Skeletal muscle heme oxygenase-1 activity regulates aerobic capacity

• Published in: Cell reports (Cambridge) 2021-04, Vol.35 (3), p.109018-109018, Article 109018
• Main Authors: Alves de Souza, Rodrigo W., Gallo, David, Lee, Ghee Rye, Katsuyama, Eri, Schaufler, Alexa, Weber, Janick, Csizmadia, Eva, Tsokos, George C., Koch, Lauren G., Britton, Steven L., Wisløff, Ulrik, Brum, Patricia C., Otterbein, Leo E.
• Format: Article
• Language: English
• Subjects: 5-Aminolevulinate Synthetase - genetics; 5-Aminolevulinate Synthetase - metabolism; Animals; DAMP; exercise training; Ferrochelatase - genetics; Ferrochelatase - metabolism; Gene Expression Regulation; heme; Heme - metabolism; heme oxygenase-1; Heme Oxygenase-1 - deficiency; Heme Oxygenase-1 - genetics; hemopexin; Isoenzymes - genetics; Isoenzymes - metabolism; Low Density Lipoprotein Receptor-Related Protein-1 - genetics; Low Density Lipoprotein Receptor-Related Protein-1 - metabolism; Male; Membrane Proteins - deficiency; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria - genetics; Mitochondria - metabolism; mitochondrial dysfunction; muscle atrophy; Muscle Fibers, Skeletal - metabolism; muscle microtrauma; Muscle Proteins - genetics; Muscle Proteins - metabolism; Muscular Atrophy - genetics; Muscular Atrophy - metabolism; Muscular Atrophy - physiopathology; MyoD Protein - genetics; MyoD Protein - metabolism; PAX7 Transcription Factor - genetics; PAX7 Transcription Factor - metabolism; Physical Conditioning, Animal - physiology; satellite cells; Signal Transduction; Tripartite Motif Proteins - genetics; Tripartite Motif Proteins - metabolism; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.109018

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-Hmox1fl/fl) 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-Hmox1fl/fl mice show remarkable muscle atrophy compared to Hmox1fl/fl controls. Collectively, these data define a role for heme and HO-1 as central regulators in the physiologic response of skeletal muscle to exercise. [Display omitted] •Aerobic exercise increases circulating free heme due to skeletal muscle microtrauma•Hemopexin-null mice show higher heme levels but no difference in running capacity•Skeletal muscle lacking HO-1 has defective mitochondria and a fatigue-prone phenotype•HO-1 is required to maintain skeletal muscle health during aerobic training Alves de Souza et al. show that deficiency in the heme-degrading enzyme heme oxygenase-1 in skeletal muscle results in atrophy, mitochondrial dysfunction, and a profound inability to adapt to exercise. Heme metabolism is an essential pathway necessary for developing and maintaining exercise capacity, tissue damage control, and muscle health.