Sarcopenia, or pathological loss of muscle mass and strength during aging, is an important contributor to loss of physical function in older adults. Sarcopenia is a multifactorial syndrome associated with intrinsic muscle and upstream neurological dysfunction. Exercise is well-established as an effective intervention for sarcopenia, but less is known about the long-term neurobiological impact of exercise. The goals of this study were to investigate the effects of exercise, alone or in combination with follistatin (FST) overexpression (antagonist of myostatin), on neuromuscular junction transmission and motor unit numbers in mice between the age of 22 and 27 months, ages at which prior studies have demonstrated that some motor unit loss is already evident. C57BL/6J mice underwent baseline assessment and were randomized to housing with or without voluntary running wheels and injection with adeno-associated virus to overexpress FST or vehicle. Groups for comparison included sedentary and running with and without FST. Longitudinal assessments showed significantly increased muscle mass and contractility in the 'running plus FST' group, but running, with and without FST, showed no effect on motor unit degeneration. In contrast, running, with and without FST, demonstrated marked improvement of neuromuscular junction transmission stability.