Grant: Project Grant

Duchenne muscular dystrophy (DMD) and myotonic dystrophy type 1 (DM1) are the most prevalent muscular dystrophies in children and adults in Canada and worldwide. There are no cures, thus the health- and life-limiting nature of these disorders is, at present, inevitable. Therefore, a critical, unmet clinical need exists for the identification and evaluation of new, effective therapies. We know that when a protein in our muscles called AMP-activated protein kinase (AMPK) is turned on, it has some benefit in reducing the severity of DMD and DM1 in animals engineered to have these disorders. However, AMPK-activating drugs that have been used to date in muscular dystrophy studies are neither safe for long-term human use, nor particularly potent. The use of better compounds to activate AMPK, those that are safe, effective, and able to be taken orally, would greatly increase their clinical impact and translation into human DMD and DM1 patients. Here we will employ new approaches to examine the effectiveness of targeting AMPK for the treatment of muscular dystrophy. Specifically, the purpose of this project is to investigate whether stimulation of AMPK with practical, next-generation compounds improves the health of mice with DMD and DM1, which would provide a better outlook for applicability in human muscular dystrophy patients. We will focus on the ability of the AMPK-activating drugs to restore the proper structure and function of dystrophic skeletal muscles, as well as explore the underlying molecular mechanisms of their action. There is no better time than the present to perform these studies since these drugs are also currently in clinical trials for treating epidemics such as diabetes and metabolic disease. This proposal is designed to reveal critical information about the therapeutic potential of a new class of AMPK-stimulating compounds, which may ultimately improve the quality and quantity of life of Canadians.