Hypophosphatemia promotes lower rates of muscle ATP synthesis

Dominik H Pesta; Dimitrios N Tsirigotis; Douglas E Befroy; Daniel Caballero; Michael J Jurczak; Yasmeen Rahimi; Gary W Cline; Sylvie Dufour; Andreas L Birkenfeld; Douglas L Rothman; Thomas O Carpenter; Karl Insogna; Kitt Mia Falck Petersen; Clemens Bergwitz; Gerald I. Shulman

doi:10.1096/fj.201600473R

Hypophosphatemia promotes lower rates of muscle ATP synthesis

Dominik H Pesta, Dimitrios N Tsirigotis, Douglas E Befroy, Daniel Caballero, Michael J Jurczak, Yasmeen Rahimi, Gary W Cline, Sylvie Dufour, Andreas L Birkenfeld, Douglas L Rothman, Thomas O Carpenter, Karl Insogna, Kitt Mia Falck Petersen, Clemens Bergwitz, Gerald I. Shulman

30 Citations (Scopus)

Abstract

Hypophosphatemia can lead to muscle weakness and respiratory and heart failure, but themechanism is unknown. To address this question, we noninvasively assessed rates of muscle ATP synthesis in hypophosphatemic micebyusing in vivo saturation transfer [31P]-magnetic resonance spectroscopy.Byusing this approach,we foundthat basal and insulin-stimulated rates of muscle ATP synthetic flux (V_ATP) and plasma inorganic phosphate (P_i) were reduced by 50% in mice with diet-induced hypophosphatemia as well as in sodium-dependent P_i transporter solute carrier family 34, member 1 (NaPi2a)-knockout (NaPi2a^-/-)mice compared with their wild-type littermate controls. Rates of V_ATP normalized in both hypophosphatemic groups after restoring plasma P_i concentrations. Furthermore, V_ATP was directly related to cellular and mitochondrial P_i uptake in L6 and RC13 rodentmyocytes and isolatedmuscle mitochondria.Similar findingswere observed ina patientwith chronichypophosphatemia as a result of amutation in SLC34A3 who had a 50% reduction in both serum P_i content and muscle V_ATP. After oral P_i repletion and normalization of serum P_i levels, muscle V_ATP completely normalized in the patient. Taken together, these data support the hypothesis that decreasedmuscle ATP synthesis, in part,may be caused by low blood P_i 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.

Original language	English
Journal	FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume	30
Issue number	10
Pages (from-to)	3378-3387
Number of pages	10
ISSN	0892-6638
DOIs	https://doi.org/10.1096/fj.201600473R
Publication status	Published - Oct 2016

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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. M. F., Bergwitz, C., & Shulman, G. I. (2016). Hypophosphatemia promotes lower rates of muscle ATP synthesis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 30(10), 3378-3387. https://doi.org/10.1096/fj.201600473R

Pesta, DH, Tsirigotis, DN, Befroy, DE, Caballero, D, Jurczak, MJ, Rahimi, Y, Cline, GW, Dufour, S, Birkenfeld, AL, Rothman, DL, Carpenter, TO, Insogna, K, Petersen, KMF, Bergwitz, C & Shulman, GI 2016, 'Hypophosphatemia promotes lower rates of muscle ATP synthesis', FASEB journal : official publication of the Federation of American Societies for Experimental Biology, vol. 30, no. 10, pp. 3378-3387. https://doi.org/10.1096/fj.201600473R

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title = "Hypophosphatemia promotes lower rates of muscle ATP synthesis",

abstract = "Hypophosphatemia can lead to muscle weakness and respiratory and heart failure, but themechanism is unknown. To address this question, we noninvasively assessed rates of muscle ATP synthesis in hypophosphatemic micebyusing in vivo saturation transfer [31P]-magnetic resonance spectroscopy.Byusing this approach,we foundthat 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 rodentmyocytes and isolatedmuscle mitochondria.Similar findingswere observed ina patientwith chronichypophosphatemia as a result of amutation 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 decreasedmuscle 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.",

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AU - Pesta, Dominik H

AU - Tsirigotis, Dimitrios N

AU - Befroy, Douglas E

AU - Caballero, Daniel

AU - Jurczak, Michael J

AU - Rahimi, Yasmeen

AU - Cline, Gary W

AU - Dufour, Sylvie

AU - Birkenfeld, Andreas L

AU - Rothman, Douglas L

AU - Carpenter, Thomas O

AU - Insogna, Karl

AU - Petersen, Kitt Mia Falck

AU - Bergwitz, Clemens

AU - Shulman, Gerald I.

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N2 - Hypophosphatemia can lead to muscle weakness and respiratory and heart failure, but themechanism is unknown. To address this question, we noninvasively assessed rates of muscle ATP synthesis in hypophosphatemic micebyusing in vivo saturation transfer [31P]-magnetic resonance spectroscopy.Byusing this approach,we foundthat 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 rodentmyocytes and isolatedmuscle mitochondria.Similar findingswere observed ina patientwith chronichypophosphatemia as a result of amutation 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 decreasedmuscle 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.

AB - Hypophosphatemia can lead to muscle weakness and respiratory and heart failure, but themechanism is unknown. To address this question, we noninvasively assessed rates of muscle ATP synthesis in hypophosphatemic micebyusing in vivo saturation transfer [31P]-magnetic resonance spectroscopy.Byusing this approach,we foundthat 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 rodentmyocytes and isolatedmuscle mitochondria.Similar findingswere observed ina patientwith chronichypophosphatemia as a result of amutation 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 decreasedmuscle 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.

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DO - 10.1096/fj.201600473R

M3 - Journal article

C2 - 27338702

SN - 0892-6638

VL - 30

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EP - 3387

JO - FASEB journal : official publication of the Federation of American Societies for Experimental Biology

JF - FASEB journal : official publication of the Federation of American Societies for Experimental Biology

IS - 10

ER -

Hypophosphatemia promotes lower rates of muscle ATP synthesis

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