaperone encoded by the HSPB5 (crystallin, alpha B) gene, are linked to multisystem disorders featuring variable combinations of cataracts, cardiomyopathy, and skeletal myopathy. This study aimed to investigate the pathological mechanisms involved in an early-onset myofibrillar myopathy manifesting in a child harboring a homozygous recessive mutation in HSPB5, 343delT. To study HSPB5 343delT protein dynamics, we utilize model cell culture systems including induced pluripotent stem cells derived from the 343delT patient (343delT/343delT) along with isogenic, heterozygous, gene-corrected control cells (WT KI/343delT) and BHK21 cells, a cell line lacking endogenous HSPB5 expression. 343delT/343delT and WT KI/343delT-induced pluripotent stem cell-derived skeletal myotubes and cardiomyocytes did not express detectable levels of 343delT protein, contributable to the extreme insolubility of the mutant protein. Overexpression of HSPB5 343delT resulted in insoluble mutant protein aggregates and induction of a cellular stress response. Co-expression of 343delT with WT prevented visible aggregation of 343delT and improved its solubility. Additionally, in vitro refolding of 343delT in the presence of WT rescued its solubility. We demonstrate an interaction between WT and 343delT both in vitro and within cells. These data support a loss-of-function model for the myopathy observed in the patient because the insoluble mutant would be unavailable to perform normal functions of HSPB5, although additional gain-of-function effects of the mutant protein cannot be excluded. Additionally, our data highlight the solubilization of 343delT by WT, concordant with the recessive inheritance of the disease and absence of symptoms in carrier individuals.
2015-05-11 | Rescue of αB Crystallin (HSPB5) Mutants Associated Protein Aggregation by Co-Expression of HSPB5 Partners
HSPB5 (also called αB-crystallin) is a ubiquitously expressed small heat shock protein. Mutations in HSPB5 have been found to cause cataract, but are also associated with a subgroup of myofibrillar myopathies. Cells expressing each of these HSPB5 mutants are characterized by the appearance of protein aggregates of primarily the mutant HSPB5. Like several members of the HSPB family, HSPB5 can form both homo-oligomeric and hetero-oligomeric complexes. Previous studies showed that co-expression of HSPB1 and HSPB8 can prevent the aggregation associated with the HSPB5 (R120G) mutant in cardiomyocytes and in transgenic mice. In this study, we systematically compared the effect of co-expression of each of the members of the human HSPB family (HSPB1-10) on the aggregation of three different HSPB5 mutants (R120G, 450 Δ A, 464 Δ CT). Of all members, co-expression of HSPB1, HSPB4 and HSPB5 itself, most effectively prevent the aggregation of these 3 HSPB5 mutants. HSPB6 and HSPB8 were also active but less, whilst the other 5 HSPB members were ineffective. Co-expression of Hsp70 did not reduce the aggregation of the HSPB5 mutants, suggesting that aggregate formation is most likely not related to a toxic gain of function of the mutants per se, but rather related to a loss of chaperone function of the oligomeric complexes containing the HSPB5 mutants (dominant negative effects). Our data suggest that the rescue of aggregation associated with the HSPB5 mutants is due to competitive incorporation of its partners into hetero-oligomers hereby negating the dominant negative effects of the mutant on the functioning of the hetero-oligomer.
