Parkin overexpression attenuates muscle atrophy and improves mitochondrial bioenergetics but not histological features of Duchenne muscular dystrophy in mice

TL;DR

Overexpressing Parkin in mice with Duchenne muscular dystrophy improves mitochondrial efficiency and reduces muscle atrophy, but does not fix all disease features.

Contribution

This study demonstrates that Parkin overexpression partially ameliorates mitochondrial and muscle dysfunction in a DMD mouse model.

Findings

Parkin overexpression increased muscle mass and fiber cross-sectional area in DMD mice.

Parkin improved mitochondrial bioenergetic efficiency and reduced mitochondrial ROS production.

Parkin overexpression did not reduce muscle damage markers or central nuclei in DMD mice.

Abstract

Duchenne Muscular Dystrophy (DMD) is the most common childhood muscular disorder. Mitochondrial dysfunctions are key disease features of the disease, and strategies that improve mitochondrial health have emerged as promising to slow disease progression. Emerging evidence indicates that impaired/insufficient mitophagy may contribute to the accumulation of mitochondrial dysfunction seen in patients and animal models of DMD. We therefore hypothesized that overexpressing Parkin, a key mitophagy regulator, may improve mitochondrial and muscle health in a mouse model of DMD. To this end, Parkin was overexpressed using intramuscular injections of adeno-associated viruses performed in 5-week-old and 18-week-old D2.B10-Dmdmdx/J mice (D2.mdx), a widely used mouse model of DMD. Four and 16 weeks of Parkin overexpression initiated in 5-week-old and 18-week-old D2.mdx, respectively, resulted in muscle hypertrophy, as indicated by an increase in muscle mass and fiber cross-sectional area. While Parkin overexpression did not impact maximal mitochondrial respiration or mitochondrial content, it increased the Acceptor Control Ratio, an index of mitochondrial bioenergetic efficiency. Parkin overexpression also decreased mitochondrial H2O2 emission, a surrogate for mitochondrial ROS production. However, Parkin overexpression failed to reduce the proportion of fibers with central nuclei and markers of muscle damage and/or necrosis. Taken all together, our results indicate that Parkin overexpression can attenuate muscle atrophy, improve mitochondrial bioenergetics and lower mitochondrial ROS production in a mouse model of DMD. These findings showcase the partial beneficial effects of overexpressing Parkin in ameliorating some, but not all, pathological features observed in a mouse model of DMD.

The online version contains supplementary material available at 10.1038/s41598-025-34223-9.

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