Grant: Operating Grant

Sepsis is a systemic disease very common in intensive care units with high mortality. Patients with sepsis frequently develop muscle weakness that involves the diaphragm and limb muscles. Muscle weakness particularly that of the diaphragm leads to prolonged mechanical ventilation and high mortality. The mechanisms behind this muscle dysfunction are unclear. In this project, we will explore whether a newly described mechanism of protein recycling, autophagy, is excessively induced in skeletal muscles in sepsis. We will also investigate whether inhibition of autophagy can restore muscle function in sepsis and will identify the mechanisms responsible for induction of autophagy in septic skeletal muscles. Murine models of sepsis will be used throughout the proposal. In addition, we will compare the diaphragm to limb muscles to identify whether the diaphragm is selectively affected by autophagy in sepsis. Our first objective is to document the extent and timing of autophagy in skeletal muscles during the course of sepsis. Our second objective is to evaluate the importance of autophagy in sepsis-induced muscle dysfunction. This will be done by inducing sepsis in mice that are incapable of inducing autophagy in skeletal muscles. Our third objective is to investigate the roles of oxidants derived from the mitochondria in inducing autophagy in septic skeletal muscles. This will be achieved by using mice overexpressing a gene that scavenges mitochondrial oxidants and by using a peptide that can selectively reduce mitochondrial oxidants. Our fourth and five objectives are to identify the contribution of selective triggering mechanisms located in the mitochondria and the nucleus of skeletal muscles in inducing autophagy and causing muscle dysfunction in sepsis. For this purpose, we will use compare sepsis-induced muscle dysfunction in normal mice and transgenic mice that are deficient in cyclophilin D, PARKIN and FoxO transcription factors.