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

Inorganic phosphate consumption in adults is two-to-three-fold higher than the recommended daily allowance due to its widespread use as a preservative and flavor enhancer in processed foods. We previously reported that 12 weeks of high-phosphate diet (HPD) reduced VO_2max and altered metabolic gene expression and mitochondrial dysfunction in mouse skeletal muscle. Here, we investigated whether exercise training reverses the negative consequences of HPD. Male mice were fed normal (NPD) or HPD for 5 weeks, then continued on NPD or HPD with 9 weeks of voluntary exercise training. Serum, urine, and fecal phosphate increased within 1 day of HPD-feeding and remained elevated throughout the study. Trained NPD- and HPD-fed mice performed similarly on forced exercise tests, but mitochondrial respiration was significantly decreased in skeletal muscle from trained HPD-fed mice. RNA sequencing revealed distinct sets of differentially expressed genes when comparing sedentary versus exercise-trained muscle of HPD-fed mice relative to the same comparison in NPD-fed mice. These findings indicate that voluntary exercise training preserves endurance but does not fully restore gene expression or mitochondrial function in muscle from HPD-fed mice. Thus, HPD-induced skeletal muscle dysregulation is not completely reversible with exercise, underscoring the importance of both diet and exercise for metabolic health.