Tetraspanin CD82 in muscle satellite cells quiescence and differentiation

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SUMMARY/ABSTRACT The tetraspanins constitute an important family of proteins known to regulate the aggregation of protein complexes at the cell membrane. Tetraspanins are known to bind and recruit other proteins at the cell surface, such as integrins and cell adhesion molecules, thus initiating important cell decisions including migration, adhesion and signaling activation. Our preliminary data demonstrate that the tetraspanin CD82 is expressed by muscle satellite cells where it binds to other proteins in a ~250Kd protein complex. One of the protein members is α7-integrin (α7-ITG). Cultured myoblasts from α7-ITGnull mice show decreased expression of CD82, suggesting a functional link between these two proteins. Additionally, muscle tissue lysates from dystrophic mdx and α7-ITGnull mice show a decrease to near absence of the CD82-α7-ITG protein complex compared to wild-type skeletal muscle. Lastly, muscle satellite cells from CD82 knockout mice show a defect in cell proliferation. In the present application we propose to identify the additional members of the CD82-α7-ITG complex, study the post-translational modifications of CD82 in satellite cells and determine the stoichiometry of the complex in normal satellite cells (Aim1). In Aim 2, we will identify the downstream signaling pathways of CD82 that lead to impaired cell proliferation of CD82 knockout satellite cells. We will investigate if these molecules are downstream signaling effectors of α7-ITG, or are unrelated to α7-ITG function. Finally, in Aim 3 we will study whether overexpression of CD82 in satellite cells can enhance their in vivo reparative capacity and improve the overall function of dystrophic muscle. These studies will advance our understanding on the role of this specific tetraspanin in satellite cell activity and will provide the groundwork for future therapies aimed at enhancing the expression of the CD82 protein complex in dystrophic muscle.