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.