Hypophosphatemia promotes lower rates of muscle ATP synthesis

Hypophosphatemia can lead to muscle weakness and respiratory and heart failure, but the mechanism is unknown. To address this question, we noninvasively assessed rates of muscle ATP synthesis in hypophosphatemic mice by using in vivo saturation transfer [31P]-magnetic resonance spectroscopy. By usin...

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Main Authors:	Pesta, Dominik H., Tsirigotis, Dimitrios N., Befroy, Douglas E., Caballero, Daniel, Jurczak, Michael J., Rahimi, Yasmeen, Cline, Gary W., Dufour, Sylvie, Birkenfeld, Andreas L., Rothman, Douglas L., Carpenter, Thomas O., Insogna, Karl, Petersen, Kitt Falk, Bergwitz, Clemens, Shulman, Gerald I.
Format:	Online
Language:	English
Published:	Federation of American Societies for Experimental Biology 2016
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5024687/

id	pubmed-5024687
recordtype	oai_dc
spelling	pubmed-50246872016-09-29 Hypophosphatemia promotes lower rates of muscle ATP synthesis Pesta, Dominik H. Tsirigotis, Dimitrios N. Befroy, Douglas E. Caballero, Daniel Jurczak, Michael J. Rahimi, Yasmeen Cline, Gary W. Dufour, Sylvie Birkenfeld, Andreas L. Rothman, Douglas L. Carpenter, Thomas O. Insogna, Karl Petersen, Kitt Falk Bergwitz, Clemens Shulman, Gerald I. Research Hypophosphatemia can lead to muscle weakness and respiratory and heart failure, but the mechanism is unknown. To address this question, we noninvasively assessed rates of muscle ATP synthesis in hypophosphatemic mice by using in vivo saturation transfer [31P]-magnetic resonance spectroscopy. By using this approach, we found that basal and insulin-stimulated rates of muscle ATP synthetic flux (VATP) and plasma inorganic phosphate (Pi) were reduced by 50% in mice with diet-induced hypophosphatemia as well as in sodium-dependent Pi transporter solute carrier family 34, member 1 (NaPi2a)-knockout (NaPi2a−/−) mice compared with their wild-type littermate controls. Rates of VATP normalized in both hypophosphatemic groups after restoring plasma Pi concentrations. Furthermore, VATP was directly related to cellular and mitochondrial Pi uptake in L6 and RC13 rodent myocytes and isolated muscle mitochondria. Similar findings were observed in a patient with chronic hypophosphatemia as a result of a mutation in SLC34A3 who had a 50% reduction in both serum Pi content and muscle VATP. After oral Pi repletion and normalization of serum Pi levels, muscle VATP completely normalized in the patient. Taken together, these data support the hypothesis that decreased muscle ATP synthesis, in part, may be caused by low blood Pi concentrations, which may explain some aspects of muscle weakness observed in patients with hypophosphatemia.—Pesta, D. H., Tsirigotis, D. N., Befroy, D. E., Caballero, D., Jurczak, M. J., Rahimi, Y., Cline, G. W., Dufour, S., Birkenfeld, A. L., Rothman, D. L., Carpenter, T. O., Insogna, K., Petersen, K. F., Bergwitz, C., Shulman, G. I. Hypophosphatemia promotes lower rates of muscle ATP synthesis. Federation of American Societies for Experimental Biology 2016-10 2016-06-23 /pmc/articles/PMC5024687/ /pubmed/27338702 http://dx.doi.org/10.1096/fj.201600473R Text en © The Author(s) http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) (http://creativecommons.org/licenses/by/4.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Pesta, Dominik H. Tsirigotis, Dimitrios N. Befroy, Douglas E. Caballero, Daniel Jurczak, Michael J. Rahimi, Yasmeen Cline, Gary W. Dufour, Sylvie Birkenfeld, Andreas L. Rothman, Douglas L. Carpenter, Thomas O. Insogna, Karl Petersen, Kitt Falk Bergwitz, Clemens Shulman, Gerald I.
spellingShingle	Pesta, Dominik H. Tsirigotis, Dimitrios N. Befroy, Douglas E. Caballero, Daniel Jurczak, Michael J. Rahimi, Yasmeen Cline, Gary W. Dufour, Sylvie Birkenfeld, Andreas L. Rothman, Douglas L. Carpenter, Thomas O. Insogna, Karl Petersen, Kitt Falk Bergwitz, Clemens Shulman, Gerald I. Hypophosphatemia promotes lower rates of muscle ATP synthesis
author_facet	Pesta, Dominik H. Tsirigotis, Dimitrios N. Befroy, Douglas E. Caballero, Daniel Jurczak, Michael J. Rahimi, Yasmeen Cline, Gary W. Dufour, Sylvie Birkenfeld, Andreas L. Rothman, Douglas L. Carpenter, Thomas O. Insogna, Karl Petersen, Kitt Falk Bergwitz, Clemens Shulman, Gerald I.
author_sort	Pesta, Dominik H.
title	Hypophosphatemia promotes lower rates of muscle ATP synthesis
title_short	Hypophosphatemia promotes lower rates of muscle ATP synthesis
title_full	Hypophosphatemia promotes lower rates of muscle ATP synthesis
title_fullStr	Hypophosphatemia promotes lower rates of muscle ATP synthesis
title_full_unstemmed	Hypophosphatemia promotes lower rates of muscle ATP synthesis
title_sort	hypophosphatemia promotes lower rates of muscle atp synthesis
description	Hypophosphatemia can lead to muscle weakness and respiratory and heart failure, but the mechanism is unknown. To address this question, we noninvasively assessed rates of muscle ATP synthesis in hypophosphatemic mice by using in vivo saturation transfer [31P]-magnetic resonance spectroscopy. By using this approach, we found that basal and insulin-stimulated rates of muscle ATP synthetic flux (VATP) and plasma inorganic phosphate (Pi) were reduced by 50% in mice with diet-induced hypophosphatemia as well as in sodium-dependent Pi transporter solute carrier family 34, member 1 (NaPi2a)-knockout (NaPi2a−/−) mice compared with their wild-type littermate controls. Rates of VATP normalized in both hypophosphatemic groups after restoring plasma Pi concentrations. Furthermore, VATP was directly related to cellular and mitochondrial Pi uptake in L6 and RC13 rodent myocytes and isolated muscle mitochondria. Similar findings were observed in a patient with chronic hypophosphatemia as a result of a mutation in SLC34A3 who had a 50% reduction in both serum Pi content and muscle VATP. After oral Pi repletion and normalization of serum Pi levels, muscle VATP completely normalized in the patient. Taken together, these data support the hypothesis that decreased muscle ATP synthesis, in part, may be caused by low blood Pi concentrations, which may explain some aspects of muscle weakness observed in patients with hypophosphatemia.—Pesta, D. H., Tsirigotis, D. N., Befroy, D. E., Caballero, D., Jurczak, M. J., Rahimi, Y., Cline, G. W., Dufour, S., Birkenfeld, A. L., Rothman, D. L., Carpenter, T. O., Insogna, K., Petersen, K. F., Bergwitz, C., Shulman, G. I. Hypophosphatemia promotes lower rates of muscle ATP synthesis.
publisher	Federation of American Societies for Experimental Biology
publishDate	2016
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5024687/
_version_	1613652637035528192

Hypophosphatemia promotes lower rates of muscle ATP synthesis

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