Drp1-FGF21 axis drives FAPs-mediated fibro-adipogenic degeneration in Duchenne muscular dystrophy

Mitochondrial dysfunction is an early pathogenic event in dystrophic muscle contributing to muscle damage. Here, we provide an in-depth characterization of the marked induction of mitochondrial fission in mdx muscle fibers, driven by excessive activation of the fission regulator Drp1. This aberrant Drp1 activity triggers the integrated stress response (ISR), resulting in muscle-derived secretion of FGF21, which in turn promotes the fibro-adipogenic differentiation of fibro-adipogenic progenitors (FAPs). Importantly, we demonstrate that inhibition of Drp1 is both necessary and sufficient to restore mitochondrial function and suppresses FGF21 upregulation, limiting its detrimental impact on FAPs and contributing to the overall improvement of DMD phenotype. Our study identifies FGF21 as a key mediator of DMD pathology and supports targeting mitochondrial dynamics as a disease-modifying therapeutic strategy.