An exploration into the proteins that regulate skeletal muscle lipid metabolism

Abstract

Dysregulation of intramuscular triglyceride (IMTG) turnover in human skeletal muscle in sedentary and obese states leads to accumulation of lipid metabolites that contribute to skeletal muscle insulin resistance and ultimately progression to type 2 diabetes (T2D). People with T2D display low levels of IMTG turnover in comparison to insulin sensitive and trained individuals. IMTG stores are used as an energy substrate during 1 h of moderate-intensity exercise in trained individuals only and can be increased by consumption of a high fat, high calorie (HFHC) diet in sedentary and trained states. This thesis explores the metabolic and molecular regulation of proteins that regulate IMTG turnover, specifically focusing on the effects of 1) a HFHC diet and 2) a moderate-intensity exercise bout and 3) IMTG stores in different diseases states (lean, obese and T2D). Chapter 2 determined there were no sex-specific differences or main effects in functional outcomes of cardiovascular (arterial stiffness) and metabolic health (glucose tolerance and metabolic flexibility) in response to 7 days HFHC diet. Chapter 3 provides novel evidence that 7 days HFHC diet induces fibre type specific increases in IMTG stores primarily underpinned by an increase in perilipin-3 (PLIN3) protein expression and a redistribution of perilipin-2 (PLIN2) to lipid droplets (LD) storing IMTG. This occurred with no impairments in skeletal muscle insulin signalling and it is therefore proposed that increases in IMTG content assisted by PLIN2 and PLIN3 minimise the accumulation of lipid metabolites known to disrupt the insulin signalling cascade. Chapter 4 revealed that hormone sensitive lipase (HSL) preferentially redistributes to LD associated with perilipin-5 (PLIN5) following 1 h of moderate-intensity exercise. Chapter 5 developed a PLIN5 immunoprecipitation mass spectrometry protocol which identified phospholipase A2- group II, subgroup A (PA2GA) as a novel protein associated to PLIN5 in muscle from lean sedentary humans. In conclusion, this thesis presents novel data on key proteins that regulate IMTG turnover in human skeletal muscle.