Targeting mitochondrial dynamics to tackle Duchenne muscular dystrophy progression

Duchenne muscular dystrophy (DMD) is a severe, progressive, muscle-wasting disorder caused by the lack of dystrophin, a crucial protein that maintains muscle integrity during contraction. Mitochondrial impairment is one of the earliest dysfunctions of mdx muscles and a plethora of metabolic defects have been identified over the years. However 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 discovered that muscle of adult dystrophic mice showed high levels of Drp1 and a less interconnected mitochondrial network compared to WT controls. Consistently, the interaction between Drp1 and its mitochondrial receptors was increased indicating an enhanced Drp1activity. Unbalanced fission could promote UPR induction culminating in myokine release and, as expected, in parallel with Drp1 activity, dystrophic muscle displayed increased FGF-21 production. After inhibiting Drp1 in 12 weeks-old mdx mice with daily intraperitoneal injections of MDIVI-1 (12,5 mg/kg) we observed overall beneficial effects at the functional, morphological, and molecular level. Specifically, fibrosis, inflammation, and necrosis were remarkably reduced and regeneration was promoted by the treatment. According to this, we are investigating whether MDIVI-1 is able to maintain the myogenic capacity of dystrophic muscle stem cells, improving in vitro myotubes formation. Dystrophic muscle ameliorations after MDIVI-1 administration were also associated with reduced FGF-21 levels, suggesting a role of this myokine in establishing dystrophic damage. In order to confirm these results obtained with MDIVI-1 we are trying to modulate Drp1 expression by intramuscular AAV-based transfer of a specific Drp1 shRNA. 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.