small molecules
2026-07-06 | Unmasking Supervillin : SVIL haploinsufficiency causes hypertrophic cardiomyopathy by impairing mechanotransduction and cellular energetics
Abstract Background Rare heterozygous loss-of-function (LoF) variants in SVIL , encoding the Z-disk and costameric protein supervillin, have recently been identified as a cause of hypertrophic cardiomyopathy (HCM). Although supervillin is implicated in actin-dependent mechanotransduction, the mechanisms linking SVIL deficiency to cardiomyopathy remain poorly understood. Homozygous LoF cause a novel skeletal Myofibrillar Myopathy-10 (MFM-10) while heterozygous LoF cause HCM without skeletal myopathy. In this study we use a human model system to disentangle the LoF pathomechanism of the scaffolding protein supervillin in cardiomyocytes and its clinical implications. Methods Using CRISPR/Cas-9 we engineered a representative pathogenic LoF variant Q255X into an isogenic induced pluripotent stem cell (iPSC) line creating the heterozygous SVIL Q255X/+ and homozygous SVIL Q255X/Q255X cell lines. These lines were differentiated into iPSC-derived cardiomyocytes (iPSC-CMs) and cellular phenotypes were assessed using bulk RNA-sequencing, LC-MS proteomics, electrophysiological and calcium handling analyses, contractility measurements, sarcomere organization analysis, Seahorse metabolic flux assay, and pharmacological intervention with mavacamten. Results The Q255X variant resulted in SVIL haploinsufficiency at both RNA and protein levels with no evidence of a truncated protein. Compared with isogenic controls, SVIL Q255X/+ iPSC-CMs demonstrated action potential shortening, calcium transient elongation, sarcomeric disorganization and hypertrophy, and impaired mitochondrial respiration. Multi-omic analyses of SVIL Q255X/+ iPSC-CMs showed a profile of cellular stress and inflammation, hypertrophic and pro-fibrotic signalling, and a pseudohypoxic state driven by decreased respiration and a HIF-induced glycolytic shift. These abnormalities were not present in SVIL Q255X/Q255X cardiomyocytes, consistent with a relatively limited cardiac phenotype reported in homozygous variant carriers. Mavacamten improved sarcomeric disorganization and hypertrophy in SVIL Q255X/+ cells but did not rescue energetic compromise. Conclusions Pathogenic heterozygous SVIL LoF produces a distinct cellular phenotype characterized by impaired mechanotransduction, mitochondrial dysfunction, and maladaptive metabolic remodelling that promotes hypertrophic and pro-fibrotic signalling. These findings define a mechanistic basis for SVIL -associated cardiomyopathy and identify metabolic dysfunction as a potential therapeutic target beyond sarcomere-directed therapy. Clinical Perspective What Is New? SVIL haploinsufficiency causes HCM through a mechanism distinct from canonical sarcomeric disease, characterized by impaired mechanotransduction, mitochondrial dysfunction, and pseudohypoxia-driven metabolic remodeling. Heterozygous SVIL loss of function produces a substantially more severe cardiomyocyte phenotype than homozygous loss of function, providing a mechanistic explanation for the predominance of cardiac disease in heterozygous variant carriers. Mavacamten improves sarcomeric organization but does not restore impaired mitochondrial respiration, demonstrating that energetic dysfunction persists despite sarcomere-directed therapy. What Are the Clinical Implications? Our findings give functional evidence to support SVIL as a clinically relevant HCM disease gene and its inclusion in clinical genetic testing panels. These findings establish SVIL -associated cardiomyopathy as a mechanistically distinct form of HCM and offer insight into the pathomechanism of Z-disk and costameric HCM The persistence of mitochondrial dysfunction despite myosin inhibition suggests that drugs targeting mitochondrial bioenergetics may be a therapeutic strategy in patients with SVIL -associated cardiomyopathy.
