Muscle-nerve communication and the molecular assessment of human skeletal muscle denervation with aging

Muscle fiber denervation is a major contributor to the decline in physical function observed with aging. Denervation can occur through breakdown of the neuromuscular junctions (NMJ) itself, affecting only that particular fiber, or through the death of a motor neuron, which can lead to a loss of all the muscle fibers in that motor unit. In this review, we discuss the muscle-nerve relationship, where signaling from both the motor neuron and the muscle fiber is required for maximal preservation of neuromuscular function in old age. Physical activity is likely to be the most important single factor that can contribute to this preservation. Furthermore, we propose that inactivity is not an innocent bystander, but plays an active role in denervation through the production of signals hostile to neuron survival. Investigating denervation in human muscle tissue samples is challenging due to the shared protein profile of regenerating and denervated muscle fibers. In this review, we provide a detailed overview of the key traits observed in immunohistochemical preparations of muscle biopsies from healthy, young, and elderly individuals. Overall, a combination of assessing tissue samples, circulating biomarkers, and electrophysiological assessments in humans will prove fruitful in the quest to gain more understanding of denervation of skeletal muscle. In addition, cell culture models represent a valuable tool in the search for key signaling factors exchanged between muscle and nerve, and which exercise has the capacity to alter.