PROJECT SUMMARY: Over time, declining muscle force and power impair mobility and quality of life. In aging rodents and humans, skeletal muscle undergoes a process of denervation and reinnervation; denervation is strongly implicated in the onset and progressive decline of skeletal muscle mass, composition, and function, termed sarcopenia. Whether muscle denervation starts at the myofiber or the central or peripheral nervous system is controversial. Answering this question is crucial for developing targeted interventions to prevent or reverse age-related decline in skeletal muscle innervation and consequent loss of mass and force. Increasing evidence supports a decline in neural influence on skeletal muscle at older ages. The neuromuscular junction (NMJ) is a tripartite synapse composed of the presynaptic motor neuron axon, postsynaptic myofiber specialization, and nonmyelinating perisynaptic or terminal Schwann cells (tSCs). With age, the NMJ becomes unstable in a process characterized by fragmentation, shrinkage, and simplification of the postterminal. Detailed studies indicate that the tripartite model includes elements that are crucial for normal skeletal muscle structure and function, so why, does the normally stable NMJ eventually destabilize? In humans, autonomic innervation and function become impaired with age. Our preliminary data support direct sympathetic innervation of the myofiber at the NMJ, sympathetic regulation of motor/somatic fiber innervation, and regulation of muscle autophagy with aging. Based on our novel preliminary data, we hypothesize that: (1) Hand2, a key transcription factor for sympathetic neuron development and maintenance, steeply declines with aging, inducing motor pre- and postsynaptic NMJ instability and disorganization, muscle denervation, and sarcopenia; and (2) Expressing Hand2 exclusively in sympathetic neurons will significantly prevent: (a) motor denervation, (b) increased ubiquitin-proteasome system (UPS) activity, (c) impaired autophagy and NMJ transmission, and (d) sarcopenia, in old (22-month) and geriatric (28-month) mice. The following specific aims are designed to test these hypotheses: Aim 1. To determine whether age-dependent sympathetic denervation causes motor denervation, NMJ disorganization and transmission failure, and sarcopenia. Aim 2. To establish whether preserving muscle sympathetic innervation prevents increased UPS, decreased autophagy flux, decreased acetylcholine receptor (AChR), and muscle motor denervation with aging. This project will be the first to define the link between two hallmarks of aging skeletal muscle—denervation and sarcopenia—and the cross-talk between the sympathetic and motor nervous systems at the skeletal muscle with aging.