Peroxisome Decline in Muscle Drives Accelerated Aging and Weakness

Skeletal muscle accounts for 40–50% of body mass and is central to glucose and lipid metabolism, energy expenditure, and whole-body homeostasis. Despite extensive research into mitochondrial contributions to muscle health, peroxisomes—dynamic organelles critical for fatty acid oxidation and reactive oxygen species detoxification—have been largely overlooked in this context. This study addresses that gap by generating a muscle-specific transgenic mouse model with targeted deletion of Pex5, the receptor responsible for importing the majority of matrix enzymes into peroxisomes.

Mice with muscle-specific Pex5 deletion exhibited early disruptions in lipid and amino acid metabolism, measurable reductions in muscle contractile force, and significantly impaired exercise performance. These functional deficits emerged before overt structural damage, suggesting metabolic compromise precedes morphological deterioration.

Over time, the peroxisomal dysfunction propagated to mitochondria. Mitochondrial ultrastructure was compromised, mitochondrial DNA content declined, and respiratory chain activity was reduced. These defects closely resembled the secondary mitochondrial myopathy described in human Peroxisomal Biogenesis Disorder (PBD) patients with Pex12 and Pex16 mutations. In addition to mitochondrial pathology, the muscles of Pex5-deleted mice showed sarcomere disorganization, neuromuscular junction degeneration, accumulation of protein aggregates, and progressive muscle atrophy—a constellation of features characteristic of accelerated aging.

A key translational finding was that naturally aging control mice also displayed a progressive decline in peroxisomal content within skeletal muscle, lending physiological relevance to the transgenic model. This suggests that peroxisomal deterioration during normal aging may be a contributing driver—rather than a bystander—of age-related muscle decline (sarcopenia).

The study establishes the peroxisome–mitochondria axis as a critical determinant of muscle health. Disruption of this interplay triggers a cascade of metabolic, structural, and functional defects that collectively accelerate muscle aging. These findings open new avenues for therapeutic targeting of peroxisomal biogenesis or function to combat sarcopenia and muscle wasting in aging and disease.