Skeletal Muscle Heme Oxygenase-1 Activity Regulates Aerobic Capacity

Abstract

Physical exercise has profound effects on quality of life and susceptibility to chronic disease, however the regulation of skeletal muscle function at the molecular level after exercise remains unclear. We tested the hypothesis that the benefits of exercise on muscle function are linked, in part, to microtraumatic events and accumulation of free heme. Effective metabolism of heme is controlled by Heme Oxygenase-1 (HO-1, Hmox1) and we find that skeletal muscle-specific  Hmox1^-/- mice (Tam-Cre-HSA-Hmox1^fl/fl) exhibit significant impairment in motor performance after exercise compared to Hmox1^fl/fl controls. Further, we observed a shift in the proportion of muscle fibers from type IIA to IIB with remarkable muscle atrophy not observed in Hmox1^fl/fl mice. Finally, there was significant disruption in mitochondrial content and functionality in fibers from Hmox1^fl/fl-deficient mice that became markedly enhanced with exercise. Collectively, these findings support heme and HO-1 as central regulators in the physiologic response of skeletal muscle to exercise.

Keywords: Exercise training, heme, heme oxygenase-1, hemopexin, DAMP, muscle microtrauma