Peripheral nerve injuries are common with more than 200,000 new cases reported each year in the United States alone. Only about 10% of these individuals regain much function. There are 17,730 new U.S. spinal cord injuries annually, and the lifetime costs can reach $5 million per person (not including lost wages). Nerve injury and especially spinal cord injury significantly impact long-term quality of life, and most injured individuals seek continued treatments for associated disabilities and pain. The most common explanation for poor functional outcomes is the slow and inefficient process of axon regeneration. Axons within the spinal cord and nerve consist of motor, sensory, and sympathetic axons, which undergo plasticity after injury. A critical knowledge gap in neuroscience is understanding the purpose of sympathetic axon terminals within the neuromuscular synapse, how sympathetic axons associated with neuromuscular junctions respond to neural injuries, and what their contribution is to functional recovery or dysfunction. Preliminary evidence suggests that the sympathetic innervation of neuromuscular junctions can modulate mitochondrial respiration and biogenesis, synaptic stability, and muscle strength as well as control the muscle response to exercise and activity. The overarching hypothesis of this K01 proposal is that sympathetic neurons are required for the functional and metabolic stability of the neuromuscular unit in normal and pathological conditions. We will first test the necessity and sufficiency of sympathetic nerve activity on metabolic and motor control using a novel technology, BioLuminescent OptoGenetics (BL-OG) in normal, uninjured animals. My research has shown that exercise and neuronal activity strikingly enhance peripheral axon regeneration and significantly improves functional recovery following complete nerve and spinal cord injuries in preclinical models. However, while clinician scientists recognize the importance of exercise to promote axon regeneration and metabolic health, the translational potential of exercise has many limitations. Many patients are not candidates for exercise due to co-morbidities that preclude rehabilitation, necessary immobilization of a limb following surgical nerve repair, unknown dose requirement of exercise, and low patient compliance. Further limitations are that nearly 70% of the skeletal muscle of people with a spinal cord injury is paralyzed, and there are no guidelines for electrically induced exercise of paralyzed muscle. Experimental evidence also shows that sympathetic axon regrowth may even be inhibited by certain types of treatments, such as electrical stimulation. Thus, other goals of this work are to investigate whether increasing sympathetic activity 1) promotes or inhibits sympathetic axon regeneration after peripheral nerve injury, and 2) can rescue the muscle bioenergetic and motor control deficits after spinal cord injury.

Functional characterization of sympathetic innervation of the neuromuscular synapse will provide an essential framework that may be immediately used to improve therapeutic interventions, e.g. electrical stimulation for nerve injury. Although this application targets traumatic axon injury, the fundamental biology revealed in this proposal may extend to many other neurological diseases characterized by progressive muscle weakness, motoneuron dysfunction and sympathetic disturbances, such as ALS, myasthenia gravis, metabolic and chronic fatigue syndrome, and aging induced sarcopenia.