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Regulation of human metabolism by hypoxia-inducible factor

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Regulation of human metabolism by hypoxia-inducible factor. / Formenti, Federico; Constantin-Teodosiu, Dumitru; Emmanuel, Yaso et al.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 28, 13.07.2010, p. 12722-12727.

Research output: Contribution to journalArticlepeer-review

Harvard

Formenti, F, Constantin-Teodosiu, D, Emmanuel, Y, Cheeseman, J, Dorrington, KL, Edwards, LM, Humphreys, SM, Lappin, TRJ, McMullin, M-F, McNamara, CJ, Mills, W, Murphy, J, O'Connor, DF, Percy, MJ, Ratcliffe, PJ, Smith, TG, Treacy, M, Frayn, KN, Greenhaff, PL, Karpe, F, Clarke, K & Robbins, PA 2010, 'Regulation of human metabolism by hypoxia-inducible factor', Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 28, pp. 12722-12727. https://doi.org/10.1073/pnas.1002339107

APA

Formenti, F., Constantin-Teodosiu, D., Emmanuel, Y., Cheeseman, J., Dorrington, K. L., Edwards, L. M., Humphreys, S. M., Lappin, T. R. J., McMullin, M-F., McNamara, C. J., Mills, W., Murphy, J., O'Connor, D. F., Percy, M. J., Ratcliffe, P. J., Smith, T. G., Treacy, M., Frayn, K. N., Greenhaff, P. L., ... Robbins, P. A. (2010). Regulation of human metabolism by hypoxia-inducible factor. Proceedings of the National Academy of Sciences of the United States of America, 107(28), 12722-12727. https://doi.org/10.1073/pnas.1002339107

Vancouver

Formenti F, Constantin-Teodosiu D, Emmanuel Y, Cheeseman J, Dorrington KL, Edwards LM et al. Regulation of human metabolism by hypoxia-inducible factor. Proceedings of the National Academy of Sciences of the United States of America. 2010 Jul 13;107(28):12722-12727. https://doi.org/10.1073/pnas.1002339107

Author

Formenti, Federico ; Constantin-Teodosiu, Dumitru ; Emmanuel, Yaso et al. / Regulation of human metabolism by hypoxia-inducible factor. In: Proceedings of the National Academy of Sciences of the United States of America. 2010 ; Vol. 107, No. 28. pp. 12722-12727.

Bibtex Download

@article{0ed069ccdfa44afe83c3e1f8f2cc7bf6,
title = "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.",
author = "Federico Formenti and Dumitru Constantin-Teodosiu and Yaso Emmanuel and Jane Cheeseman and Dorrington, {Keith L} and Edwards, {Lindsay Martin} and Humphreys, {Sandy M} and Lappin, {Terence R J} and Mary-Frances McMullin and McNamara, {Christopher J.} and Wendy Mills and John Murphy and O'Connor, {David F} and Percy, {Melanie J} and Ratcliffe, {Peter J.} and Smith, {Thomas G} and Marilyn Treacy and Frayn, {Keith N} and Greenhaff, {Paul L} and Fredrik Karpe and Kieran Clarke and Robbins, {Peter A.}",
year = "2010",
month = jul,
day = "13",
doi = "10.1073/pnas.1002339107",
language = "English",
volume = "107",
pages = "12722--12727",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Acad Sciences",
number = "28",

}

RIS (suitable for import to EndNote) Download

TY - JOUR

T1 - Regulation of human metabolism by hypoxia-inducible factor

AU - Formenti, Federico

AU - Constantin-Teodosiu, Dumitru

AU - Emmanuel, Yaso

AU - Cheeseman, Jane

AU - Dorrington, Keith L

AU - Edwards, Lindsay Martin

AU - Humphreys, Sandy M

AU - Lappin, Terence R J

AU - McMullin, Mary-Frances

AU - McNamara, Christopher J.

AU - Mills, Wendy

AU - Murphy, John

AU - O'Connor, David F

AU - Percy, Melanie J

AU - Ratcliffe, Peter J.

AU - Smith, Thomas G

AU - Treacy, Marilyn

AU - Frayn, Keith N

AU - Greenhaff, Paul L

AU - Karpe, Fredrik

AU - Clarke, Kieran

AU - Robbins, Peter A.

PY - 2010/7/13

Y1 - 2010/7/13

N2 - 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.

AB - 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.

U2 - 10.1073/pnas.1002339107

DO - 10.1073/pnas.1002339107

M3 - Article

C2 - 20616028

VL - 107

SP - 12722

EP - 12727

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 28

ER -

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