2026-04-17 | Cure MFM13 and Drug Repurposing Strategies for Myofibrillar Myopathy Type 13
Myofibrillar Myopathy type 13 with Rimmed Vacuoles (MFM13), (OMIM#621078) is an ultra-rare disease caused by a frameshift mutation in the HSPB8 gene. This mutation produces an abnormal HSPB8 protein with an elongated C-terminal tail, leading to toxic gain-of-function, promoting protein aggregation and autophagy impartment with muscle weakness phenotype. Currently, there are no approved treatments, and awareness of the disease remains limited. To address this critical gap, Cure MFM13 was established, as the first and only charitable initiative dedicated exclusively to this disease. Our mission is to improve the lives of all individuals affected by MFM13 by accelerating therapeutic development, advocating for patients, and building a global and empowered community. We are currently focused on drug repurposing screening. We have developed several cellular models, including patient-derived fibroblasts and iPSCs. Because selecting the most appropriate cell model is critical to repurposing project success, we conducted extensive research on the use of C2C12 murine myoblasts and primary human myoblasts in studies of autophagy and muscle-related diseases. In addition, we are generating multiple research tools for the scientific community. Since the mutant HSPB8 protein differs structurally from the wild-type form, we developed a mutation-specific antibody targeting the frameshift variant (c.515dupC). To further accelerate progress, we are developing mouse model which next will be under investigation at a Czech Centre for Phenogenomics (CCP) in preparation for future preclinical testing. At this stage, key questions remain: What is the most appropriate model for drug repurposing, considering that MFM13 is a slow-progressing, adult-onset, autophagy and muscle-related disease? Which assays best show the efficacy of candidate small molecules? And strategically, where to find collaborators and where to look for additional funding?
2025-10-15 | Novel truncating Desmin mutation Arg150Stop disrupts structural integrity and cellular homeostasis by formation of persistent aggregate-like structure
Abstract Desminopathies are a heterogeneous group of myofibrillar myopathies defined by the presence of desmin-positive aggregates that compromise cytoskeletal integrity in skeletal and cardiac muscle. Although desmin knockout models and several truncating mutations typically result in a functional null phenotype without inclusion body formation, the molecular consequences of specific stop-gain variants remain poorly understood. In this study, we investigated the pathogenic mechanism of a novel DES nonsense mutation, NM_001927.4:c.448C>T; p.(Arg150Stop), previously identified in an Indian patient with congenital myopathy. This premature stop codon lies within the Linker 1A domain and is predicted to generate a truncated protein lacking the C-terminal tail. To delineate its functional consequences, we used two complementary experimental approaches: transient overexpression of the R150X mutant in skeletal and cardiac myocytes, and a CRISPR/Cas9-engineered homozygous R150X cardiomyocyte line (Des-R150X-CRISPR). Both models consistently revealed the formation of persistent aggregate-like structures, in striking contrast to desmin knockout systems that do not generate inclusions. These aggregate-like structures disrupted actin filament organization, impaired filament bundling, and induced organelle mislocalization. Biochemical analysis indicated that the aggregates were resistant to proteasomal degradation, yet they were partially cleared by autophagy, underscoring a role for protein quality control pathways in modulating disease severity. Importantly, the Des-R150X-CRISPR line demonstrated aggregate-driven pathology at endogenous levels, confirming that this mutation acts through a toxic gain-of-function mechanism rather than simple loss of desmin function. Our findings establish the Arg150Stop variant as a mechanistically distinct truncating mutation that generates aggregation-prone protein rather than a null state. By reproducing hallmark features of desminopathy in a physiologically relevant human cell models, this work not only broadens the known pathogenic spectrum of DES variants but also highlights aggregate formation as a central driver of cellular dysfunction and a promising therapeutic target in desminopathies.
2025-06-09 | Myofibrillar myopathy: towards a mechanism-based definition as a Z-disk-opathy.
Myofibrillar myopathies (MFMs) are traditionally defined by histopathology, but recent genetic discoveries have broadened the spectrum of causative genes beyond Z-disk components. This review aims to address the resulting terminological inconsistency by proposing a refined, mechanism-based definition of MFM centered on its identity as a "Z-disk-opathy." This re-evaluation is timely and relevant for improving diagnostic clarity and guiding future research. The literature increasingly reports MFM-like pathology in conditions caused by mutations in genes not directly encoding Z-disk structural proteins or their interacting chaperones. This review highlights the pathogenic mechanisms distinguishing true MFMs, which involve disruption of Z-disk protein structure or Z-disk protein homeostasis, from "myopathies with MFM pathology" that share histological features but stem from different molecular etiologies. Key themes include the dominant nature of mutations in Z-disk structural proteins and the critical role of chaperone dysfunction in MFM pathogenesis. A refined definition classifying MFM as a "Z-disk-opathy" offers a clearer framework for diagnosis and mechanistic understanding. This distinction has significant implications for clinical practice, facilitating more accurate diagnosis, and for research, by supporting the development of targeted therapeutic strategies aimed at either restoring Z-disk proteostasis or mitigating the effects of aberrant protein accumulation.
