Inhibition of Mitochondrial Fission Protein Drp1 Ameliorates Myopathy in the D2-mdx Model of Duchenne Muscular Dystrophy

Authors
H Grace Rosen, Nicolas J Berger, Shantel N Hodge, Atsutaro Fujishiro, Jared Lourie, Vrusti Kapadia, Melissa A Linden, Eunbin Jee, Jonghan Kim, Yuho Kim, Kai Zou


Lab

Journal
bioRxiv

Abstract
The main finding of the present study is that D2-mdx mice treated with Mdivi-1, a pharmacological inhibitor of Drp1, showed significantly improved muscle strength and reduced muscle damage compared to their vehicle-treated counterparts. Consistent with our findings, Rexius-Hall et al. recently reported that Mdivi-1 increased contractility generated by engineered muscle fibersin vitro(59). In DMD, muscle weakness and dysfunction are largely due to the presence of elevated fibrosis and chronic inflammation within the skeletal muscle tissue, which results from the degeneration of muscle fibers caused by the lack of dystrophin protein (35). Our findings of reduced expressions of Col1a1 and IL-6 in skeletal muscle tissues from Mdivi-1 treated DMD mice suggest that the improved skeletal muscle strength observed in D2-mdx mice may be due to the attenuated fibrosis and inflammation. The extracellular matrix (ECM) is primarily comprised of collagens (>80%) with the most common type of collagen in skeletal muscle tissue as Collagen I (36). Skeletal muscle from DMD models normally exhibit high levels of muscle collagen content, leading to fibrosis, compromised muscle quality and strength (49). It has been shown that targeting fibrosis in DMD models was effective to improve muscle strength and function (16,32,68). In addition, we observed reduced IL-6 gene expression in skeletal muscle tissue from D2-mdx mice treated with Mdivi-1. IL-6 is an inflammatory cytokine that is chronically elevated in DMD, which can promote inflammation and necrosis, leading to fibrosis (53). In line with this, studies using anti-IL-6 receptor antibody in mdx mice have shown attenuated muscle fibrosis, atrophy and improved muscle regeneration and strength (52,70). Overall, our data suggest that Mdivi-1 treatment may reduce IL-6 production in skeletal muscle, which subsequently attenuate inflammation and fibrosis, leading to improved muscle strength in D2-mdx mice. It is worth noting that we did not perform direct evaluations of fibrosis with histology (e.g. hematoxylin and eosin (H&E) and Masson's trichrome staining) in this study, which is one of the limitations. Future studies should warrant such assessment of fibrosis to provide definitive evidence as to whether Mdivi-1 can effectively reduce fibrosis in skeletal muscle from DMD mice.

Keywords/Topics
muscular dystrophy ; mitochondria dynamics ; Drp1 ; lipid peroxidation ; muscle IDuchenne muscular dystrophy ( DMD )

BIOSEB Instruments Used:
Grip strength test (BIO-GS4)

Source :

https://pmc.ncbi.nlm.nih.gov/articles/PMC11703253/

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Test d'agrippement

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