Exercise training does not mitigate high-phosphate diet induced mitochondrial dysfunction in skeletal muscle

Inorganic phosphate (Pi) consumption is two-to-three-fold higher than the recommended daily allowance for adults due to its use as a preservative and flavor enhancer in processed foods. We reported previously that mice fed high-Pi diet (HPD) for 12 weeks exhibited reduced VO2max, altered metabolic gene expression, and mitochondrial dysfunction in skeletal muscle. Exercise is a common intervention for metabolic diseases as it improves metabolic flexibility and mitochondrial function, so we tested the hypothesis that exercise training reverses the negative consequences of HPD. Male mice were fed HPD for five weeks to induce muscle mitochondrial dysfunction and were subsequently subjected to HPD and voluntary exercise training for nine weeks. Serum, urine, and fecal Pi were increased within one day of HPD feeding which was sustained throughout the study. No differences in food intake, body weight, or body composition were detected between NPD- and HPD-fed mice, in either sedentary or exercised trained groups. Trained HPD- and NPD-fed mice performed similarly in forced exercise tests, but mitochondrial respiration was significantly decreased in skeletal muscle from trained HPD-fed mice. RNA sequencing revealed unique differentially expressed genes in HPD-fed sedentary versus exercise trained, compared to NPD-fed sedentary versus exercise trained muscle. These data indicate that voluntary exercise training restores exercise capacity of HPD-fed mice but does not completely restore muscle gene expression or mitochondrial function. Thus, HPD-induced skeletal muscle dysregulation is not fully reversible with exercise and highlights the importance of considering both healthy diet and exercise as part of a healthy lifestyle.