2026-08-15 | An Ultrastructural and Proteomic Analysis in DM1 Young Adults' Myoblasts: Stressed RER and Mitochondrial Dysfunction Involvement.
Myotonic dystrophy type 1 (DM1) is a progressive muscular disorder caused by the expansion of CTG repeats in the 3' UTR of the DMPK gene. Although the pathogenic mechanisms remain unclear, recent evidence suggests that activation of innate immune responses may contribute to disease progression. In this study, we examined the ultrastructure and proteomic data of myoblasts from young adult DM1 patients carrying approximately 800 and 1300 CTG repeats in order to investigate a link between cellular stress and immune activation. We observed activation of the type I interferon (IFN-I) pathway associated with rough endoplasmic reticulum stress (sRER). The sRER response is likely triggered by the accumulation of toxic RNA species generated from the expanded DMPK allele. Our data suggest that this inappropriate activation of the IFN-I pathway contributes to muscle pathology, not by blocking differentiation directly, but through chronic stress signalling. These findings support a model in which innate immune dysregulation plays a central role in DM1 muscle degeneration and highlight the IFN1 pathway as a potential therapeutic target for restoring normal muscle function.
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2026-08-04 | A bitter melon natural compound ameliorates the myotonic dystrophy type 1 skeletal muscle phenotype in a sex-specific manner.
Myotonic Dystrophy Type 1 (DM1) is a multisystemic neuromuscular disease characterized by severe skeletal muscle dysfunction. The etiology of DM1 is primarily driven by RNA toxicity resulting from a gain-of-function mutation in DMPK mRNAs. Beyond this hallmark, DM1 is also characterized by the repression of the AMP-activated protein kinase (AMPK) pathway. Previous work has shown that targeting AMPK represents a novel therapeutic avenue for DM1. In this study, we investigated the therapeutic potential of novel AMPK activators derived from Momordica charantia (bitter melon). A screen of 26 bitter melon-derived compounds (BMCs) in C2C12 myotubes identified BMC-25 as a potent AMPK activator. Acute treatment of DM1 (HSALR) mice with BMC-25 induced an expected activation of AMPK in DM1 mice, while chronic treatment restored several DM1 histopathological features, including toxic ribonuclear foci. Interestingly, BMC-25 treatment induced distinct, sex-dependent molecular benefits. In female DM1 mice, BMC-25 treatment corrected the pattern of expression of RNA-binding proteins including CELF1, MBNL1, and Staufen1 in skeletal muscle and achieved a much greater correction of alternative splicing of multiple transcripts relative to their respective controls. In contrast, male DM1 mice exhibited very limited improvements in these parameters. Collectively, our findings indicate that sustained AMPK activation with BMC-25 confers multifaceted benefits to DM1 skeletal muscle by improving core DM1 pathogenic features in a sex-dependent manner. Finally, these results highlight the potential of natural compounds like BMCs as novel, promising and accessible therapeutics for the DM1 muscle pathology.
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2026-07-28 | Impaired Myogenic Differentiation Is a Shared Feature Across Genetic Myopathies.
There is a shared hallmark of defective differentiation across genetic myopathies, a process that has been extensively described in Duchenne muscular dystrophy and also observed in Emery-Dreifuss muscular dystrophy. In this article, we broaden the discussion on myopathies associated with differentiation defects, examining their implications in less characterized muscle conditions that can have onset in adulthood, including facioscapulohumeral muscular dystrophy (FSHD), oculopharyngeal muscular dystrophy (OPMD), and myotonic dystrophies (DM), as well as myopathies caused by genetic variants in FHL1, GNE, DES, CAPN3, and members of the HNRNP family. Muscle damage can result from injury, exercise, or disease, necessitating a highly coordinated repair process to restore normal strength and function. Resident satellite cells are activated, differentiate, and fuse with the damaged tissue to facilitate this repair. This overview emphasizes the importance of muscle differentiation in the pathogenesis of myopathies with diverse etiologies and a broad range of underlying molecular mechanisms. These insights highlight differentiation as a potential convergent therapeutic target.
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2026-07-23 | Fatty-acid-based antimiR-23b delivery in the DMSXL model: A potential therapeutic strategy for brain dysfunction in myotonic dystrophy type 1.
Myotonic dystrophy type 1 (DM1) is a severe neuromuscular disorder caused by CTG repeat expansions in the DMPK gene, leading to the formation of toxic RNA foci that sequester essential splicing regulators MBNL1/2. Beyond muscle impairment, DM1 affects also the brain, leading to significant cognitive deficits, behavioral abnormalities, and intellectual disabilities. This study evaluates the therapeutic potential of the lipid-conjugated antimiR-23b, X82108, designed to promote MBNL1/2 upregulation through inhibition of miR-23b. Systemic administration of X82108 in mice and non-human primates efficiently crosses the blood-brain barrier, increasing MBNL1 in the brain. In DMSXL transgenic mice, treatment increases Mbnl1/2, reduces toxic DMPK, and restores normal splicing patterns across all brain regions. These molecular improvements correlate with improved behavioral outcomes, including reduced impulsivity and normalized exploratory activity. Collectively, the findings highlight X82108 as a promising systemic therapy for DM1, targeting not only muscular features as we have previously shown but also DM1-related CNS alterations.
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2026-07-23 | HSP90 inhibition partially rescues alternative splicing dysregulation in cell models of myotonic dystrophy.
Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are multisystemic diseases caused by the expression of toxic expansion RNAs that sequester muscleblind-like (MBNL) proteins, resulting in extensive alternative splicing dysregulation. Given that there are no current disease-modifying treatments for DM, we sought to identify compounds that rescue the underlying splicing dysregulation. A medium throughput splicing screen utilizing DM1 patient-derived fibroblasts was developed and used to screen 1584 compounds from the NIH NCI Diversity Set VI, leading to the identification of macbecin II, an HSP90 inhibitor. Macbecin II-mediated HSP90 inhibition corrects several MBNL-regulated splicing events in DM1 myotubes, and a structurally distinct HSP90 inhibitor, CCT018159, produces similar effects. Using RT-PCR splicing analysis, siRNA knockdown, RT-qPCR, immunoblotting, and RNA fluorescence in situ hybridization we examined the effects of HSP90 inhibition in DM models. HSP90 inhibition increases MBNL1 and MBNL2 transcript levels, increases MBNL2 protein, and reduces toxic CUG RNA and nuclear foci in DM1 cell models. An analysis of individual HSP90 isoforms reveals that knocking down HSP90AA1, HSP90AB1, and TRAP1 partially improves splicing defects, whereas HSP90B1 knockdown exacerbates mis-splicing. We also show that treatment with HSP90 inhibitors corrects mis-splicing in DM2 myotubes. Together, these data identify HSP90 as a modifier of RNA toxicity and alternative splicing in DM and support further evaluation of HSP90-directed therapeutic strategies.
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