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EDITORIAL FOCUS

ENVIRONMENTAL, EXERCISE AND RESPIRATORY PHYSIOLOGY

HIF-1 in endurance training: suppression of oxidative metabolism

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 (HIF-1), which upregulates glycolysis and angiogenesis in response to low levels of tissue oxygenation. To examine the role of HIF-1 in endurance training, we have created mice specifically lacking skeletal muscle HIF-1 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 null mice have already upregulated this parameter without training. Furthermore, untrained HIF-1 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 null muscles. Additionally, HIF-1 null muscles have decreased expression of pyruvate dehydrogenase kinase I, a HIF-1 target that inhibits oxidative metabolism. These data demonstrate that removal of HIF-1 causes an adaptive response in skeletal muscle akin to endurance training and provides evidence for the suppression of mitochondrial biogenesis by HIF-1 in normal tissue.

skeletal muscle; hypoxia; exercise; gene regulation

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