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This Article Full Text Full Text (PDF) All Versions of this Article: 297/1/H392    most recent 00164.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Rhodes, M. A. Articles by Suliman, H. B. PubMed PubMed Citation Articles by Rhodes, M. A. Articles by Suliman, H. B.

Carbon monoxide, skeletal muscle oxidative stress, and mitochondrial biogenesis in humans

Departments of ¹Anesthesiology, ²Medicine, and ³Pathology and ⁴Center for Hyperbaric Medicine and Environmental Physiology, Duke University Medical Center, Durham, North Carolina

Submitted 19 February 2009 ; accepted in final form 18 May 2009

Given that the physiology of heme oxygenase-1 (HO-1) encompasses mitochondrial biogenesis, we tested the hypothesis that the HO-1 product, carbon monoxide (CO), activates mitochondrial biogenesis in skeletal muscle and enhances maximal oxygen uptake (O_2max) in humans. In 10 healthy subjects, we biopsied the vastus lateralis and performed O_2max tests followed by blinded randomization to air or CO breathing (1 h/day at 100 parts/million for 5 days), a contralateral muscle biopsy on day 5, and repeat O_2max testing on day 8. Six independent subjects underwent CO breathing and two muscle biopsies without exercise testing. Molecular studies were performed by real-time RT-PCR, Western blot analysis, and immunochemistry. After O_2max testing plus CO breathing, significant increases were found in mRNA levels for nuclear respiratory factor-1, peroxisome proliferator-activated receptor- coactivator-1, mitochondrial transcription factor-A (Tfam), and DNA polymerase (Pol) with no change in mitochondrial DNA (mtDNA) copy number or O_2max. Levels of myosin heavy chain I and nuclear-encoded HO-1, superoxide dismutase-2, citrate synthase, mitofusin-1 and -2, and mitochondrial-encoded cytochrome oxidase subunit-I (COX-I) and ATPase-6 proteins increased significantly. None of these responses were reproduced by O_2max testing alone, whereas CO alone increased Tfam and Pol mRNA, and COX-I, ATPase-6, mitofusin-2, HO-1, and superoxide dismutase protein. These findings provide evidence linking the HO/CO response involved in mitochondrial biogenesis in rodents to skeletal muscle in humans through a set of responses involving regulation of the mtDNA transcriptosome and mitochondrial fusion proteins autonomously of changes in exercise capacity.

heme oxygenase-1; superoxide dismutase-2; peroxisome proliferator-activated receptor- coactivator-1; nuclear respiratory factor-1; oxygen uptake