Skeletal muscle metabolic flexibility: contribution of genetics and lifestyle
Creators: name: Rivas, Donato
Publisher: name: RMIT University
Year: 2024

description: Chronic metabolic diseases such as insulin resistance, obesity and type 2 diabetes develop from the complex interaction of environmental and genetic factors. However, the extent to which each contributes to these disease states is currently unknown. Whole-body metabolic health is associated with the ability of skeletal muscle to transition between the uptake and oxidation of carbohydrate- and lipid-based fuels in response to their availability and the prevailing hormonal milieu, a process described as “metabolic flexibility”. However, in several lifestyle-related diseases such as obesity and type 2 diabetes, there is a loss of skeletal muscle plasticity or “metabolic inflexibility” such that rates of lipid oxidation do not suppress effectively in response to insulin, nor do they effectively increase during the transition to fasting conditions. The primary aim of the experiments undertaken for this thesis was to enhance our understanding of some of the mechanisms by which lifestyle and genetic factors contribute to skeletal muscle metabolic flexibility/inflexibility. The first investigation (Chapter three) was designed to determine the contribution of intrinsic oxidative capacity of skeletal muscle to metabolic flexibility in a rodent model in which aerobic running capacity was artificially manipulated to generate divergent phenotypes for this trait. Hind limb perfusion for the measures of glucose and lipid metabolism revealed that the skeletal muscle of rats selected for high intrinsic running capacity (HCR) were metabolically ‘flexible’ compared to animals selected for low running capacity (LCR). The superior fuel-handling capacity in HCR was, in part, explained by fibre-type specific increases in insulin-stimulated phosphorylation to components of the insulin signalling cascade, along with a substantial increase in mitochondrial volume density. <br><br>The second experimental chapter (described in Chapter four) determined if a six week programme of endurance exercise training could reverse the skeletal muscle metabolic ‘inflexibility’ observed in LCR (Chapter three). Aerobic exercise training-induced improvements in insulin sensitivity were associated with increased fatty acid oxidation, increased phosphorylation of selected components of the insulin signalling pathway and the increased expression of β-adrenergic components and target proteins. <br><br>In order to ascertain a mechanism for skeletal muscle metabolic inflexibility, the final study (described in Chapter five) determined the independent and interactive effects of increased lipid availability and aerobic exercise training on the mammalian target of rapamycin pathway (mTOR) in a model of diet-induced metabolic inflexibility, the high-fat fed rat. A high-fat diet decreased insulin-stimulated glucose transport and was linked to an increase in the association of mTOR with its binding partners, rictor and raptor. These increases were coupled with the increased activation of the downstream substrates Akt1, S6K1 and the inhibitory serine phosphorylation of IRS1. Aerobic exercise training restored skeletal muscle insulin sensitivity possibly through the activation of the AMP-activated protein kinase and thus the inhibition of the mTOR signalling pathway. In summary, the results from the studies undertaken for this thesis provide novel information regarding the mechanisms by which lifestyle (exercise, nutrition) and genetics determine the metabolic flexibility of skeletal muscle.