Skeletal muscle heme oxygenase-1 activity regulates aerobic capacity

Cell Rep. 2021 Apr 20;35(3):109018. doi: 10.1016/j.celrep.2021.109018.

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 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.

Keywords: DAMP; exercise training; heme; heme oxygenase-1; hemopexin; mitochondrial dysfunction; muscle atrophy; muscle microtrauma; satellite cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 5-Aminolevulinate Synthetase / genetics
  • 5-Aminolevulinate Synthetase / metabolism
  • Animals
  • Ferrochelatase / genetics
  • Ferrochelatase / metabolism
  • Gene Expression Regulation
  • Heme / metabolism*
  • Heme Oxygenase-1 / deficiency
  • Heme Oxygenase-1 / genetics*
  • 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
  • Muscle Fibers, Skeletal / metabolism*
  • 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*
  • Signal Transduction
  • Tripartite Motif Proteins / genetics
  • Tripartite Motif Proteins / metabolism
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • Isoenzymes
  • Low Density Lipoprotein Receptor-Related Protein-1
  • Lrp1 protein, mouse
  • Membrane Proteins
  • Muscle Proteins
  • Mymx protein, mouse
  • MyoD Protein
  • MyoD1 myogenic differentiation protein
  • PAX7 Transcription Factor
  • Pax7 protein, mouse
  • Tripartite Motif Proteins
  • Heme
  • Heme Oxygenase-1
  • Hmox1 protein, mouse
  • 5-Aminolevulinate Synthetase
  • ALAS2 protein, mouse
  • Trim63 protein, mouse
  • Ubiquitin-Protein Ligases
  • Ferrochelatase