Alves de Souza, Rodrigo W; Gallo, David; Lee, Ghee R; Katsuyama, Eri; Schaufler, Alexa; Weber, Janick; Csizmadia, Eva; Tsokos, George C; Koch, Lauren G; Britton, Steven L; Wisløff, Ulrik; Brum, Patri C; Otterbein, L E
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 partly to microtraumatic events that result in accumulation of circulating heme. Effective metabolism of heme is controlled by Heme Oxygenase-1 (HO-1, Hmox1), and we find that mouse skeletal muscle-specific HO-1 deletion (Tam-Cre-HSA-Hmox1) shifts the proportion of muscle fibers from type IIA to type IIB concomitant with a disruption in mitochondrial content and function. In addition to a significant impairment in running performance and response to exercise training, Tam-Cre-HSA-Hmox1 mice show remarkable muscle atrophy compared to Hmox1 controls. Collectively, these data define a role for heme and HO-1 as central regulators in the physiologic response of skeletal muscle to exercise.