2025-04-17 | Mitochondrial dysfunction is driven by imbalanced fission and fusion of mitochondria in myofibrillar myopathy type 5.
Myofibrillar myopathy type 5 (MFM5) is a dominantly inherited myopathy caused by mutations in the FLNC gene. The underlying pathogenic mechanisms of MFM5 remain unclear, and there are currently no effective treatments available. This study hypothesizes that mitochondrial dysfunction plays a key role in the pathogenesis of MFM5, on the basis of the COX-negative fibres observed in MFM5 patients. To test this hypothesis, a zebrafish model was developed to explore the impact of filamin-C on mitochondrial dynamics. These results demonstrated that defects in filamin-C disrupt mitochondrial fission, leading to mitochondrial dysfunction and mitophagy. This hypothesis was further validated through the analysis of skeletal muscle samples from MFM5 patients. These findings suggest that mitochondrial dysfunction caused by imbalanced fission and fusion of mitochondria and mitophagy contributes to MFM5 pathology. Importantly, this study identified potential therapeutic targets for MFM5 treatment, opening avenues for future research aimed at developing targeted interventions.
gene therapies
2026-07-02 | AAV-Delivered RNAi Targeting Mutant LDB3 Prevents and Reverses Myofibrillar Myopathy through Mechanosignaling Restoration.
The autosomal dominant p.Ala165Val mutation in LIM Domain Binding Protein 3 (LDB3) causes myofibrillar myopathy marked by Z-disc disruption, accumulation of filamin-C (FLNc) and chaperone proteins, and progressive muscle weakness. We previously showed that this mutation interferes with the LDB3-protein kinase C alpha (PKCα)-FLNc mechanosensing axis and impairs chaperone-assisted selective autophagy (CASA), establishing a gain-of-function mechanism. In this study, we examined whether mutant allele-specific knockdown could reverse the disease or mitigate disease progression in-vivo. A single intramuscular-injection of an AAV9-delivered microRNA-based shRNA produced substantial knockdown of mutant Ldb3 transcripts and protein in Ldb3 Ala165Val/+ knock-in mice treated either before or after the onset of pathology. Treatment after disease onset reduced filamin-C and CASA protein aggregates and improved muscle strength, whereas early intervention prevented development of molecular and histological features of myopathy. Phosphoproteomic profiling further showed broad remodeling of dysregulated phosphorylation networks, including restoration of PKCα-responsive sites and normalization of altered sarcomeric and cytoskeletal signaling observed in Ldb3 Ala165Val/+ mice. These findings identify disruption of the LDB3-PKCα-FLNc mechanosensing pathway as a central disease driver and suggest that restoring this signaling axis may complement mutant allele-specific RNA interference (RNAi). Overall, our results support RNAi as a promising therapeutic strategy for dominant LDB3-related myofibrillar myopathy.
2026-06-26 | A Novel Variant in the Desmin Gene: Case Report
Desminopathies are rare myofibrillar myopathies caused by variants in the desmin (DES) gene on chromosome 2q35, encoding the protein desmin. These variants, typically autosomal dominant missense, result in diverse clinical phenotypes, including progressive skeletal myopathy and cardiac involvement. Over 180 pathogenic variants and 700 variants of uncertain significance have been reported. We describe a 46-year-old male with progressive distal and proximal muscle weakness since age 30, functional impairment, and intermittent dysphagia. There was no family history or respiratory involvement. Electromyography demonstrated a myopathic pattern, and muscle biopsy revealed desmin- positive aggregates. The patient had a prior syncopal episode with minor chronic electrocardiographic abnormalities, suggesting possible cardiac involvement. Whole exome sequencing identified a novel heterozygous DES variant, c.1327_1328delinsTT, p.(Lys443Leu). The combined clinical, electrophysiological, and histopathological findings strongly support the likely pathogenicity of the identified variant. This case expands the spectrum of DES variants and highlights the importance of multidisciplinary evaluation.
