Targeting mitochondrial dynamics to tackle Duchenne Muscular Dystrophy progression

Duchenne muscular dystrophy (DMD) is a progressive muscle-wasting disorder caused by the lack of dystrophin protein, crucial for muscle integrity during contraction. Mitochondrial impairment is one of the earliest dysfunctions of mdx muscles and a plethora of metabolic defects have been identified. The organization of the mitochondrial network is also compromised, but few studies have addressed the involvement of mitochondrial dynamics in the pathophysiology of DMD. We created a DMD model with intrinsically fluorescent and photoconvertible mitochondria, which allowed us to point out that mdx oxidative fibers have an altered and a less interconnected mitochondrial network compared to WT controls. Consistently, high levels of the pro-fission protein Drp1 were detected in dystrophic muscle and the interaction between Drp1 and its receptors was also increased, indicating an enhanced Drp1 activity. This unbalanced fission could promote mitochondrial stress and UPR induction culminating in myokine release and, as expected, dystrophic muscle displayed increased FGF-21 production. We therefore inhibited Drp1 with daily intraperitoneal injections of MDIVI-1 and we observed beneficial effects at functional and histological level. Inflammation was also remarkably reduced and the levels of FGF-21 were downregulated after the treatment, suggesting a role of this myokine in establishing dystrophic damage. We also focused on another strategy to modulate Drp1-mediated excessive fission in mdx mice injecting an AAV-vector encoding for a specific Drp1 shRNA. The viral genome was still present after 11 weeks from the injection, suggesting a therapeutic advantage in keeping it in the muscle. Indeed, AAV-shDrp1 had a positive effect on ex-vivo muscle fragility and hypertrophy, possibly due to the observed reduction of fibrotic markers. In summary, Drp1 is emerging as a relevant target in DMD and the modulation of its activity is a promising approach to counteract muscular dystrophy progression.