Aug 2026· Neurotherapeutics· Vol 23· 0 citations· 99 references
Medicine
TL;DR
Results 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, and highlights the potential of natural compounds like BMCs as novel, promising and accessible therapeutics for the DM1 muscle pathology.
Abstract
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.
It is suggested that restoring LKB1 activity via HDAC inhibition or miRNA targeting may represent a therapeutic avenue to address dystrophic muscle dysfunction in Duchenne muscular dystrophy.
Brigida Boccanegra, Lisamaura Tulimiero, R. Quarta et al.· Annals of the New York Acade...· 0 citations
A variant-specific insight is revealed into CMT2A disease mechanisms and HDAC6 is confirmed as a promising target for further therapeutic development by showing that mitochondrial trafficking defects could be alleviated by treatment with an HDAC6 inhibitor.
Lydia H. Jestice, Larissa Butler, Rebecca A. Lea et al.· JCI Insight· 0 citations
This study evaluates the therapeutic potential of the lipid-conjugated antimiR-23b, X82108, designed to promote MBNL1/2 upregulation through inhibition of miR-23b, and highlights X82108 as a promising systemic therapy for DM1.
D. Piqueras-Losilla, Andrea García-Rey, Aline Huguet-Lachon et al.· Cell Reports Medicine· 0 citations
Duchenne Muscular Dystrophy (DMD) is a severe X-linked disorder characterized by progressive degeneration of skeletal and cardiac muscles caused by mutations in the DMD gene encoding dystrophin, a protein essential for cytoskeletal integrity and muscle function. A truncated dystrophin leads to increased muscle susceptibility to contraction-induced damage, driving chronic inflammation and fibrosis. Although corticosteroids remain the standard of care, novel therapeutic strategies are urgently needed. Niclosamide, a long-established anthelmintic drug, has recently been repurposed in inflammatory and fibrotic conditions, including neuromuscular diseases. We investigated the effects of niclosamide in vitro using primary macrophages from mdx mice, human DMD myoblasts, and murine C2C12 myoblast cultures, and in vivo in a proof-of-concept study in mdx mice. In primary mdx macrophages, niclosamide reduced inflammation and reactive oxygen species production, while promoting an anti-inflammatory/pro-regenerative phenotype. In parallel, niclosamide enhanced the differentiation of human DMD myoblasts, and conditioned medium from niclosamide-treated macrophages significantly improved C2C12 myoblast differentiation. In treated mdx mice, niclosamide improved muscle resistance and reduced muscle damage, as indicated by decreased plasma creatine kinase levels and lower immunoglobulin infiltration. These effects were accompanied by modulation of key markers involved in muscle proliferation and differentiation, supporting a beneficial role of niclosamide in promoting muscle repair in dystrophic muscle. Overall, these findings indicate that niclosamide promotes an anti-inflammatory and pro-regenerative environment, enhancing myoblast differentiation and limiting muscle degeneration, supporting its potential role as a promising therapeutic candidate for Duchenne muscular dystrophy.
M. Milani, Ilaria Della Valle, Alessio Torcinaro et al.· Biochemical Pharmacology· 0 citations
A previously unrecognized HO-1–dependent pathway by which CBD dampens profibrotic activation in human DMD and control hiPSC-cFib is uncovered, highlighting its potential as a therapeutic approach to limit cardiac fibrosis in Duchenne muscular dystrophy.
L. Savchenko, S. Soussi, D. Rovina et al.· Redox Biology· 0 citations
A cardinal sign of myotonic dystrophy type 1 (DM1) is myotonia, slow muscle relaxation after voluntary contraction. Myotonia results from mis-regulated splicing of chloride channel 1 (ClC-1), leading to loss of channel function and runs of involuntary action potentials in muscle fibers. Preceding the onset of weakness, myotonia is often the first symptom of DM1, and thus this raises the possibility that muscle hyperexcitability contributes to the subsequent weakness and myopathy. Here, we show that genomic deletion of ClC-1 exon 7a (E7a), a cryptic exon abnormally regulated in DM1, completely rescues of ClC-1 function and yields permanent elimination of myotonia in the muscleblind-like 1 (Mbnl1) knockout mouse model of DM1. The restoration of normal excitability results in normalization of muscle force generation, correction of fiber-type distribution, and improvement of muscle histology. E7a deletion also partially corrects the muscle transcriptome, including changes of differential gene expression and alternative splicing. These results indicate that E7a inclusion is a lynchpin splice event that contributes to myotonic myopathy, and support myotonia reduction as a therapeutic objective in DM1. Myotonia is a hallmark symptom of myotonic dystrophy (DM1). Eliminating myotonia in a DM1 mouse model improved muscle function and corrected transcriptome dysregulation, supporting myotonia as a driver of myopathy and a potential therapeutic target.
Matthew T. Sipple, S. Hamazaki, Vanessa Todorow et al.· Nature Communications· 0 citations
We use cookies to run the site and, with your consent, for analytics and to show ads.
See our Cookie Policy.
