Inhibition of mitochondrial fission protein Drp1 ameliorates skeletal myopathy in the D2-mdx model of Duchenne muscular dystrophy.

Although current treatments for Duchenne muscular dystrophy (DMD) have proven to be effective in delaying myopathy, there remains a strong need to identify novel targets to develop additional therapies. Mitochondrial dysfunction is an early pathological feature of DMD. A fine balance of mitochondrial dynamics (fission and fusion) is crucial to maintain mitochondrial function and skeletal muscle health. Excessive activation of dynamin-related protein 1 (Drp1)-mediated mitochondrial fission was reported in animal models of DMD. However, whether Drp1-mediated mitochondrial fission is a viable target for treating myopathy in DMD remains unknown. Here, we treated a D2.B10-/J (D2-mdx) model of DMD (9-10 wk old) with mitochondrial division inhibitor 1 (Mdivi-1), a selective Drp1 inhibitor, every other day (intraperitoneal injection) for 5 wk. We demonstrated that Mdivi-1 effectively improved skeletal muscle strength and reduced serum creatine kinase concentration. Mdivi-1 treatment also effectively inhibited mitochondrial fission regulatory protein markers, Drp1(Ser616) phosphorylation, and mitochondrial fission protein 1 (Fis1) in skeletal muscles from D2-mdx mice, which resulted in reduced content of damaged and fragmented mitochondria. Furthermore, Mdivi-1 treatment attenuated lipid peroxidation product, 4-hydroxynonenal (4-HNE), in skeletal muscle from D2-mdx mice, which was inversely correlated with muscle grip strength. Finally, we revealed that Mdivi-1 treatment downregulated the expression of markers of fibrosis [alpha 1 type I collagen (Col1a1), metalloproteinases 2 and 9 (MMP2 and MMP9)] and inflammation [IL-6, monocyte chemoattractant protein-1 (MCP1), and CXC motif chemokine ligand 12 (CXCL12)]. In summary, these results demonstrate that inhibition of Drp1-mediated mitochondrial fission by Mdivi-1 is effective in improving muscle strength and alleviating muscle damage in D2-mdx mice. These improvements are associated with improved skeletal muscle mitochondrial integrity, leading to attenuated lipid peroxidation. The therapeutic potential of targeting mitochondrial dynamics in treating myopathy in Duchenne muscular dystrophy (DMD) remains unknown. This study is the first to target Drp1-mediated mitochondrial fission to alleviate myopathy in DMD. We reported that Mdivi-1, a pharmacological inhibitor targeting Drp1-mediated mitochondrial fission, was effective in reducing muscle damage and improving skeletal muscle strength in D2-mdx mice. These responses were associated with improved mitochondrial morphology and reduced lipid peroxidation.