We propose to develop new strategies to mobilize skeletal muscle tissue-associated stem cells as a tool for efficient tissue repair. This will be combined with exploring novel approaches that limit tissue damage, and will focus on agents that modify muscle and muscle vasculature progenitor cells. These molecules include nitric oxide associated with non-steroidal anti-inflammatory drugs, HMGB1, Cripto, NAC, and present and improved deacetylase inhibitors. Three clinical trials will be run in tandem with efforts to dissect the underlying mechanisms of action. Importantly, we have already initiated a monocentric clinical trial that focuses on the efficacy of NO-donors plus NSAIDs in muscle pathologies. Our efforts will be complemented by novel biodelivery systems for effective targeting. Our efforts will be complemented by novel biodelivery systems for effective targeting. The most promising drugs, used alone or in combination, will be first validated in small and large animal models. Our project brings together leading investigators to examine how vascular and muscle progenitors participate in postnatal growth and muscle tissue repair. A key issue that this project addresses is the tissue environment in which endogenous stem cells are activated. We propose that muscle degeneration and fibrosis provokes altered vascularization and immune responses, which eventually affect negatively stem cell functions. Molecules that can be used to therapeutically target these key cells, and their communication with neighboring vascular, inflammatory and fibrotic cell types, will lead to more effective approaches to muscle regenerative medicine and to novel cures for degenerative diseases, including atherosclerosis, vascular damage in diabetes and in peripheral ischemic vascular disease.