Exercise-induced muscle injury in Duchenne muscular dystrophy: impaired mitophagy and altered PINK1-PARKIN pathway in mdx mice.

OBJECTIVE

Duchenne muscular dystrophy (DMD) is a severe hereditary disorder characterized by dystrophin deficiency, leading to progressive muscle weakness. Mitochondrial dysfunction and impaired quality control, particularly via the PTEN-induced putative kinase 1 (PINK1)-E3 ubiquitin ligase PARK2 (PARKIN) mitophagy pathway, are implicated in DMD pathogenesis, but the impact of exercise remains unclear. This study investigated the effects of short-term high-intensity exercise on skeletal muscle pathology and mitophagy in mdx mice.

METHODS

Skeletal muscle from DMD patients and non-dystrophic controls (CTR) was analyzed for mitochondrial content and PINK1-PARKIN expression. Eight-week-old male mdx and C57 control mice underwent a 5-day rotarod exercise protocol. Muscle pathology was assessed using hematoxylin and eosin (HE), acid phosphatase (ACP), and succinate dehydrogenase (SDH) staining. Mitophagy was evaluated via immunofluorescence for microtubule-associated protein 1 light chain 3 (LC3), cytochrome c oxidase subunit IV (COXIV), and voltage-dependent anion channel (VDAC), as well as western blotting for PINK1 and PARKIN. Transmission electron microscopy (TEM) was used to visualize mitochondrial ultrastructure.

RESULTS

In DMD patients, skeletal muscle showed reduced mitochondrial content and dysregulated PINK1-PARKIN expression. In mdx mice, basal mitophagy markers were elevated. Short-term high-intensity exercise exacerbated muscle necrosis and inflammation in mdx mice while impairing the activation of PINK1-PARKIN-mediated mitophagy, contrasting with the adaptive response in wild-type mice.

CONCLUSION

Short-term high-intensity exercise exacerbates skeletal muscle pathology in mdx mice, which is associated with impaired activation of PINK1-PARKIN-mediated mitophagy, underscoring the critical role of mitochondrial quality control in DMD and the need for tailored exercise regimens.