2026-05-15 | Autophagy activation via BAG3 gene therapy improves phenotype in a mouse model of LGMD1A.
Myofibrillar myopathies (MFMs) are a group of protein aggregate diseases characterized by abnormal protein aggregations and myofibrillar disintegration. Myotilinopathy, also named MFM3 or limb-girdle muscular dystrophy type 1A (LGMD1A), is caused by myotilin mutations. Myotilin is degraded by the ubiquitin-proteasome system; however, when this pathway is overloaded under pathophysiological conditions, the protein quality control system leans on the autophagy-lysosome pathway (ALP) to mediate degradation of aggregates. BCL2-associated athanogene 3 (BAG3) protein facilitates aggresome formation and initiates ALP. In this study, we assessed our strategy of reducing the aggregate burden in muscle by overexpressing human BAG3 in TgT57I mice, a model for LGMD1A. Overexpression was achieved by systemic delivery of AAVrh74.tMCK.hBAG3, and outcome measures included functional, histological, and molecular studies. The hBAG3-treated cohort demonstrated increased rotarod duration, treadmill running distance, grip strength, and maximum tetanic response compared to the untreated cohort. Myotilin aggregate burden was significantly decreased, and autophagy levels were normalized in the treated group. As an adaptive response, hBAG3 normalized the endogenous Bag1/Bag3 ratio to that of 3-month-old TgT57I mice. This study provides evidence that our strategy of reducing the aggregate burden in muscle by overexpressing BAG3 may be used as a treatment for protein aggregate myopathies.
2026-04-15 | Profile of Inherited Neuromuscular and Movement Disorders Among Filipinos: A Referral Single-Center Retrospective Study
Background: Neuromuscular and movement disorders comprise a heterogeneous group of acquired and inherited conditions affecting the motor unit and central movement pathways. Genetic data from underserved populations, including Filipinos, remain limited, highlighting the need for population-specific characterization. Objective: To characterize inherited neuromuscular and movement disorders among Filipinos and determine the diagnostic yield and genetic spectrum using next-generation sequencing (NGS). Methods: This referral single-center retrospective study reviewed Filipino patients who underwent genetic testing for suspected inherited neuromuscular and movement disorders. Variants were classified according to the American College of Medical Genetics and Genomics (ACMG) criteria. Results: Among 85 patients, 24 (28.2%) had pathogenic/likely pathogenic variants, 33 (38.8%) had variants of uncertain significance (VUS) and 28 (32.9%) were negative. Confirmed diagnoses included pediatric cases of limb-girdle muscular dystrophy, Duchenne muscular dystrophy, spinal muscular atrophy and GNE-related myopathy, and adult cases with myofibrillar myopathy, spinocerebellar ataxia and amyotrophic lateral sclerosis. Pathogenic variants involved 26 genes, most commonly SMN1. Conclusion: This NGS-based characterization of inherited neuromuscular and movement disorders in Filipinos showed 28% diagnostic yield and a spectrum comparable to other Asian cohorts. The high rate of VUS underscores the need for family segregation studies and careful genotype–phenotype correlation. This study highlights the critical role of genetic testing in accurate diagnosis and targeted management to improve outcomes for patients with these rare disorders.
2026-04-12 | Blockage of autophagy causes severe skeletal muscle disruption in a mouse model for myofibrillar myopathy 6.
