Mitochondria-targeted engineered peptide promotes myogenesis, mitigates fibrosis, and reduces inflammation in duchenne muscular dystrophy by suppressing mitoROS-mediated NF-κB activation.

Duchenne Muscular Dystrophy (DMD) is a severe X-linked genetic disorder caused by a mutation in the dystrophin gene. Current treatments primarily rely on symptomatic management of DMD pathophysiology by corticosteroid treatment, as exon skipping drugs are inaccessible to the majority of the DMD population due to their high treatment cost. However, long-term corticosteroid treatment is associated with a range of adverse effects. To address this, we developed a peptide library derived from a myogenesis-promoting micropeptide and identified M.P-2 as a lead candidate for promoting myogenesis. M.P-2 was further engineered to E.M.P-2, a mitochondrial-targeted peptide to address DMD's secondary pathologies. E.M.P-2 promotes myogenic differentiation by upregulating MyHC and MyoD at a nanomolar dose (0.156 μM) while suppressing fibrosis. It effectively chelates calcium ions to reduce mitochondrial reactive oxygen species (ROS), and maintain mitochondrial membrane potential. E.M.P-2 also demonstrates significant potential in modulating inflammation via inhibiting the expression of IL-6 and TGFβ. Mechanistically, E.M.P-2 functions through inhibition of mitoROS-driven activation of the NF-κB pathway, which collectively promotes myogenesis, suppresses fibrosis, and manages inflammation. Overall, E.M.P-2 holds potential for addressing DMD pathophysiology as the first peptide-based therapeutic providing a safer alternative to corticosteroids.