Fig. 7: Schematic overview of the phenotypical alterations observed in the muscle-specific Pex5 KO mouse model.

Upper panel: In control mice, a reduction in peroxisomal content, early mitochondrial alterations such as decreased mitochondrial cristae number, and reduced exercise performance are already evident by 18 months of age. These precede the age-related defects typically observed after 24 months, including further peroxisome loss, progressive mitochondrial dysfunction, and consequential impairments in muscle structure, metabolism, strength, and mass. The decline in muscle force and mass is known as sarcopenia. Lower panel: Pex5 deletion in skeletal muscle leads to abnormal peroxisomal assembly with impaired peroxisomal protein import (peroxisomal ghosts). These changes result in pexophagy flux impairment, altered lipid and amino acid metabolism, reduced mitochondria cristae number, early decline in muscle force, and reduced exercise performance by 3 months of age. Moreover, at this stage, peroxisome (PO)-mitochondria (MT) proximity is reduced, however, the causal or consequential nature of this relationship remains unclear. By 9 months, mitochondrial content is affected, characterized by reduced mitochondrial biogenesis and increased mitophagy. At 18 months, KO muscles exhibit mitochondrial dysfunction and an accelerated onset of age-related muscle atrophy and impairment, marked by the accumulation of tubular aggregates, proteolytic sarcomere breakdown, and neuromuscular junction degeneration. The alterations occurring earlier in KO mice compared to control mice are highlighted in red. Created in BioRender. DAVIGO, I. (2025) https://BioRender.com/bp2gfbd.