Myofibrillar myopathy 6 is a rare, autosomal-dominant neuromuscular disorder caused by an amino acid exchange Pro209Leu in the co-chaperone BAG3, which disrupts muscle protein turnover and causes severe muscle weakness and shortened lifespan. We generated transgenic mice overexpressing the human mutant BAG3P209L-GFP, which rapidly develop skeletal muscle weakness unlike controls expressing BAG3WT-GFP. Here we show that mutant mice exhibit sarcomere breakdown, inflammation, protein aggregates, centralized nuclei and mitochondrial defects in their skeletal muscles, thereby reducing contraction force by ~90%. Omics profiling uncovered impaired protein synthesis, blocked autophagy, impaired mitophagy and loss of sarcomere proteins. Pathway modulation in vitro and in vivo showed autophagy dysfunction as the primary driver for the pathology, while BAG3 knockdown gene therapy markedly restored muscle function in vivo. In summary, this model recapitulates core disease features, revealing how BAG3 aggregates and loss of BAG3 function impair autophagy to drive muscle degeneration.
other
2023-10-01 | P164 Development of a myotube model for C-terminal titin studies
Mutations in the extreme C-terminal part of titin cause myopathies with different clinical pictures and modes of inheritance. The most common of these is tibial muscular dystrophy (TMD), a dominant adult-onset distal myopathy. Other diseases caused by C-terminal titin mutations are juvenile-onset recessive distal titinopathy, and the severe recessive limb-girdle muscular dystrophy R10 (LGMDR10). The genotype–phenotype correlation of the mutations is, however, complex and not fully understood. The TMD-causing mutations lead to a secondary proteolytic cleavage of the mutant titin C-terminus, and we believe that the propensity of the mutant protein to this cleavage event may explain the variable effects of the mutations. The large size of titin poses challenges to functional studies on titin mutations in the sarcomeric context. To overcome these limitations, we are developing a novel myotube model, C2C12-CTE (C-Terminal Titin Exchange), based on C2C12 mouse myoblasts. Heterospecific lox sites were introduced flanking the last Ttn exons in C2C12 genome using the Cytosurge CellEDIT technology. Transfection of these C2C12-CTE master cells with the Cre recombinase and a donor plasmid drives replacement of the targeted Ttn region with genetic material from the donor construct through recombinase-mediated cassette exchange (RMCE), allowing quick and economical introduction of modifications such as mutations or tags to C-terminal titin. The recombinant cells are selected using positive (G418 resistance) and negative (ganciclovir sensitivity) selection strategies and used as polyclonal pools for myotube differentiation. We expect this system to provide a valuable tool for characterizing the pathological cleavage of mutant titin and other effects of titinopathy mutations, as well as for other studies on C-terminal titin. Mutations in the extreme C-terminal part of titin cause myopathies with different clinical pictures and modes of inheritance. The most common of these is tibial muscular dystrophy (TMD), a dominant adult-onset distal myopathy. Other diseases caused by C-terminal titin mutations are juvenile-onset recessive distal titinopathy, and the severe recessive limb-girdle muscular dystrophy R10 (LGMDR10). The genotype–phenotype correlation of the mutations is, however, complex and not fully understood. The TMD-causing mutations lead to a secondary proteolytic cleavage of the mutant titin C-terminus, and we believe that the propensity of the mutant protein to this cleavage event may explain the variable effects of the mutations. The large size of titin poses challenges to functional studies on titin mutations in the sarcomeric context. To overcome these limitations, we are developing a novel myotube model, C2C12-CTE (C-Terminal Titin Exchange), based on C2C12 mouse myoblasts. Heterospecific lox sites were introduced flanking the last Ttn exons in C2C12 genome using the Cytosurge CellEDIT technology. Transfection of these C2C12-CTE master cells with the Cre recombinase and a donor plasmid drives replacement of the targeted Ttn region with genetic material from the donor construct through recombinase-mediated cassette exchange (RMCE), allowing quick and economical introduction of modifications such as mutations or tags to C-terminal titin. The recombinant cells are selected using positive (G418 resistance) and negative (ganciclovir sensitivity) selection strategies and used as polyclonal pools for myotube differentiation. We expect this system to provide a valuable tool for characterizing the pathological cleavage of mutant titin and other effects of titinopathy mutations, as well as for other studies on C-terminal titin.
