Molecular mechanisms of telomere function in muscle stem cells

University Of Pennsylvania, Philadelphia PA

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Abstract

Project Summary/Abstract Duchenne Muscular Dystrophy (DMD) is the most common childhood form of muscular dystrophy and arises from mutations in the dystrophic gene. DMD is characterized by progressive skeletal muscle degeneration, the presence of focal groups of necrotic myofibers, muscle hypertrophy and high levels of serum creatine kinase. While over focused progress as been made the last decade with respect to otential treatments for DMD, current strategies are on treatment of skeletal muscle and do not take satellite cells into consideration. h p We recently demonstrated that telomere shortening is a district feature of dystrophic muscle stem cells (MuSCs) in both mice and DMD patients already at a very young age. The studies proposed here will study determine stem cells within their native tissue environment of live mice and will the cellular consequence of telomere shortening in MuSCs (Aim 1). This proposal will also investigate a previously unknown crosstalk between NF-κB and telomeres (Aim 2) and will determine the function of a telomeric protein in the progression of muscular dystrophy (Aim 3). Understanding the molecular the link between stem cell functional exhaustion and telomere shortening will provide potential alternative methods to bypass the use of long-term corticosteroid treatment currently in use.