Peroxisome proliferator-activated receptor delta : regulation of skeletal muscle metabolism

Peroxisome Proliferator-Activated Receptor (PPAR) δ is a nuclear transcription factor which has been implicated in the regulation of lipid metabolism in skeletal muscle. In addition to the postural and locomotive functions of skeletal muscle, this organ has a major impact role on whole body metabolism. Reduced insulin sensitivity is a characteristic feature in subjects with type 2 diabetes mellitus. Physical exercise/muscle contraction alters the metabolic properties of skeletal muscle, and renders the muscle more sensitive to insulin. The underlying molecular mechanisms mediating this effect remain largely elusive. This thesis has investigated the role of PPARδ in skeletal muscle glucose- and lipid metabolism, exercise responses and fibre-type composition in human skeletal muscle. The effect of low-intensity exercise on clinical characteristics and skeletal muscle gene expression was evaluated in subjects with Type 2 diabetes mellitus. Skeletal muscle protein and mRNA expression of PPARδ increased in an exercise-dependent manner. The increase skeletal muscle PPARδ was coincident with improvements in the clinical profile of the study participants. Furthermore, despite performing the exercise protocol, some individuals did not show improvements in insulin-sensitivity or increases in skeletal muscle PPARδ expression. Increased expression of PPARδ was coincident with increased expression of uncoupling protein 3, possibly indicating enhanced mitochondrial function and/or content. This finding suggests that the exercise-training induced activation of PPARδ is critical for mediating the beneficial effects of exercise. We hypothesised that this is dependent on PPARδ-responsive genes altering skeletal muscle metabolism, which subsequently has an impact on whole body metabolism and the clinical profile. To test the hypothesis that PPARδ expression may be a regulator of oxidative metabolism and an insulin sensitive phenotype; we determined the expression of PPARδ in elite endurance cyclists, normally active individuals and spinal cord injured individuals. These groups have profound differences in skeletal muscle fibre-type composition, with elite cyclists displaying the highest proportion of type 1 oxidative muscle fibres, and spinal cord injured subjects an almost total loss. We found that PPARδ expression was positively correlated with the amount of oxidative skeletal muscle fibres in these groups. The increased expression of PPARδ in type I muscle was accompanied by increased expression of PPAR gamma coactivator (PGC) 1alpha and PGC1beta. To specifically address the role of PPARδ in human skeletal muscle metabolism we utilised primary cultures of human skeletal muscle, and pharmacological activators of PPARδ. Activation of PPARδ in primary cultured human skeletal muscle increases fatty acid uptake and oxidation. This effect is linked to an increased expression of key genes involved in the intracellular transport of fatty acids, fatty acid uptake into the mitochondria and subsequent metabolism. These changes were concomitant with improved insulin sensitivity and glucose uptake. In addition to PPARδ-dependent changes, we noted that the pharmacological PPARδ activator induced a PPARδ independent alteration in the cellular ATP:AMP ratio. This resulted in an increase in AMP-activated protein kinase phosphorylation, and an AMPactivated protein kinase dependent increase in glucose uptake. In conclusion, PPARδ plays a central role in the adaptive metabolic response of human skeletal muscle to exercise. Furthermore, PPARδ orchestrates changes in skeletal muscle metabolism. Thus, PPARδ is an interesting drug target for the treatment of metabolic diseases, such as type 2 diabetes mellitus