Skeletal muscle heme oxygenase-1 [HO-1] activity regulates aerobic capacity

Physical exercise is enormously important for quality of life, and a cellular hallmark of exercise is the release of free heme following muscle micro trauma. Heme is an important signaling molecule but can be toxic at high doses. Two enzymes are responsible for heme degradation, Hpx, and HO-1. Hpx is an enzyme that scavenges free heme and transports it into cells where it is degraded by the enzyme HO-1. The products of heme degradation by HO-1, among which are carbon monoxide, are highly protective and anti inflammatory. In this paper produced by members of my lab, the hypothesis that heme metabolism is critical in skeletal muscle cell recovery and maintenance of function after aerobic exercise was tested. We show that in the absence of Hpx, the enzyme responsible for scavenging free heme, both untrained and trained mice exhibit no muscle deficits. In contrast, mice lacking HO-1 selectively in skeletal muscle fibers show dramatic structural and functional remodeling toward a fast and more fatigue-prone phenotype. We discovered that loss of HO-1 within muscle fibers impaired the benefits of aerobic exercise training (TR) and altered the muscle phenotype within weeks of deletion, driven largely by changes in metabolism and mitochondrial bioenergetics. Collectively, this study provides insights into the role of heme flux, and HO-1 activity, as an essential pathway necessary for developing and maintaining exercise capacity and muscle physiology.