Identification of neuroprotective mechanisms activated by exercise in a mouse model of type 2 spinal muscular atrophy.

Summary Infantile spinal muscular atrophy (ISA) is a neuromuscular disease of children, induced by a low level of SMN (Survival of Motor Neuron) protein in the body and for which no curative therapy is known to date. In this work, we show that the delayed maturation of motor units, observed in ASI type II mice, is correlated with motor neuron death. Physical exercise delays motor neuron death and induces an acceleration of motor unit maturation. Furthermore, exercise is able to specifically increase the expression of the gene coding for the activating subunit of the NMDA receptor and majority in motor neurons, named NR2A, which is under expressed in the spinal cord of ASI type II mice. Consequently, inhibiting NMDA receptor activity blocks the effects of exercise on muscle development, neuroprotection and lifespan. Thus, restoring NMDA receptor function may be a promising therapeutic approach for the treatment of ASI.