HIF-1alpha in endurance training: suppression of oxidative metabolism.
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-1alpha (HIF-1alpha), which upregulates glycolysis and angiogenesis in response to low levels of tissue oxygenation. To examine the role of HIF-1alpha in endurance training, we have created mice specifically lacking skeletal muscle HIF-1alpha 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-1alpha null mice have already upregulated this parameter without training. Furthermore, untrained HIF-1alpha 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-1alpha null muscles. Additionally, HIF-1alpha null muscles have decreased expression of pyruvate dehydrogenase kinase I, a HIF-1alpha target that inhibits oxidative metabolism. These data demonstrate that removal of HIF-1alpha causes an adaptive response in skeletal muscle akin to endurance training and provides evidence for the suppression of mitochondrial biogenesis by HIF-1alpha in normal tissue.
Mason
Steven D
SD
Div. of Biologicay, University of California, San Diego, La Jolla, CA 92093-0377, USA.
Rundqvist
Helene
H
Papandreou
Ioanna
I
Duh
Roger
R
McNulty
Wayne J
WJ
Howlett
Richard A
RA
Olfert
I Mark
IM
Sundberg
Carl Johan
CJ
Denko
Nicholas C
NC
Poellinger
Lorenz
L
Johnson
Randall S
RS
D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004906:Erythrocyte Count; D015870:Gene Expression / Q000502:physiology; D006400:Hematocrit; D006454:Hemoglobins / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000097:blood / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000201:enzymology / Q000378:metabolism; D032446:Myoblasts / Q000502:physiology; D010084:Oxidation-Reduction; D010100:Oxygen / Q000097:blood; D010101:Oxygen Consumption / Q000235:genetics / Q000502:physiology; D010805:Physical Conditioning, Animal / Q000502:physiology*; D010807:Physical Endurance / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics
D006454:Hemoglobins; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D017868:Cyclic AMP-Dependent Protein Kinases; D010100:Oxygen