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Am J Physiol Regul Integr Comp Physiol 293: R2059-R2069, 2007. First published September 12, 2007; doi:10.1152/ajpregu.00335.2007
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EDITORIAL FOCUS

ENVIRONMENTAL, EXERCISE AND RESPIRATORY PHYSIOLOGY

HIF-1{alpha} in endurance training: suppression of oxidative metabolism

Steven D. Mason,1 Helene Rundqvist,3 Ioanna Papandreou,4 Roger Duh,1 Wayne J. McNulty,1 Richard A. Howlett,5 I. Mark Olfert,5 Carl Johan Sundberg,2 Nicholas C. Denko,4 Lorenz Poellinger,3 and Randall S. Johnson1

1Molecular Biology Section, Division of Biology and 5Division of Physiology, School of Medicine, University of California San Diego, San Diego, California; Departments of 2Physiology and Pharmacology and 3Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden; and 4Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Palo Alto, California

Submitted 11 May 2007 ; accepted in final form 7 August 2007

ABSTRACT

During endurance training, exercising skeletal muscle experiences severe and repetitive oxygen stress. The primary transcriptional response factor for acclimation to hypoxic stress is hypoxia-inducible factor-1{alpha} (HIF-1{alpha}), which upregulates glycolysis and angiogenesis in response to low levels of tissue oxygenation. To examine the role of HIF-1{alpha} in endurance training, we have created mice specifically lacking skeletal muscle HIF-1{alpha} and subjected them to an endurance training protocol. We found that only wild-type mice improve their oxidative capacity, as measured by the respiratory exchange ratio; surprisingly, we found that HIF-1{alpha} null mice have already upregulated this parameter without training. Furthermore, untrained HIF-1{alpha} null mice have an increased capillary to fiber ratio and elevated oxidative enzyme activities. These changes correlate with constitutively activated AMP-activated protein kinase in the HIF-1{alpha} null muscles. Additionally, HIF-1{alpha} null muscles have decreased expression of pyruvate dehydrogenase kinase I, a HIF-1{alpha} target that inhibits oxidative metabolism. These data demonstrate that removal of HIF-1{alpha} causes an adaptive response in skeletal muscle akin to endurance training and provides evidence for the suppression of mitochondrial biogenesis by HIF-1{alpha} in normal tissue.

skeletal muscle; hypoxia; exercise; gene regulation


Address for reprint requests and other correspondence: R. S. Johnson, Div. of Biological Sciences, Univ. of California, San Diego, 9500 Gilman Dr., Mail Code 0377, La Jolla, CA 92093-0377 (e-mail: rsjohnson{at}ucsd.edu)






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