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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE325957 | GEO | 2026/07/01

REPOSITORIES: GEO

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Project description:Purpose: Aerobic capacity is a strong predictor of cardiovascular mortality. To determine the relationship between inborn aerobic capacity and soleus gene expression we examined genome-wide gene expression in soleus muscle of rats artificially selected for high and low running capacity (HCR and LCR, respectively) over 16 generations. The artificial selection of LCR caused accumulation of risk factors of cardiovascular disease similar to the metabolic syndrome seen in man, whereas HCR had markedly better cardiac function. We also studied alterations in gene expression in response to exercise training in the two groups, since accumulating evidence indicates that exercise has profound beneficial effects on the metabolic syndrome. Methods:; Soleus gene expression of both sedentary and exercise trained HCR and LCR was characterized by microarray- and gene ontology analysis. Results: Although HCR and LCR had an inborn 347% difference in running capacity, only three genes were found differentially expressed in the soleus muscle between the two groups. Up-regulation of the mitochondrial enzyme leucyl-transferRNA synthetase (LARS2) was found in the sedentary LCR. Increased expression of LARS2 has been associated with a mitochondrial DNA mutation linked to maternally inherited diabetes and mitochondrial dysfunction. In line with our findings, a growing body of evidence suggests that LCR have compromised mitochondrial function. After exercise training, 58 genes were altered in the soleus muscle of HCR, in contrast to only one in the LCR group. This suggests that animals born with different levels of fitness respond different to the same type of exercise training. Adaptations to exercise in HCR seemed to be associated with increased lipid metabolism and fatty acid elongation in the mitochondria. Also, genes associated with the peroxisomes, seemed to be central in the adaptation to exercise. Conclusion: The results indicate that (i) LCR might have mitochondrial dysfunction, which may be a contributing factor of the low inborn aerobic capacity, (ii) animals born with different levels of fitness respond different to the same exercise program. Experiment Overall Design: There are 16 samples in this study.

Project description:Purpose: Aerobic capacity is a strong predictor of cardiovascular mortality. To determine the relationship between inborn aerobic capacity and soleus gene expression we examined genome-wide gene expression in soleus muscle of rats artificially selected for high and low running capacity (HCR and LCR, respectively) over 16 generations. The artificial selection of LCR caused accumulation of risk factors of cardiovascular disease similar to the metabolic syndrome seen in man, whereas HCR had markedly better cardiac function. We also studied alterations in gene expression in response to exercise training in the two groups, since accumulating evidence indicates that exercise has profound beneficial effects on the metabolic syndrome. Methods: Soleus gene expression of both sedentary and exercise trained HCR and LCR was characterized by microarray- and gene ontology analysis. Results: Although HCR and LCR had an inborn 347% difference in running capacity, only three genes were found differentially expressed in the soleus muscle between the two groups. Up-regulation of the mitochondrial enzyme leucyl-transferRNA synthetase (LARS2) was found in the sedentary LCR. Increased expression of LARS2 has been associated with a mitochondrial DNA mutation linked to maternally inherited diabetes and mitochondrial dysfunction. In line with our findings, a growing body of evidence suggests that LCR have compromised mitochondrial function. After exercise training, 58 genes were altered in the soleus muscle of HCR, in contrast to only one in the LCR group. This suggests that animals born with different levels of fitness respond different to the same type of exercise training. Adaptations to exercise in HCR seemed to be associated with increased lipid metabolism and fatty acid elongation in the mitochondria. Also, genes associated with the peroxisomes, seemed to be central in the adaptation to exercise. Conclusion: The results indicate that (i) LCR might have mitochondrial dysfunction, which may be a contributing factor of the low inborn aerobic capacity, (ii) animals born with different levels of fitness respond different to the same exercise program. Keywords: aerobic capacity, metabolic syndrome, soleus muscle, gene expression, metabolism

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

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