Gene expression centroids that link with low intrinsic aerobic exercise capacity and complex disease risk

Abstract

A strong link exists between low aerobic exercise capacity and complex metabolic diseases. To probe this linkage, we utilized rat models of low and high intrinsic aerobic endurance running capacity that differ also in the risk for metabolic syndrome. We investigated in skeletal muscle gene-phenotype relationships that connect aerobic endurance capacity with metabolic disease risk factors. The study compared 12 high capacity runners (HCRs) and 12 low capacity runners (LCRs) from generation 18 of selection that differed by 615% for maximal treadmill endurance running capacity. On average, LCRs were heavier and had increased blood glucose, insulin, and triglycerides compared with HCRs. HCRs were higher for resting metabolic rate, voluntary activity, serum high density lipoproteins, muscle capillarity, and mitochondrial area. Bioinformatic analysis of skeletal muscle gene expression data revealed that many genes up-regulated in HCRs were related to oxidative energy metabolism. Seven mean mRNA expression centroids, including oxidative phosphorylation and fatty acid metabolism, correlated significantly with several exercise capacity and disease risk phenotypes. These expression-phenotype correlations, together with diminished skeletal muscle capillarity and mitochondrial area in LCR rats, support the general hypothesis that an inherited intrinsic aerobic capacity can underlie disease risks.—Kivelä, R., Silvennoinen, M., Lehti, M., Rinnankoski-Tuikka, R., Purhonen, T., Ketola, T., Pullinen, K., Vuento, M., Mutanen, N., Sartor, M. A., Reunanen, H., Koch, L. G., Britton, S. L., Kainulainen, H. Gene expression centroids that link with low intrinsic aerobic exercise capacity and complex disease risk.

Effects of intrinsic aerobic capacity, aging and voluntary running on skeletal muscle sirtuins and heat shock proteins

“…Furthermore, LCRs have increased cardiovascular disease risk and higher susceptibility to tachyarrhythmia's than HCRs . Previous studies have also shown that LCRs have poor capillarization, less subsarcolemmal and intermyofibrillar mitochondria, and reduced mitochondrial respiratory capacity in skeletal muscle compared to HCRs (Kivelä et al 2010;Rivas et al 2011;Walsh et al 2006). In liver tissue, LCRs exhibit reduced hepatic mitochondrial oxidative capacity that in turn increases susceptibility to hepatic steatosis and liver injury (Thyfault et al 2009).…”

“…After six generations of selection the rat lines already differed in running capacity by 171%, with most of the change occurring in the HCR line . After 18 generations of breeding the low and high capacity lines differed in maximal running capacity by 615 % (Kivelä et al 2010). VO2max was 12 % higher in HCRs after 7 generations and 24 % higher after 22 generations of selection compared to LCRs (Gonzalez et al 2006;Johnsen et al 2013).…”

“…HCR/LCR rats have been extensively studied. At the whole-body level, in addition to poor running capacity, LCRs have lower physical activity level, higher body weight gain and increased complex disease risk compared to HCRs (Kivelä et al 2010). Furthermore, LCRs have increased cardiovascular disease risk and higher susceptibility to tachyarrhythmia's than HCRs .…”

“…On the other hand, compared to LCRs, HCRs represent a lean, healthy phenotype with decreased metabolic risk factors, higher physical activity level and increased energy expenditure (Kivelä et al 2010;. The difference in fuel selection has been associated to the healthy phenotype of HCRs, which more efficiently oxidizes fatty acids and branched-chain amino acids than LCRs (Overmyer et al 2015).…”

“…In rodents, it has been shown that good intrinsic aerobic capacity, even without particular physical training, is associated with long lifespan . Good aerobic capacity also promotes a so-called healthy phenotype, whereas low aerobic capacity is associated with obesity and increased risk of metabolic and cardiovascular diseases (Kivelä et al 2010;. Since exercise increases individuals' aerobic capacity, it is of general interest to study the effects of physical activity on longevity.…”