title: Hypophosphatemia promotes lower rates of muscle ATP synthesis.
abstract: 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 Pitransporter solute carrier family 34, member 1 (NaPi2a)-knockout (NaPi2a-/-) mice compared with their wild-type littermate controls. Rates of VATPnormalized in both hypophosphatemic groups after restoring plasma Piconcentrations. Furthermore, VATPwas directly related to cellular and mitochondrial Piuptake 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 Picontent and muscle VATPAfter oral Pirepletion and normalization of serum Pilevels, muscle VATPcompletely normalized in the patient. Taken together, these data support the hypothesis that decreased muscle ATP synthesis, in part, may be caused by low blood Piconcentrations, 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.
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Dominik H
authors.initials: DH
authors.lastname: Pesta
authors.affiliation: Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Dimitrios N
authors.initials: DN
authors.lastname: Tsirigotis
authors.affiliation: Department of Radiology and Biomedical Engineering, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Befroy
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Caballero
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Jurczak
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Yasmeen
authors.initials: Y
authors.lastname: Rahimi
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Gary W
authors.initials: GW
authors.lastname: Cline
authors.affiliation: Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Dufour
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Andreas L
authors.initials: AL
authors.lastname: Birkenfeld
authors.affiliation: Department of Radiology and Biomedical Engineering, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Rothman
authors.affiliation: Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, USA; and.
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Carpenter
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Karl
authors.initials: K
authors.lastname: Insogna
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Kitt Falk
authors.initials: KF
authors.lastname: Petersen
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Clemens
authors.initials: C
authors.lastname: Bergwitz
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA; Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut, USA; Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark gerald.shulman@yale.edu.
authors.forename: Gerald I
authors.initials: GI
authors.lastname: Shulman
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis*; D000818:Animals; D006801:Humans; D017674:Hypophosphatemia / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008931:Mitochondria, Muscle / Q000378:metabolism*; D018908:Muscle Weakness / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*; D010710:Phosphates / Q000378:metabolism
chemical_list: D007328:Insulin; D010710:Phosphates; D000255:Adenosine Triphosphate
keywords: [31P]MRS; inorganic phosphate; saturation transfer