Mechanisms of Nup210 Regulation of Muscle Development and Regeneration

Sanford Burnham Prebys Medical Discovery Institute, La Jolla CA

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Abstract

DESCRIPTION (provided by applicant): Nuclear pore complexes (NPCs) are multiprotein channels that penetrate the nuclear envelope and connect the nucleus with the cytoplasm. Besides controlling nucleocytoplasmic transport, NPCs are involved in chromatin organization and gene expression regulation. Changes in the composition of these structures have been recently linked to myoblast differentiation, suggesting a role for specialized NPCs in muscle physiology. In adults, muscle regeneration and repair requires the efficient function of satellite cells. Upon injury, these muscle stem cells are induced to proliferate, differentiate into myoblasts and fuse to regenerate muscle fibers. Because satellite cells are essential for muscle repair and regeneration, transplantation of these cells represents a promising therapy for the treatment of damaged muscle, muscular dystrophies and sarcopenia. Therefore, understanding the mechanisms of satellite cell function has become of great interest for regenerative medicine. Previous studies have found that the expression of the nuclear pore complex protein Nup210 is required for myoblast differentiation and survival, indicating an essential role for this protein i skeletal muscle differentiation and regeneration. Additionally, up-regulation of Nup210 levels in myoblasts has been shown to accelerate myogenesis, suggesting that modulation of its activity could be exploited to stimulate muscle regeneration. The overall objectives of this proposal are to establish the molecular mechanisms through which the nucleoporin Nup210 regulates myogenesis and to define its function in muscle formation and maintenance, with the ultimate goal of defining its potential as a therapeutic target for muscle regeneration. By combining in vivo and in vitro genetic approaches with muscle injury studies we expect to establish the role of Nup210 in muscle formation, growth and repair (Aim 1) and define the molecular mechanisms of myogenic regulation by Nup210 (Aim 2). In addition, we will determine if modulating the activity of this nuclear pore complex component can stimulate muscle regeneration and reverse the myogenic defects of dystrophic myoblasts. Defining the function of Nup210 in muscle physiology and understanding its molecular mechanisms of action are critical steps to determine whether this pathway could be used to develop therapies directed to stimulate muscle healing and prevent muscle degeneration. Our contribution here is expected to be a detailed understanding of the role of Nup210 in myogenesis, muscle development and muscle regeneration. These studies will significantly advance our knowledge of how changes in nuclear pore complex composition and function regulate these processes and could uncover new targets on which therapies to improve muscle function or prevent muscle degeneration can be developed.