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.

Figure 1.

Course of the experiments.

Figure 2.

A) LCR rats were heavier from young to adult age (P<0.001); however, the relative difference remained similar (∼20%) throughout the study. B) HCR rats ran ∼4 times the distance in a day compared with LCR rats (P<0.001) during the 3 wk period in cages with running wheels. C) LCR rats had higher unfed (fasting) blood glucose and serum insulin than HCR rats, but no statistical difference was observed in intraperitoneal glucose tolerance test or random glucose. D) LCR rats had higher serum triglyceride concentration, and HCR rats, in turn, had higher HDL cholesterol, and NEFA. *P < 0.05; **P < 0.01; ***P < 0.001.

Figure 3.

A) Capillary-to-fiber ratio was higher in HCR rats in all studied muscles: slow soleus, fast EDL and mixed gastrocnemius muscles. B) HCR rats had significantly larger subsarcolemmal and intermyofibrillar mitochondrial area compared with LCR rats. C) Large mitochondrial stocks were found under sarcolemma in HCR animals. These stocks were located close to nuclei and blood capillaries (arrows). D) In LCR rat muscle, subsarcolemmal mitochondrial stocks were usually much smaller than in HCR rats (arrows). Scale bars = 5 μm. *P < 0.05; **P < 0.01.

Figure 4.

Expression of oxidative phosphorylation (A, C, E) and lipid metabolism genes (B, D, F) predict aerobic capacity (A, B; running distance), insulin sensitivity (C, D; glucose tolerance), and serum triglyceride concentration (E, F). Diamonds indicate HCR values; green lines indicate outer values. Squares indicate LCR values; red lines indicate outer values. Explanatory power and significance are shown.

Figure 5.

Real-time PCR results from the 3 studied muscles showed that several genes related to lipid oxidation were up-regulated in HCR rats compared with LCR rats: Lpl (A); Cpt1a; (B) Cpt1b (C); Cpt2 (D); Hadhb (E); Ucp2 (F); Ucp3 (G); Aco1 (H); Aco2 (I). *P < 0.05; **P < 0.01; ***P < 0.001.