Low intrinsic running capacity is associated with reduced skeletal muscle substrate oxidation and lower mitochondrial content in white skeletal muscle

Abstract

Chronic metabolic diseases develop from the complex interaction of environmental and genetic factors, although the extent to which each contributes to these disorders is unknown. Here, we test the hypothesis that artificial selection for low intrinsic aerobic running capacity is associated with reduced skeletal muscle metabolism and impaired metabolic health. Rat models for low- (LCR) and high- (HCR) intrinsic running capacity were derived from genetically heterogeneous N:NIH stock for 20 generations. Artificial selection produced a 530% difference in running capacity between LCR/HCR, which was associated with significant functional differences in glucose and lipid handling by skeletal muscle, as assessed by hindlimb perfusion. LCR had reduced rates of skeletal muscle glucose uptake (∼30%; P = 0.04), glucose oxidation (∼50%; P = 0.04), and lipid oxidation (∼40%; P = 0.02). Artificial selection for low aerobic capacity was also linked with reduced molecular signaling, decreased muscle glycogen, and triglyceride storage, and a lower mitochondrial content in skeletal muscle, with the most profound changes to these parameters evident in white rather than red muscle. We show that a low intrinsic aerobic running capacity confers reduced insulin sensitivity in skeletal muscle and is associated with impaired markers of metabolic health compared with high intrinsic running capacity. Furthermore, selection for high running capacity, in the absence of exercise training, endows increased skeletal muscle insulin sensitivity and oxidative capacity in specifically white muscle rather than red muscle. These data provide evidence that differences in white muscle may have a role in the divergent aerobic capacity observed in this generation of LCR/HCR.

Low intrinsic exercise capacity in rats predisposes to age-dependent cardiac remodeling independent of macrovascular function

“…The present study used female rats from generations 16,20, and 22, as the body weight differences between phenotypes are less marked in females than in males at the same age (16), and hence body weight is less likely to represent a confounding influence to our observations. Rats were phenotyped for intrinsic running capacity at 11 wk of age (26,43,49) and were studied in two age groups, young (ϳ12 wk) and mature adulthood (ϳ35 wk). Conscious fasting glucose tolerance tests were determined (26,43,49) Tissue collection and histology.…”

“…Rats were selectively bred to yield divergent phenotypes with either low (LCR) or high (HCR) intrinsic running capacity. When compared with HCR, LCR rats have reduced whole body insulin sensitivity, glucose tolerance, and hyperlipidemia, indicative of poor metabolic health (26,43,46,49). Furthermore, LCR rats exhibit modest but significantly higher systolic blood pressure (SBP) compared with HCR, particularly in males (6, 49).…”

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).…”

“…The larger contractile-mediated decrease in pH in the triceps surae of LCRs was likely related to the larger glycolytic ca-pacity in fast-twitch muscle fibers (type 2b) of LCRs compared to HCRs (Termin, Staron & Pette 1989;Fuchtbauer et al 1991;Kivelä et al 2010). Additionally, HCRs may have more efficient hydrogen ion buffering and a delayed decline in Ca 2+ release due to higher oxidative capacity in skeletal muscle (Kivelä et al 2010;Rivas et al 2011), which might help resist fatigue.…”

“…Nonetheless, in our study it seems that the spontaneous activity level is not solely determining the level of thermogenesis ( Figure 16). Since it is known that HCRs have higher mitochondrial content and function in skeletal muscle (Kivelä et al 2010;Rivas et al 2011;Walsh et al 2006), it may be speculated that the higher thermogenesis of HCRs is an adaptation to maintain the large mitochondria reservoir viable also during resting state. On the other hand, it has been proposed that low body temperature is also one reason for the onset of obesity in humans ) even though recent studies have not found a difference in the core temperatures of lean and obese subjects (Heikens et al 2011;Hoffmann et al 2012).…”