The hypoxia-inducible factor (HIF) family of transcription factors regulates the expression of a number of genes relating to metabolism. In the recessive condition of Chuvash Polycythemia (CP), the normal degradation of the HIF family is compromised by a mutation in the von Hippel-Lindau gene, resulting in elevated levels of these factors at normal oxygen tensions. We have found a reduced exercise capacity in patients with CP compared with controls. A few patients have been diagnosed with heterozygous ‘gain-of-function’ mutations in the HIF-2alpha gene. These patients provide an opportunity to understand whether an isolated upregulation of HIF-2alpha limits exercise capacity. In addition to the 5 CP patients, we recruited 3 HIF-2alpha patients and 6 matched control participants. We measured work rate and concentration of lactate in venous blood during an exercise test to exhaustion. One patient with the HIF-2a mutation was no different from his controls. The other two had a limited exercise capacity, and stopped at low levels of venous lactate (Fig.1) – both of these patients had a sedentary lifestyle. As at least one patient did not have the marked lactate accumulation and exercise limitation observed in CP patients, we conclude that isolated upregulation of HIF-2alpha does not necessarily result in the marked reduction in exercise capacity observed in CP.
University of Manchester (2010) Proc Physiol Soc 19, PC177
Poster Communications: Isolated upregulation of hypoxia-inducible factor 2?? does not consistently reduce exercise capacity in humans
F. Formenti1, P. Beer5, Q. P. Croft1, K. L. Dorrington1, D. P. Gale2, T. R. Lappin3, G. Lucas4, P. H. Maxwell2, M. F. McMullin3, D. F. O’Connor1, M. J. Percy3, T. G. Smith1, N. P. Talbot1, P. A. Robbins1
1. University of Oxford, Oxford, United Kingdom. 2. University College London, London, United Kingdom. 3. Queen's University Belfast, Belfast, United Kingdom. 4. Manchester Royal Infirmary, Manchester, United Kingdom. 5. University of Cambridge, Cambridge, United Kingdom.
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