Regulation of human metabolism by hypoxia-inducible factor.
The hypoxia-inducible factor (HIF) family of transcription factors directs a coordinated cellular response to hypoxia that includes the transcriptional regulation of a number of metabolic enzymes. Chuvash polycythemia (CP) is an autosomal recessive human disorder in which the regulatory degradation of HIF is impaired, resulting in elevated levels of HIF at normal oxygen tensions. Apart from the polycythemia, CP patients have marked abnormalities of cardiopulmonary function. No studies of integrated metabolic function have been reported. Here we describe the response of these patients to a series of metabolic stresses: exercise of a large muscle mass on a cycle ergometer, exercise of a small muscle mass (calf muscle) which allowed noninvasive in vivo assessments of muscle metabolism using (31)P magnetic resonance spectroscopy, and a standard meal tolerance test. During exercise, CP patients had early and marked phosphocreatine depletion and acidosis in skeletal muscle, greater accumulation of lactate in blood, and reduced maximum exercise capacities. Muscle biopsy specimens from CP patients showed elevated levels of transcript for pyruvate dehydrogenase kinase, phosphofructokinase, and muscle pyruvate kinase. In cell culture, a range of experimental manipulations have been used to study the effects of HIF on cellular metabolism. However, these approaches provide no potential to investigate integrated responses at the level of the whole organism. Although CP is relatively subtle disorder, our study now reveals a striking regulatory role for HIF on metabolism during exercise in humans. These findings have significant implications for the development of therapeutic approaches targeting the HIF pathway.
Formenti
Federico
F
Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, United Kingdom.
Constantin-Teodosiu
Dumitru
D
Emmanuel
Yaso
Y
Cheeseman
Jane
J
Dorrington
Keith L
KL
Edwards
Lindsay M
LM
Humphreys
Sandy M
SM
Lappin
Terence R J
TR
McMullin
Mary F
MF
McNamara
Christopher J
CJ
Mills
Wendy
W
Murphy
John A
JA
O'Connor
David F
DF
Percy
Melanie J
MJ
Ratcliffe
Peter J
PJ
Smith
Thomas G
TG
Treacy
Marilyn
M
Frayn
Keith N
KN
Greenhaff
Paul L
PL
Karpe
Fredrik
F
Clarke
Kieran
K
Robbins
Peter A
PA
D000328:Adult; D015444:Exercise / Q000502:physiology; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D000860:Hypoxia / Q000235:genetics* / Q000378:metabolism*; D007773:Lactates / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism; D009132:Muscles / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D011086:Polycythemia / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D007773:Lactates; D014157:Transcription Factors; D019344:Lactic Acid; D010100:Oxygen