Voluntary Exercise does not Prevent High-Phosphate Diet-Induced Mitochondrial Dysfunction

Introduction: Inorganic phosphate (Pi) is used extensively as a preservative and a flavor enhancer in processed foods. Chronic hyperphosphatemia results in vascular calcification, arteriosclerosis, and chronic kidney disease. We published that healthy humans who consume excess Pi have decreased exercise capacity despite normal cardiac function and glomerular filtration rate. Similarly, healthy mice fed high-Pi diet (HPD) for 12 weeks display decreased maximal exercise capacity but normal cardiac function. Expression of fatty acid metabolism and carbohydrate metabolism genes in mice are decreased and increased, respectively, and mitochondrial function is significantly impaired in muscle after HPD. Hypothesis: Voluntary exercise training prevents the negative metabolic consequences of HPD. Methods: Male mice housed in voluntary wheel running cages were fed a normal-Pi diet (NPD) or HPD for 12 weeks. Results: We observed increased exercise capacity in HPD trained mice. Despite improved exercise capacity, muscle mitochondrial function was decreased after 12 weeks of HPD and voluntary exercise. Expression of fatty acid and carbohydrate metabolism genes were decreased and increased, respectively. Conclusion: These data suggest that voluntary exercise training does not prevent the negative metabolic consequences of HPD in skeletal muscle. Understanding the role of skeletal muscle in regulating Pi homeostasis is critical for treatment and prevention of Pi-related diseases such as arteriosclerosis, vascular calcification, and chronic kidney disease. National Heart, Lung, and Blood Institute; The Ohio State University Foods for Health SEED grant. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.