Forelimb Resistance Exercise Protects Against Neuromuscular Junction Denervation in the SOD1-G93A Rat Model of ALS

Hiroshi Nishimune,1,2 Kimberly G Stanford,3 Jie Chen,1 James D Odum,3 Alexander D Rorie,3 Robert S Rogers,4 Joshua L Wheatley,3 Paige C Geiger,3 John A Stanford3 1Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS, USA; 2Tokyo Metropolitan Institute of Gerontology, Neurobiology of Aging, Tokyo, Japan; 3Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, USA; 4Departments of Physiology and Basic Sciences, Kansas City University of Medicine and Biosciences, Joplin, MO, USACorrespondence: John A Stanford, Department of Molecular & Integrative Physiology, University of Kansas Medical Center, 3901 Rainbow Blvd., MS 3051, Kansas City, KS, 66160, USA, Tel +913-588-7416, Fax +913-588-5677, Email jstanford@kumc.eduIntroduction: The symptoms of Amyotrophic Lateral Sclerosis (ALS) include muscle weakness and eventual paralysis. These symptoms result from denervation of the neuromuscular junction (NMJ) and motor neuron cell death in the brain and spinal cord. Due to the “dying back” pattern of motor neuron degeneration, protecting NMJs should be a therapeutic priority. Although exercise has the potential to protect against NMJ denervation, its use in ALS has been controversial. Most preclinical studies have focused on aerobic exercise, which report that exercise can be beneficial at moderate intensities. The effects of resistance exercise on NMJ preservation in limb muscles have not been explored.Methods: We trained male SOD1-G93A rats, which model ALS, to perform a unilateral isometric forelimb resistance exercise task. This task allows within-animal comparisons of trained and untrained forelimbs. We then determined the effects of isometric resistance exercise on NMJ denervation and AMP kinase (AMPK) activation in forelimb muscles.Results: Our results revealed that SOD1-G93A rats were able to learn and perform the task similarly to wildtype rats, even after loss of body weig