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.
Key Findings
Results
Skeletal muscle from DMD patients showed reduced mitochondrial content compared to non-dystrophic controls.
Human skeletal muscle samples from DMD patients and non-dystrophic controls (CTR) were analyzed for mitochondrial content
Mitochondrial content was assessed through histological and molecular analyses
PINK1-PARKIN expression was found to be dysregulated in DMD patient muscle tissue
These findings in human tissue provided translational context for the subsequent mouse model experiments
Results
DMD patients exhibited dysregulated PINK1-PARKIN expression in skeletal muscle compared to non-dystrophic controls.
Both PINK1 and PARKIN expression levels were analyzed in human skeletal muscle biopsies
Samples were compared between DMD patients and non-dystrophic control (CTR) subjects
Dysregulation of the PINK1-PARKIN pathway suggests impaired mitophagy signaling in human DMD muscle
This finding implicates mitochondrial quality control dysfunction as a feature of human DMD pathology
Results
Basal mitophagy markers were elevated in mdx mice compared to wild-type C57 control mice under non-exercised conditions.
Eight-week-old male mdx mice and C57 control mice were used
Mitophagy was evaluated via immunofluorescence for LC3, COXIV, and VDAC, as well as western blotting for PINK1 and PARKIN
Elevated basal mitophagy markers suggest a compensatory upregulation of mitophagy in resting dystrophic muscle
Transmission electron microscopy (TEM) was used to visualize mitochondrial ultrastructure supporting these findings
Results
Short-term high-intensity exercise exacerbated muscle necrosis and inflammation in mdx mice.
Mice underwent a 5-day rotarod exercise protocol starting at 8 weeks of age
Muscle pathology was assessed using hematoxylin and eosin (HE), acid phosphatase (ACP), and succinate dehydrogenase (SDH) staining
HE staining revealed increased necrotic fibers following exercise in mdx mice
ACP staining indicated heightened inflammatory and lysosomal activity in exercised mdx muscle
These pathological changes were not observed to the same degree in wild-type C57 mice undergoing the same protocol
Results
Short-term high-intensity exercise impaired activation of PINK1-PARKIN-mediated mitophagy in mdx mice, contrasting with an adaptive mitophagy response in wild-type mice.
Following the 5-day rotarod exercise protocol, PINK1 and PARKIN protein levels were assessed by western blotting
Immunofluorescence co-localization of LC3 with mitochondrial markers COXIV and VDAC was used to assess mitophagy flux
Wild-type C57 mice showed an adaptive upregulation of PINK1-PARKIN mitophagy in response to exercise
mdx mice failed to appropriately activate the PINK1-PARKIN pathway post-exercise, indicating impaired mitochondrial quality control
TEM confirmed altered mitochondrial ultrastructure in exercised mdx muscle
Results
SDH staining revealed altered mitochondrial enzyme activity in mdx mouse skeletal muscle following exercise.
Succinate dehydrogenase (SDH) staining was used to evaluate mitochondrial oxidative capacity in muscle cross-sections
Changes in SDH staining patterns were observed in exercised mdx mice compared to both resting mdx mice and exercised C57 controls
SDH activity reflects mitochondrial content and function, providing histochemical evidence of mitochondrial dysfunction
Findings were consistent with impaired mitochondrial quality control in dystrophic muscle under exercise stress
What This Means
This research suggests that in Duchenne muscular dystrophy (DMD), the muscles' internal system for cleaning up damaged mitochondria (the cell's energy-producing structures) is already under strain at rest and breaks down further under intense exercise. The researchers studied muscle tissue from DMD patients and found reduced mitochondrial content and disrupted signaling through a pathway called PINK1-PARKIN, which normally tags damaged mitochondria for removal. They then tested this in a mouse model of DMD (mdx mice) by having them perform 5 days of high-intensity rotarod exercise and found that this caused significant muscle damage, inflammation, and cell death, while the same exercise produced healthy adaptive responses in normal mice.
The key discovery is that while healthy muscles respond to intense exercise by ramping up mitochondrial cleanup (mitophagy) through the PINK1-PARKIN pathway, dystrophic mdx muscles fail to do this. Instead of activating this protective quality control response, the damaged muscles become overwhelmed, leading to worsening pathology. This was confirmed through multiple methods including microscopy, protein analysis, and electron microscopy showing physically abnormal mitochondria in the muscle tissue.
This research suggests that the type and intensity of exercise matters greatly for individuals with DMD. High-intensity exercise may worsen muscle damage rather than helping, potentially because the mitochondrial quality control system in dystrophic muscles cannot keep pace with the increased demand. These findings highlight the need for carefully designed, tailored exercise programs for DMD patients rather than standard high-intensity regimens, and point to the PINK1-PARKIN mitophagy pathway as a potential therapeutic target for the disease.
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Li J, Zhao Q, He H, Song X. (2026). Exercise-induced muscle injury in Duchenne muscular dystrophy: impaired mitophagy and altered PINK1-PARKIN pathway in mdx mice.. Brain & development. https://doi.org/10.1016/j.braindev.2026.104547