ABSTRACT. Preservation of muscle function through Schwann cell regulation of motor unit expansion The loss of skeletal muscle mass and function with aging, known as sarcopenia, is a universal health challenge for the growing elderly population, contributing to decreased mobility, increased disability, loss of independence, and poor quality of life. Studies from our group and others have shown that disruptions of muscle fiber innervation and a reduction in the number of motor units (MU) are significant factors in sarcopenia. A major compensatory mechanism that preserves muscle under conditions of denervation, is MU expansion, which requires axon sprouting and guidance from innervated to denervated neuromuscular junctions (NMJ). In this proposal we will for the first time define cellular responses and molecular pathways critical for MU expansion with the goal of facilitating the development of effective preventive and rehabilitative interventions that exploit this existing protective process. It is widely accepted that axon growth between NMJs occurs through bridges formed by proliferating terminal Schwann cells (tSCs). Exciting new data from our lab using experimental as well as bioinformatic approaches point to the induction during MU remodeling of the secreted phosphoprotein 1 (Spp1)- CD44-protein kinase C alpha pathway from myelinating Schwann cells (SC) onto tSCs. This signaling pathway has not previously been studied in sarcopenia, but published reports show increased Spp1 levels in nerves following denervation injury, the ability of Spp1 to induced SC proliferation through interactions with its receptor CD44, and CD44 expression on tSCs that is increased with nerve injury and during ongoing denervation/ reinnervation in an animal model of amyotrophic lateral sclerosis (ALS). Collectively, rigorous preliminary and published data strongly support SCs as critical effectors of MU expansion via signaling by Spp1. The goals of this project are to establish the effects of age on this pathway in SCs, define the links between denervation and Spp1 signaling, and determine whether this pathway can be targeted to develop protective and rehabilitative therapies for muscle loss. Our overall hypothesis is that MU expansion requires a specific population of tSCs that proliferate in response to denervation through Spp1 signaling mediated by CD44. Using a combination of powerful mouse models, technically sophisticated surgical interventions and assessments of MU properties, and rigorous multidisciplinary genomic and analytical approaches we will show (i) how the number and function of various populations of SCs change with aging and loss of innervation, (ii) the patterns of expression of Spp1 and its signaling partners during denervation and reinnervation, and (iii) the impact of altered Spp1 signaling on MU expansion. By exploiting this physiological compensatory protective mechanism as a therapeutic target, rehabilitative interventions may be developed to p...