Grant: Operating Grant

Cachexia is a major complication of cancer that causes significant morbidity and loss of quality of life. A major feature of cachexia is muscle wasting which causes weakness. We are exploring the biochemical pathways in muscle that lead to loss of muscle proteins and wasting. We have identified a gene, USP19, in the ubiquitin pathway which is the major pathway of protein breakdown in cells. USP19 is activated in rats in skeletal muscle wasting from cancer. We have recently observed that mice lacking USP19 lose less muscle mass in conditions of muscle wasting. Furthermore, lowering USP19 levels in muscle cells results in accumulation of the major contractile proteins in muscle. Thus, we propose in this application to further define how USP19 exerts these effects on skeletal muscle, identify mechanisms for inhibiting it and explore its role in patients with cancers that predispose them to cachexia.