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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2026-07-31 | Energy expenditure and the accuracy of predictive equations in myotonic dystrophy type 1.
BackgroundMyotonic dystrophy type 1 (DM1) is associated with reduced physical activity, overweight and cardiovascular morbidity. Nutritional management requires accurate estimation of total daily energy expenditure (TEE), based on basal metabolic rate (BMR) and physical activity level (PAL). However, DM1-related changes in body composition may reduce the accuracy of commonly used BMR equations. This study evaluated BMR equation accuracy in DM1 versus controls, and assessed PAL and substrate oxidation.MethodsIn this secondary analysis of a prospective case-control study, 15 DM1 patients were compared with 15 age-, sex-, and BMI-matched controls. Body composition was measured using dual-energy X-ray absorptiometry. Overnight metabolic rate (OMR) was assessed by room calorimetry and compared with standard predictive equations (Harris-Benedict, WHO, Mifflin-St Jeor). Additionally, OMR was compared to body composition-based equations (Wang, Nelson, Sabounchi structures 4, 5, and 11). TEE was measured over 15 days using doubly labeled water. PAL was calculated as TEE/OMR, and substrate oxidation was assessed using the respiratory exchange ratio (RER).ResultsStandard predictive equations significantly overestimated metabolic rate in DM1, with median biases of +100 to +165 kcal/day (+7% to +12%, p<0.01), with no significant bias in controls. Structure 11 performed best in DM1 (+0.0%, p=1.000). PAL was lower in DM1 than in controls (1.42 vs. 1.69, p<0.001), whereas RER did not differ.ConclusionCommon predictive equations overestimate energy requirements in DM1. Body composition-based approaches or correction factors may improve estimation, while low PAL should be considered when estimating TEE. These findings have direct implications for nutritional management in DM1.
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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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2026-07-26 | Differential Effects of Protein Kinase C Inhibitors on Nuclear and Cytoplasmic DMPK Transcript Dynamics in Myotonic Dystrophy Type 1 Cells
The major molecular basis for myotonic dystrophy type 1 disorder is the occurrence of a mutation leading to expanded CTG triplet units in the 3’-untranslated region of Dystrophia Myotonica Protein Kinase (DMPK) gene, which leads to the formation of foci in the nuclei of these cells. An assay based on the DMPK transcript (Bpm I polymorphism) was developed to test the effect of compounds of protein Kinase C inhibitors- hypericin and Ro 31-8220- to determine whether either inhibitor affected the transport of DMPK transcripts from nucleus to the cytoplasm or reduced the proportion of the transcript in both fibroblast and myoblast cells. The results from this study showed that the protein kinase C inhibitors were not able to affect the relocation of mutant DMPK transcripts from the nucleus to the cytoplasm in both DM1 fibroblasts and myoblasts, but Ro 31-8220 significantly reduced mutant transcripts in the nuclear fraction of DM1 fibroblasts. In the nuclei of fibroblasts, Ro 31-8220 treatment showed a 38.5±5.4% proportion of mutant transcript, hypericin treatment exhibited 54.2±3.5% mutant transcript, while those of DMSO treatment and untreated were 43.7±3.0% and 51.4±0.8%, respectively. For cytoplasmic fractions of DM1 fibroblasts, Ro 31-8220-treated cells indicated 94.4±1.7% normal transcript, hypericin treatment showed 91.6±1.0%, with DMSO-treated and untreated cells having 90.0±1.9% ad 89.5±2.3%, respectively. In the DM1 myoblasts nuclear fraction, 61.8±1.7% mutant transcript was observed in Ro 31-8820- treated cells, 67.5±2.8% mutant transcript occurred in hypericin treatment, while DMSO treatment and untreated cells had 52.4±1.7% and 48.7±0.8%, respectively. In myoblast cytoplasmic fractions, hypericin and Ro 31-8220 showed 90.6±2.7% and 80.8±0.3% normal transcripts, respectively, with DMSO treatment showing 81.1±0.5% normal transcript, while the untreated showed 80.0±5.7% normal transcript. This study has discovered the role of Ro 31-8220 in reducing the proportion of mutant transcripts I nuclear fraction while increasing the levels of the normal transcripts was increased in the cytoplasmic fraction of DM1 cells. Taken together, results from this study suggest that Ro 31-8220 may have therapeutic potential for reducing mutant DMPK transcript levels with potential therapeutic value
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