Exercise training reverses impaired skeletal muscle metabolism induced by artificial selection for low aerobic capacity

We have used a novel model of genetically imparted endurance exercise capacity and metabolic health to study the genetic and environmental contributions to skeletal muscle glucose and lipid metabolism. We hypothesized that metabolic abnormalities associated with low intrinsic running capacity would be ameliorated by exercise training. Selective breeding for 22 generations resulted in rat models with a fivefold difference in intrinsic aerobic capacity. Low (LCR)- and high (HCR)-capacity runners remained sedentary (SED) or underwent 6 wk of exercise training (EXT). Insulin-stimulated glucose transport, insulin signal transduction, and rates of palmitate oxidation were lower in LCR SED vs. HCR SED (P < 0.05). Decreases in glucose and lipid metabolism were associated with decreased β2-adrenergic receptor (β2-AR), and reduced expression of Nur77 target proteins that are critical regulators of muscle glucose and lipid metabolism [uncoupling protein-3 (UCP3), fatty acid transporter (FAT)/CD36; P < 0.01 and P < 0.05, respectively]. EXT reversed the impairments to glucose and lipid metabolism observed in the skeletal muscle of LCR, while increasing the expression of β2-AR, Nur77, GLUT4, UCP3, and FAT/CD36 (P < 0.05) in this tissue. However, no metabolic improvements were observed following exercise training in HCR. Our results demonstrate that metabolic impairments resulting from genetic factors (low intrinsic aerobic capacity) can be overcome by an environmental intervention (exercise training). Furthermore, we identify Nur77 as a potential mechanism for improved skeletal muscle metabolism in response to EXT. low aerobic exercise capacity is a predictor of all-cause mortality (37), a relationship that is particularly strong in individuals with type 2 diabetes (28). The importance of this association is highlighted by the observation that individuals with type 2 diabetes and their first-degree relatives have lower aerobic exercise capacity than age- and weight-matched controls (38). Recent evidence suggests that adolescents with type 2 diabetes also exhibit impaired exercise capacity compared with age-matched peers, indicating that this impairment is present early in the onset of the disease (38). However, the complex interplay between environmental and genetic factors that contribute to both a reduced exercise capacity (5, 6) and an increased risk for developing type 2 diabetes (36) make it difficult to demonstrate a cause and effect relationship. To study the contribution of aerobic exercise capacity to the etiology of complex disease states such as type 2 diabetes, we have developed unique animal models generated by artificial selection for low and high aerobic exercise capacity (26). In these models, 11 generations of selection resulted in a 347% difference in running capacity between low (LCR)- and high (HCR)-capacity runners (50). Importantly, selection for low aerobic capacity simultaneously resulted in metabolic dysfunction, including impaired cardiovascular function, increased adiposity, dyslipidemia, and whole body insulin resistance (50). The molecular defect(s) that result in aberrant fuel metabolism in LCR are unclear. However, we have recently reported that LCR have impaired skeletal muscle glucose and lipid metabolism (30, 39). Furthermore, we have also demonstrated that impaired skeletal muscle metabolism is associated with reduced β2-adrenergic receptor (β2-AR) content, impaired adrenergic signal transduction, and reduced expression Nur77 in the skeletal muscle of LCR (30). Nur77 is a nuclear receptor that is downregulated in several models of insulin resistance and type 2 diabetes (12) and induces the transcription of important metabolic genes [i.e., glucose transporter-4 (GLUT4), CD36, uncoupling protein-3 (UCP3)] in response to β-adrenergic stimulation (10, 33). Indeed, altered β-adrenergic signal transduction has been proposed to contribute to metabolic disease (4), and variant alleles of the β2-AR have been identified as risk factors for obesity, dyslipidemia, and type 2 diabetes in humans (21, 34, 43, 51). Therefore, defects to whole body and skeletal muscle metabolism that occur following artificial selection for low aerobic capacity are similar to the impairments observed in individuals at risk for developing type 2 diabetes (36, 42). Accordingly, our model of divergent aerobic capacity offers a unique opportunity to investigate some of the intrinsic metabolic traits that link reduced exercise capacity to increased risk for the development of type 2 diabetes. Although a genetic predisposition to the onset of obesity and type 2 diabetes is evident, lifestyle interventions, such as exercise training, may be used to overcome the increased risk for metabolic disease imparted via inheritance (14, 19). For example, the risk of diabetes in offspring of patients with type 2 diabetes is greatly reduced in physically fit individuals compared with their sedentary counterparts (1). Accordingly, the aim of the present investigation was to determine the genetic (inherent exercise capacity) and environmental (exercise training) contributions to skeletal muscle metabolism in animal models of low and high intrinsic aerobic capacity. We hypothesized that impaired skeletal muscle carbohydrate and lipid metabolism observed after artificial selection for low aerobic capacity would be reversed by exercise training