Grant: Project Grant

Muscular dystrophies (MDs) are a heterogeneous group of rare genetic diseases that frequently affect children and are often accompanied by severe skeletal muscle wasting leading to premature death. Presently no effective treatment options are available for MD. The diversity and heterogeneity of genetic defects (mutations) causing MD poses a major challenge for the development and manufacturing of genome targeted therapeutics. Therefore, mutation-independent treatment approaches that are applicable to a broad spectrum of MD patients represent an important therapeutic opportunity. We were first to identify defects in the skeletal muscle microvasculature as a common feature in preclinical models of Duchenne, LAMA2, and Collagen-related MD. In a screen for drugs that can ameliorate these defects by stimulating the growth of blood vessels, we identified the small hormone Apelin. Importantly, we observed that by restoring the microvasculature, Apelin treatment significantly improved skeletal muscle regeneration and the function of endogenous muscle stem cells (MuSCs). As a consequence, the animals showed improved survival, healthier muscles, and a remarkable increase in strength. Together with an interdisciplinary team of collaborators, we now propose several independent aims that will improve our understanding of Apelin signaling in normal and dystrophic muscles and advance our work towards the clinics. To this end we will assess how MuSCs and microvessels interact upon Apelin stimulation and study how loss of the respective signaling mechanisms affects skeletal muscle. We will also use medicinal chemistry to generate more effective drug analogues of Apelin. The proposed studies will improve our understanding of the role of Apelin in skeletal muscle and provide the groundwork for the development of a highly effective drug for MD.