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.

It has not been established which physiological processes contribute to endurance training-related changes (Δ) in aerobic performance. For example, the relationship between intramuscular metabolic responses at the intensity used during training and improved human functional capacity has not been examined in a longitudinal study. In the present study we hypothesized that improvements in aerobic capacity (V̇o_2max) and metabolic control would combine equally to explain enhanced aerobic performance. Twenty-four sedentary males (24 ± 2 yr; 1.81 ± 0.08 m; 76.6 ± 11.3 kg) undertook supervised cycling training (45 min at 70% of pretraining V̇o_2max) 4 times/wk for 6 wk. Performance was determined using a 15-min cycling time trial, and muscle biopsies were taken before and after a 10-min cycle at 70% of pretraining V̇o_2maxto quantify substrate metabolism. Substantial interindividual variability in training-induced adaptations was observed for most parameters, yet “low responders” for ΔV̇o_2maxwere not consistently low responders for other variables. While V̇o_2maxand time trial performance were related at baseline ( r²= 0.80, P < 0.001), the change in V̇o_2maxwas completely unrelated to the change in aerobic performance. The maximal parameters ΔV̇e_maxand ΔVeq_max(ΔV̇e/V̇o_2max) accounted for 64% of the variance in ΔV̇o_2max( P < 0.001), whereas Δperformance was related to changes in the submaximal parameters Veq_submax( r²= 0.33; P < 0.01), muscle Δlactate ( r²= 0.32; P < 0.01), and Δacetyl-carnitine ( r²= 0.29; P < 0.05). This study demonstrates that improvements in high-intensity aerobic performance in humans are not related to altered maximal oxygen transport capacity. Altered muscle metabolism may provide the link between training stimulus and improved performance, but metabolic parameters do not change in a manner that relates to aerobic capacity changes.

The adaptation of mitochondrial ATP production rate (MAPR) to training and detraining was evaluated in nine healthy men. Muscle samples (approximately 60 mg) were obtained before and after 6 wk of endurance training and after 3 wk of detraining. MAPR was measured in isolated mitochondria by a bioluminometric method. In addition, the activities of mitochondrial and glycolytic enzymes were determined in skeletal muscle. In response to training, MAPR increased by 70%, with a substrate combination of pyruvate + palmitoyl-L-carnitine + alpha-ketoglutarate + malate, by 50% with only pyruvate + malate, and by 92% with palmitoyl-L-carnitine + malate. With detraining MAPR decreased by 12–28% from the posttraining rate (although not significantly for all substrates). No differences were found when MAPR was related to the protein content in the mitochondrial fraction. The largest increase in mitochondrial enzyme activities induced by training was observed for cytochrome-c oxidase (78%), whereas succinate cytochrome c reductase showed only an 18% increase. The activity of citrate synthase increased by 40% and of glutamate dehydrogenase by 45%. Corresponding changes in maximal O2 uptake were a 9.6% increase by training and a 6.0% reversion after detraining. In conclusion, both MAPR and mitochondrial enzyme activities are shown to increase with endurance training and to decrease with detraining.