The intracellular control of Thyroid hormone signaling in muscle stem cells and in Duchenne Muscular Dystrophy

Duchenne Muscular Dystrophy (DMD) is the most common form of muscular dystrophy, affecting 1 in 3,500 male births. DMD patients suffer from severe, progressive muscle wasting, with clinical symptoms first detected at 2-5 years of age. As the disease progresses, patients are confined to a wheelchair in their teens and die in their early 20s from cardiopulmonary failure. Despite years of intense research, there is still no effective treatment or cure for DMD. The active thyroid hormone (T3) derives either directly from thyroid secretion or by the deiodination of the prohormone thyroxine (T4) by one of two enzymes, the deiodinases D1 and D2. Much of the T3 derived from D2, the only activating-deiodinase expressed in muscle, remains within the cell. A third member of the deiodinase family, D3, has an opposing function, catalyzing the inactivation of both T4and T3. Taken together, the actions of the three deiodinases constitute a potent mechanism for regulation of thyroid hormone action at the cellular level. Stem cells are frequently being used as tools in regenerative medicine and drug discovery. Our preliminary data clearly indicate that D2 in the stem cells is an essential component of the myogenic program in muscle development and regeneration. The general objective of this proposal is to dissect the role of thyroid hormone signaling in the control of stem cells biology. Through the study of genetically manipulated mouse lines and primary culture of stem cells, it aims to alter thyroid hormone concentrations in the muscle stem cell with a therapeuticalobjective in DMD context. This work will provide novel insights into the previously unrecognized role of deiodinases in the myogenic program in physiological and pathological settings. In addition it will set the stage to use hormonal regulation as a tool to manipulate at will the physiology of muscle stem cell, modulatingtheir expansion and differentiation in the mdx mouse in a therapeutical context.