Grant: Project Grant

Sepsis is a leading cause of death in the intensive care units and is responsible for ten thousand deaths in Canada each year. Skeletal muscle dysfunction manifested as fiber atrophy and weakness is a primary clinical observation in critically ill septic patients during the acute phase of sepsis . Long-term ramifications of limb muscle weakness include functional impairment and poor quality of life. Sepsis-induced skeletal muscle atrophy and weakness are associated with accumulation of damaged and dysfunctional mitochondria (the main source of cellular energy). In normal skeletal muscles, dysfunctional mitochondria are selectively recycled through the autophagy pathway, a process known as mitophagy. In this process, autophagosomes recognize dysfunctional mitochondria primarily through the PINK1-Parkin pathway. This process is inhibited by a protein called P53 which retains Parkin in the cytosol. The main aim of this proposal is to evaluate the therapeutic potentials of enhancing mitophagy by overexpressing Parkin and PINK1 selectively in skeletal muscles or by inhibiting p53 on mitochondrial function, atrophy and depressed contractility in two models of sepsis in mice. To achieve this aim, we have assembled an experienced team of leading investigators in the field of muscle research, Hussain, and Gouspillou, who have extensive expertise in skeletal muscle disease, mitochondrial function, proteolysis, and autophagy and have produced many papers linking mitochondrial injury to skeletal muscle dysfunction in catabolic conditions. Overexpression of Parkin and PINK1 will be achieved by injection of adeno-associated viruses in limb muscles and these muscles will be examined under control and septic conditions. P53 inhibition will be achieved by using mice defective in muscle p53 or by using a pharmacological p53 inhibitor. Mitochondrial function and morphology as well as muscle fiber size and contractile performance will be evaluated in both control and septic mice.