title: The HO-1/CO system regulates mitochondrial-capillary density relationships in human skeletal muscle.
abstract: The heme oxygenase-1 (HO-1)/carbon monoxide (CO) system induces mitochondrial biogenesis, but its biological impact in human skeletal muscle is uncertain. The enzyme system generates CO, which stimulates mitochondrial proliferation in normal muscle. Here we examined whether CO breathing can be used to produce a coordinated metabolic and vascular response in human skeletal muscle. In 19 healthy subjects, we performed vastus lateralis muscle biopsies and tested one-legged maximal O2 uptake (V̇o2max) before and after breathing air or CO (200 ppm) for 1 h daily for 5 days. In response to CO, there was robust HO-1 induction along with increased mRNA levels for nuclear-encoded mitochondrial transcription factor A (Tfam), cytochrome c, cytochrome oxidase subunit IV (COX IV), and mitochondrial-encoded COX I and NADH dehydrogenase subunit 1 (NDI). CO breathing did not increase V̇o2max (1.96 ± 0.51 pre-CO, 1.87 ± 0.50 post-CO l/min; P = not significant) but did increase muscle citrate synthase, mitochondrial density (139.0 ± 34.9 pre-CO, 219.0 ± 36.2 post-CO; no. of mitochondrial profiles/field), myoglobin content and glucose transporter (GLUT4) protein level and led to GLUT4 localization to the myocyte membrane, all consistent with expansion of the tissue O2 transport system. These responses were attended by increased cluster of differentiation 31 (CD31)-positive muscle capillaries (1.78 ± 0.16 pre-CO, 2.37 ± 0.59 post-CO; capillaries/muscle fiber), implying the enrichment of microvascular O2 reserve. The findings support that induction of the HO-1/CO system by CO not only improves muscle mitochondrial density, but regulates myoglobin content, GLUT4 localization, and capillarity in accordance with current concepts of skeletal muscle plasticity.
authors.affiliation: Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina; Center for Hyperbaric Medicine and Environmental Physiology, Duke University Medical Center, Durham, North Carolina; and.
authors.forename: Shelly R H
authors.initials: SR
authors.lastname: Pecorella
authors.affiliation: Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina; Center for Hyperbaric Medicine and Environmental Physiology, Duke University Medical Center, Durham, North Carolina; and.
authors.forename: Jennifer V F
authors.initials: JV
authors.lastname: Potter
authors.affiliation: Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina; Center for Hyperbaric Medicine and Environmental Physiology, Duke University Medical Center, Durham, North Carolina; and.
authors.forename: Anne D
authors.initials: AD
authors.lastname: Cherry
authors.affiliation: Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina; Center for Hyperbaric Medicine and Environmental Physiology, Duke University Medical Center, Durham, North Carolina; and.
authors.forename: Dionne F
authors.initials: DF
authors.lastname: Peacher
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, North Carolina;
authors.forename: Karen E
authors.initials: KE
authors.lastname: Welty-Wolf
authors.affiliation: Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina; Department of Medicine, Duke University Medical Center, Durham, North Carolina; Center for Hyperbaric Medicine and Environmental Physiology, Duke University Medical Center, Durham, North Carolina; and.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Moon
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, North Carolina; Center for Hyperbaric Medicine and Environmental Physiology, Duke University Medical Center, Durham, North Carolina; and Department of Pathology, Duke University Medical Center, Durham, North Carolina claude.piantadosi@dm.duke.edu.
authors.forename: Claude A
authors.initials: CA
authors.lastname: Piantadosi
authors.affiliation: Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina; Center for Hyperbaric Medicine and Environmental Physiology, Duke University Medical Center, Durham, North Carolina; and.
authors.forename: Hagir B
authors.initials: HB
authors.lastname: Suliman
mesh_terms: D000293:Adolescent; D000328:Adult; D002196:Capillaries / Q000033:anatomy & histology; D002248:Carbon Monoxide / Q000378:metabolism*; D004272:DNA, Mitochondrial / Q000235:genetics; D005080:Exercise Test; D005260:Female; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006801:Humans; D008297:Male; D046529:Microscopy, Electron, Transmission; D008931:Mitochondria, Muscle / Q000378:metabolism / Q000648:ultrastructure; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000378:metabolism* / Q000648:ultrastructure; D010101:Oxygen Consumption; D052097:Quadriceps Muscle / Q000098:blood supply / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D004272:DNA, Mitochondrial; D051275:Glucose Transporter Type 4; D009124:Muscle Proteins; D012333:RNA, Messenger; C495692:SLC2A4 protein, human; D002248:Carbon Monoxide; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1
keywords: GLUT 4; V̇o2max; carbon monoxide; heme oxygenase-1; mitochondrial biogenesis; myoglobin; nuclear respiratory factor-1; oxygen uptake