2020-11-02 | Genetic compensation prevents myopathy and heart failure in an in vivo model of Bag3 deficiency
Mutations in the molecular co-chaperone Bcl2-associated athanogene 3 (BAG3) are found to cause dilated cardiomyopathy (DCM), resulting in systolic dysfunction and heart failure, as well as myofibrillar myopathy (MFM), which is characterized by protein aggregation and myofibrillar disintegration in skeletal muscle cells. Here, we generated a CRISPR/Cas9-induced Bag3 knockout zebrafish line and found the complete preservation of heart and skeletal muscle structure and function during embryonic development, in contrast to morpholino-mediated knockdown of Bag3. Intriguingly, genetic compensation, a process of transcriptional adaptation which acts independent of protein feedback loops, was found to prevent heart and skeletal muscle damage in our Bag3 knockout model. Proteomic profiling and quantitative real-time PCR analyses identified Bag2, another member of the Bag protein family, significantly upregulated on a transcript and protein level in bag3-/- mutants. This implied that the decay of bag3 mutant mRNA in homozygous bag3-/- embryos caused the transcriptional upregulation of bag2 expression. We further demonstrated that morpholino-mediated knockdown of Bag2 in bag3-/- embryos evoked severe functional and structural heart and skeletal muscle defects, which are similar to Bag3 morphants. However, Bag2 knockdown in bag3+/+ or bag3+/- embryos did not result in (cardio-)myopathy. Finally, we found that inhibition of the nonsense-mediated mRNA decay (NMD) machinery by knockdown of upf1, an essential NMD factor, caused severe heart and skeletal muscle defects in bag3-/- mutants due to the blockade of transcriptional adaptation of bag2 expression. Our findings provide evidence that genetic compensation might vitally influence the penetrance of disease-causing bag3 mutations in vivo.
2020-01-17 | Ppp1r1b-lncRNA inhibits PRC2 at myogenic regulatory genes to promote cardiac and skeletal muscle development in mouse and human
Long noncoding RNAs (lncRNAs) have emerged as critical epigenetic regulators and play important roles in cardiac development and congenital heart disease. In a previous study, we identified a novel lncRNA, Ppp1r1b, with expression highly correlated with myogenesis. However, the molecular mechanism that underlies Ppp1r1b-lncRNA function in myogenic regulation is unknown. By silencing Ppp1r1b-lncRNA, mouse C2C12 and human skeletal myoblasts failed to develop fully differentiated myotubes. Myogenic differentiation was also impaired in PPP1R1B-lncRNA deficient human-induced pluripotent stem cell-derived cardiomyocytes (hiPSCs-CMs). The expression of myogenic transcription factors, including MyoD, Myogenin, and Tbx5, as well as sarcomere proteins, was significantly suppressed in Ppp1r1b-lncRNA inhibited myoblast cells and neonatal mouse heart. Histone modification analysis revealed increased H3K27 tri-methylation at MyoD1 and Myogenin promoters in GapmeR treated C2C12 cells. Furthermore, Ppp1r1b-lncRNA was found to bind to Ezh2, and chromatin isolation by RNA purification (ChIRP) assay revealed enriched interaction of Ppp1r1b-lncRNA with Myod1 and Tbx5 promoters, suggesting that Ppp1r1b-lncRNA induces transcription of myogenic transcription factors by interacting with the polycomb repressive complex 2 (PRC2) at the chromatin interface. Correspondingly, the silencing of Ppp1r1b-lncRNA increased EZH2 binding at promoter regions of myogenic transcription factors. Therefore, our results suggest that Ppp1r1b-lncRNA promotes myogenic differentiation through competing for PRC2 binding with chromatin of myogenic master regulators during heart and skeletal muscle development.
