Regulation of human metabolism by hypoxia-inducible factor

Abstract

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.

Fig. 1.

Responses of CP patients and control participants to incremental exercise on a cycle ergometer. (A) Venous blood lactate concentration, (B) end-tidal partial pressure of carbon dioxide (PCO₂), and (C) ventilation expressed as a function of work rate. Empty circles show results from the control group; filled circles show results from CP group. Data are mean ± SD. Number of individual values averaged per data point varies depending on number of participants who achieved the work rate; individuals’ maximum work rates are reported in Table 1. Horizontal lines indicate that each underlying average value for the CP patients differs significantly from the corresponding value for the control participants. *P < 0.05; **P < 0.01.

Fig. 2.

Examples of spectra obtained from calf muscle during ³¹P MRS. (A and B) Spectra for a representative control participant. (C and D) Spectra for a representative CP patient. (A and C) Spectra recorded at rest. (B and D) Spectra recorded in the last minute of the 5-W exercise period. The depletion of PCr and increase in P_i with exercise was much more marked in the Chuvash patient than in the control participant.

Fig. 3.

Results from CP group and control group for ³¹P MRS on calf muscle: (A) PCr concentration, (B) P_i concentration, and (C) pH as a function of time. The vertical broken lines indicate the onset and offset of the 5-min plantar-flexion exercise sessions, and the associated black bars indicate the power outputs (3, 4, and 5 W). Empty circles show results from the control group (n = 5); filled circles show results from the CP group (n = 5). Values are minute averages ± SD. Hatched horizontal bars indicate periods of significant difference (P < 0.05) between groups.