Deletion of heart-type cytochrome c oxidase subunit 7a1 impairs skeletal muscle angiogenesis and oxidative phosphorylation

Key points Cytochrome c oxidase (Cox) is the proposed rate-limiting enzyme of aerobic metabolism in mammals. This study examined a mouse model that has a heart/skeletal muscle-specific isoform of Cox deleted and represents a mild form of mitochondrial myopathy. The results indicated that endurance capacity was severely limited in the knockout animals compared with controls. The observed exercise intolerance was accompanied by decreased capillarity in the hindlimb muscle as well as reduced energy production. The results suggest that mild mitochondrial myopathy results in adverse structural and functions changes in muscle bioenergetics. Abstract Oxidative metabolism is needed for sustained skeletal muscle function. A key component of such metabolism is cytochrome c oxidase, the 13-subunit terminal complex of the mitochondrial electron transport chain. We used mice null for one of the two isoforms of Cox subunit 7a, heart/skeletal muscle-specific Cox7a1, to examine the cellular and functional responses of muscle adaptation in response to mitochondrial dysfunction. Specifically we determined if deletion of Cox7a1 would (1) limit exercise capacity, and (2) alter genes responsible for skeletal muscle capillarity and mitochondrial biogenesis. Sixteen male mice (Cox7a1 null mice, n= 8, and littermate controls, n= 8) performed incremental and run-to-exhaustion treadmill tests. The hindlimb muscles for both groups were analysed. The results indicated that capillary indices were reduced (by 30.744.9%) in the Cox7a1 null mice relative to controls. In addition, resting ATP levels and Cox specific activity were significantly reduced (>60%) in both glycolytic and oxidative muscle fibre types despite an increase in a major regulator of mitochondrial biogenesis, PGC-1 beta. These changes in the skeletal muscle resulted in exercise intolerance for the Cox7a1 null mice. Thus, our data indicate that deletion of the Cox7a1 isoform results in reduced muscle bioenergetics and hindlimb capillarity, helping to explain the observed impairment of muscle structure and function.