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Identification of a link between exercise and brain function in humans through mapping of skeletal muscle enhancers [ChIP-Seq]

ABSTRACT: Regular exercise improves health and prevents many chronic disorders such as obesity, cardiovascular and neurological diseases. Here, we hypothesized that skeletal muscle gene enhancers undergo epigenetic remodeling after exercise training and overlap with known disease variants from genome-wide association studies (GWAS). Overlapping exercise-remodeled enhancers with GWAS and cis-expression Quantitative Trait Loci data revealed enrichment with traits related to platelet function, cognitive traits and cardiovascular disease. We identify FBXW4 and PLEKHO2 as candidate genes regulated by variant-containing, exercise-responsive enhancers, and that are potentially involved in the distal modulation of brain function. Our results identify a list of genes differentially regulated after exercise training in humans, and which may cooperatively control brain function through the cardiovascular system.

ORGANISM(S): Homo sapiens

PROVIDER: GSE144132 | GEO | 2021/07/20

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.

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Identification of a link between exercise and brain function in humans through mapping of skeletal muscle enhancers [ChIP-Seq]

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