Publications

Latest publication 07/07/2025

Inhibition of mitochondrial fission protein Drp1 ameliorates skeletal myopathy i

The main finding of the present study is that D2-mdx mice treated with Mdivi-1, a pharmacological inhibitor of Drp1, showed significantly improved...

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    [title] => Inhibition of mitochondrial fission protein Drp1 ameliorates skeletal myopathy i
    [paragraph] => Inhibition of mitochondrial fission protein Drp1 ameliorates skeletal myopathy in the D2-mdx model of Duchenne muscular dystrophy | American Journal of Physiology-Cell Physiology | American Physiological Society
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Authors
H. Grace  Rosen, Nicolas J.  Berger, Shantel N.  Hodge, Atsutaro  Fujishiro, Jared  Lourie, Vrusti  Kapadia, Tessa  Duzz, Melissa A.  Linden, Eunbin  Jee, Jonghan  Kim, Yuho  Kim, Kai  Zou

 Lab

Journal
American Journal of Physiology-Cell Physiology
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 with their vehicle-treated counterparts. Consistent with our findings, Rexius-Hall et al. (29) recently reported that Mdivi-1 increased contractility generated by engineered muscle fibers in vitro. 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 (47). Our findings of reduced expressions of fibrosis and inflammation 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 composed of collagens with the most common type of collagen in skeletal muscle tissue as collagen I and III (48). Skeletal muscle from DMD models normally exhibits high levels of muscle collagen content, leading to fibrosis, compromised muscle quality and strength (49,50). It has been shown that targeting fibrosis in DMD models was effective to improve muscle strength and function (51–53). Although not tested in skeletal muscle, Mdivi-1 has been shown to alleviate fibrosis in both cardiac and liver tissues (54,55), which is consistent with our results in muscle tissue. In addition, we observed reduced gene expression of several inflammation markers (i.e., IL6, MCP-1, and CXCL12) in skeletal muscle tissue from D2-mdx mice treated with Mdivi-1. Among these markers, the reduced IL6 and MCP1 expression in skeletal muscle from D2-mdx mice is of particular interest. IL-6 is an inflammatory cytokine that is chronically elevated in DMD, which can promote inflammation and necrosis, leading to fibrosis (56). In addition, IL-6 plays a crucial role in stimulating the production of MCP1 in myoblasts (57), suggesting that Mdivi-1 treatment may suppress fibrosis by altering IL-6/MCP1 pathway in skeletal muscle from D2-mdx mice. 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 (58,59). Overall, our data suggest that Mdivi-1 treatment attenuates inflammation, which may further alleviate 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
Drp1; lipid peroxidation; mitochondria dynamics; muscle; muscular dystrophy
BIOSEB Instruments Used:
Grip strength test (BIO-GS4)
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An easy way to objectively quantify the muscular strength of mice and rats, and to assess the effect of drugs, toxins, muscular (i.e. myopathy) and neurodegenerative diseases on muscular degeneration. It is widely used in conjunction with the ROTAROD motor coordination test: a normally coordinated rodent will show a decreased latency to fall off the rotating rod if its muscular strength is low. The Grip Strength Test is a must for your research on activity, motor control & coordination, and is particularly well suited for studies on Parkinson's & Huntington's disease.
New features GS4 - 2023: Color display with permanent backlight screen for easier reading, reset by footswitch, Improved battery time, Larger data memory of 500 values, Animal counter, USB port (charging/data transfer)

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