Effect of Denervation on Skeletal Muscle Mitochondria in Heterozygous mtDNA Mutator Mice

ABSTRACT Mitochondrial function is essential for skeletal muscle health, and its disruption leads to atrophy and functional decline. This study examines the impact of denervation on skeletal muscle mitochondria in polymerase gamma (PolG) (+/mut) mice, which accumulate mitochondrial DNA (mtDNA) mutations due to a partial deficiency in polymerase gamma proofreading. Using a 14‐day denervation protocol, we assessed muscle mass, mtDNA copy number, oxidative stress and mitochondrial dynamics in wild‐type (WT) and PolG (+/mut) mice. Our findings reveal that while denervation significantly reduced muscle wet weight and mitochondrial enzyme activity, no genotype‐specific differences in muscle atrophy were observed. However, PolG (+/mut) mice displayed more disorganized mitochondrial cristae and elevated oxidative stress markers, indicating greater mitochondrial vulnerability. Despite these changes, the lack of significant differences in mitochondrial proteins and gene expression between genotypes may reflect an adaptive antioxidant response, including increased catalase expression, although the compensatory nature of this response cannot be conclusively determined. These results suggest that oxidative stress–related responses are involved in mitochondrial adaptations during denervation‐induced muscle atrophy. The increased expression of antioxidant enzymes, such as catalase, in PolG (+/mut) mice suggests that antioxidant mechanisms are activated in response to increased oxidative stress. These findings underscore the importance of controlling oxidative stress for maintaining muscle health.