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

Health Innovations Research Institute, School of Medical Sciences, RMIT University, Bundoora, Australia.
AJP Regulatory Integrative and Comparative Physiology (Impact Factor: 3.11). 04/2011; 300(4):R835-43. DOI: 10.1152/ajpregu.00659.2010
Source: PubMed


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.

Download full-text


Available from: Donato Rivas, Feb 12, 2014
  • [Show abstract] [Hide abstract]
    ABSTRACT: Both muscle mass and strength decline with ageing, but the loss of strength far surpasses what is projected based on the decline in mass. Interestingly, the accumulation of fat mass has been shown to be a strong predictor of functional loss and disability. Furthermore, there is a known attenuated hypertrophic response to skeletal muscle overload with ageing. The purpose of this study was to determine the effect of 28 days of overload on the storage of intramuscular triglycerides (IMTG) and metabolic regulators of lipid synthesis in young and old skeletal muscle. The phosphorylation and expression of essential lipogenic regulators were determined in the plantaris of young (YNG; 6-month-old) and aged (OLD; 30-month-old) rats subjected to bilateral synergist ablation (SA) of two-thirds of the gastrocnemius muscle or sham surgery. We demonstrate that age-induced increases in IMTG are associated with enhancements in the expression of lipogenic regulators in muscle. We also show that the phosphorylation and concentration of the 5'AMP-activated protein kinase (AMPK) isoforms are altered in OLD. We observed increases in the expression of lipogenic regulators and AMPK signalling after SA in YNG, despite no increase in IMTG. Markers of oxidative capacity were increased in YNG after SA. These overload-induced effects were blunted in OLD. These data suggest that lipid metabolism may be altered in ageing skeletal muscle and is unaffected by mechanical overload via SA. By determining the role of increased lipid storage on skeletal muscle mass during ageing, possible gene targets for the treatment of sarcopenia may be identified.
    No preview · Article · Mar 2011 · Acta Physiologica
  • [Show abstract] [Hide abstract]
    ABSTRACT: Although low exercise capacity is a risk factor for stroke, the exact mechanisms that underlie this connection are not known. As a model system for exploring the association between aerobic capacity and disease risks we applied two-way artificial selection over numerous generations in rats to produce low capacity runners (LCR) and high capacity runners (HCR). Here we compared intracerebral hemorrhage (ICH)-induced brain injury in both genders of these rat lines. HCR and LCR rats had 100μl blood injected into the right caudate and were killed at days 1, 3, 7 and 28 for brain water content determination, immunohistochemistry, histology, Western blot, and behavioral tests. Compared to male HCRs, male LCRs had more severe ICH-induced brain injury including worse brain edema, necroptosis, brain atrophy, and neurological deficits, but not increased numbers of Fluoro-Jade C positive cells or elevated cleaved caspase-3 levels. This was associated with greater microglial activation, and heme oxygenase-1 and protease activated receptor (PAR)-1 upregulation. In females, edema was also greater in LCRs than in HCRs, although it was less severe in females than in males for both LCRs and HCRs. Thus, ICH-induced brain injury was more severe in LCRs, a model of low exercise capacity, than in HCRs. Increased activation of microglia and PAR-1 may participate mechanistically in increased ICH-susceptibility. Females were protected against ICH-induced brain edema formation in both HCRs and LCRs.
    No preview · Article · Aug 2012 · Neurobiology of Disease
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Inactivity-related diseases are becoming burden on Western society. Whilst there is a major environmental contribution to metabolic health, the intrinsic properties that predispose or protect against particular health traits are harder to define. We have used rat models of inborn high-(HCR) and low-running capacity (LCR) to determine inherent differences in mitochondrial volume and function, hypothesizing that HCR have greater skeletal muscle respiratory capacity due to a greater mitochondrial volume. Additionally, we sought to determine if there was a link between the expression of the nuclear receptor Neuron-derived Orphan Receptor-1 (Nor1) and inherent skeletal muscle respiratory capacity. LCR were 28% heavier (P<0.0001) and fasting serum insulin concentrations were 62% greater than HCR (P=0.02). In contrast, HCR had better glucose tolerance and reduced adiposity. In the soleus, maximal respiratory capacity was 21% greater in HCR (P=0.001), for which the relative contribution of fat oxidation was 20% higher than LCR (P=0.02). This was associated with increased citrate synthase (CS; 33%, P=0.009) and β-hydroxyacyl-CoA (β-HAD; 33%, P=0.0003) activities. In the EDL, CS activity was 29% greater (P=0.01) and β-HAD activity was 41% (P=0.0004) greater in HCR compared to LCR. MtDNA copy number was elevated in HCR EDL (35%, P=0.049). Additionally, HCR had increased protein expression of individual mitochondrial respiratory complexes, CS and UCP3 in both muscles (all P<0.05). Nor1 protein was greater in EDL and soleus of HCR compared to LCR (P<0.05). We propose that the differential expression of Nor1 may contribute to the differences in metabolic regulation between the LCR and HCR phenotypes.
    Full-text · Article · Aug 2012 · Journal of Applied Physiology
Show more