High Phosphate Diet Induces Exercise Intolerance and Impairs Fatty Acid Metabolism in Mice

Inorganic phosphate (Pi) is used extensively as a preservative and a flavor enhancer in the Western diet. Physical inactivity, a common feature of Western societies, increases cardiovascular morbidity and mortality. We explore the relationship between dietary Pi excess and impaired exercise tolerance and physical inactivity. Analysis of the Dallas Heart Study shows association of higher serum Pi with reduced time spent in moderate to vigorous physical activity and increased sedentary time in humans. To test for causality, we investigated the impact of chronic exposure of high dietary Pi on exercise capacity in mice. Consumption of a high Pi diet for 3 months does not change the body weight but reduces maximal oxygen uptake, treadmill duration, and spontaneous locomotor activity, which is accompanied by substantial reduction in fat oxidation and fatty acid (FA) levels and downregulation of genes involved in FA synthesis, release, and oxidation, including Fabp4, Hsl, Fasn, and Ppar in muscle. Similar results are recapitulated in in vitro by incubating C2C12 myotubes with high Pi media. In conclusion, our findings indicate that dietary phosphotoxicity reduces skeletal muscle FA metabolism and impairs exercise capacity independent of obesity, and may represent a novel and modifiable risk factor for cardiovascular disease. To understand the mechanistic basis of high intake of dietary phosphate we profiled the transcriptomes (using RNA-seq), of gastrocnemius muscle tissue treated with high phosphate diet for 12 weeks compared to normal phosphate diet.