2016-04-01 | Myosin heavy chain is stabilized by BCL-2 interacting cell death suppressor (BIS) in skeletal muscle
BCL-2 interacting cell death suppressor (BIS), which is ubiquitously expressed, has important roles in various cellular processes, such as apoptosis, the cellular stress response, migration and invasion and protein quality control. In particular, BIS is highly expressed in skeletal and cardiac muscles, and BIS gene mutations result in human myopathy. In this study, we show that mRNA and protein levels of BIS were markedly increased during skeletal myogenesis in C2C12 cells and mouse satellite cells. BIS knockdown did not prevent the early stage of skeletal myogenesis, but did induce muscle atrophy and a decrease in the diameter of myotubes. BIS knockdown significantly suppressed the expression level of myosin heavy chain (MyHC) without changing the expression levels of myogenic marker proteins, such as Mgn, Cav-3 and MG53. In addition, BIS endogenously interacted with MyHC, and BIS knockdown induced MyHC ubiquitination and degradation. From these data, we conclude that molecular association of MyHC and BIS is necessary for MyHC stabilization in skeletal muscle. The protein known as BCL-2 interacting cell death suppressor (BIS) is essential for the formation and maintenance of skeletal muscle. Mutations in the gene for BIS have previously been linked to muscle dysfunction in humans, but the mechanism of the protein's effect was unclear. Jeong-Hwa Lee and colleagues at The Catholic University of Korea, with co-workers elsewhere in South Korea, used genetic studies on mouse muscle cells to investigate the role of BIS. Their results reveal a direct link between BIS and the heavy chain of the protein myosin, an essential component of muscle fibers. BIS binds to and stabilizes the myosin, protecting it from being degraded by cell turnover processes. Modifying the activity of the gene that codes for BIS might offer a new approach for treating various muscle diseases.
2014-02-18 | Novel excitation-contraction coupling related genes reveal aspects of muscle weakness beyond atrophy—new hopes for treatment of musculoskeletal diseases
Research over the last decade strengthened the understanding that skeletal muscles are not only the major tissue in the body from a volume point of view but also function as a master regulator contributing to optimal organismal health. These new contributions to the available body of knowledge triggered great interest in the roles of skeletal muscle beyond contraction. The World Health Organization, through its Global Burden of Disease (GBD) report, recently raised further awareness about the key importance of skeletal muscles as the GDB reported musculoskeletal (MSK) diseases have become the second greatest cause of disability, with more than 1.7 billion people in the globe affected by a diversity of MSK conditions. Besides their role in MSK disorders, skeletal muscles are also seen as principal metabolic organs with essential contributions to metabolic disorders, especially those linked to physical inactivity. In this review, we have focused on the unique function of new genes/proteins (i.e. MTMR14, MG29, sarcalumenin, KFL15) that during the last few years have helped provide novel insights about muscle function in health and disease, muscle fatigue, muscle metabolism, and muscle aging. Next, we provide an in depth discussion of how these genes/proteins converge into a common function of acting as regulators of intracellular calcium homeostasis. A clear link between dysfunctional calcium homeostasis is established and the special role of store-operated calcium entry is analyzed. The new knowledge that has been generated by the understanding of the roles of previously unknown modulatory genes of the skeletal muscle excitation-contraction coupling (ECC) process brings exciting new possibilities for treatment of MSK diseases, muscle regeneration, and skeletal muscle tissue engineering. The next decade of skeletal muscle and MSK research is bound to bring to fruition applied knowledge that will hopefully offset the current heavy and sad burden of MSK diseases on the
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
1 orphan drug designation for Myofibrillar myopathy.
1 orphan drug designation for Myofibrillar myopathy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Chaenomelis Fructus Extract | small molecules | FDA | 2023-11-29 | — | Centre for Chinese Herbal Medicine Drug Development Limited |
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.