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 [(31)P]-magnetic resonance spectroscopy. By using this approach, we found that 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 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 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 decreased muscle 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.