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The HO-1/CO system regulates mitochondrial-capillary density relationships in human skeletal muscle
Journal article   Open access   Peer reviewed

The HO-1/CO system regulates mitochondrial-capillary density relationships in human skeletal muscle

Shelly R H Pecorella, Jennifer V F Potter, Anne D Cherry, Dionne F Peacher, Karen E Welty-Wolf, Richard E Moon, Claude A Piantadosi and Hagir B Suliman
American journal of physiology. Lung cellular and molecular physiology, Vol.309(8), pp.L857-L871
10/15/2015
DOI: 10.1152/ajplung.00104.2015
PMCID: PMC4609945
PMID: 26186946
url
https://doi.org/10.1152/ajplung.00104.2015View
Published (Version of record) Open Access

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.
 Microscopy, Electron, Transmission Heme Oxygenase-1 - metabolism Glucose Transporter Type 4 - metabolism Humans Mitochondria, Muscle - metabolism RNA, Messenger - genetics Muscle, Skeletal - ultrastructure Oxygen Consumption Male Muscle, Skeletal - metabolism Capillaries - anatomy & histology Carbon Monoxide - metabolism RNA, Messenger - metabolism Quadriceps Muscle - blood supply Young Adult Exercise Test DNA, Mitochondrial - genetics Adolescent Muscle Proteins - metabolism Adult Female Mitochondria, Muscle - ultrastructure Quadriceps Muscle - metabolism Muscle, Skeletal - blood supply

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