Grant: Project Grant

Duchenne muscular dystrophy (DMD) is a lethal muscle-wasting disease where the mutant gene, dystrophin, plays roles both in structural integrity of myofibers and in regulating muscle stem cell polarity and asymmetric division. Interestingly, DMD is also associated with an elevated risk of cancer and Dystrophin is a tumour-suppressor gene in many cancers Importantly, we found that Dystrophin is markedly down-regulated in muscle stem cells during cancer induced loss of muscle mass known as cachexia. The resulting increase in numbers of muscle stem cells was previously implicated in causing muscle wasting in cachexia. Here, we propose a comprehensive set of experiments to understand the mechanisms involved with the dysfunction of muscle stem cells in cancer cachexia and evaluate whether restoration of muscle stem cell function slows the progression of cachexia. We will first identify the factors secreted by the tumour cells that cause the reduction of dystrophin protein in muscle stem cells. Second, we will identify the factors that trigger the degradation of dystrophin protein within muscle stem cells and test whether inhibition of these factors prevents dystrophin degradation and delays or prevents the progression of cachexia. Third, we will evaluate how degradation of dystrophin perturbs the function of muscle stem cells. Finally, we will test whether interventions that restore function of muscle stem cells prevents the development of cachexia, in mouse models, and in muscle fibers isolated from human biopsies. In conclusion, our proposed experiments will elucidate the mechanisms regulating dystrophin protein degradation and the loss of polarity in MuSC, and provide important new insights into the molecular pathobiology of muscle stem cells in DMD and cancer. These experiments will not only clarify molecular defects in DMD satellite cells but will point the way forward to strategies for potential therapeutic intervention.