Exercise affects skeletal-muscle reinnervation after nerve crush via TrkB-A2A receptor crosstalk

Exercise affects skeletal-muscle reinnervation after nerve crush via TrkB-A2A receptor crosstalk Sartini S1, Di Palma M1, Ambrogini P1, Lattanzi D1, Pellegrino MA2, Bottinelli R2, Cuppini R1 1Dept. of Biomolecular Sciences, University of Urbino Carlo Bo, Italy; 2Dept. of Molecular Medicine, University of Pavia, Italy The mechanisms behind the recovery of skeletal muscle innervation after peripheral nerve injury remain poorly understood. We previously showed that an intermittent, mid-intensity treadmill activity induces axonal sprouting and faster muscle re-innervation, but these effects were only partially explained by TrkB activation by muscle-derived BDNF. In the present work no significant difference in NT4, IGF1, CNTF, and GDNF expression was found between sedentary and running rats. Muscle activity increases adenosine release, and, moreover, a pivotal role of adenosine in TrkB activation has been recently demonstrated in brain. Therefore, we evaluated the role of A2A-TrkB crosstalk in muscle re-innervation by intracellular electrophysiological recordings. Ten days after nerve crush, the percentage of multiply innervated muscle cells (an index of nerve sprouting) was about 10 % in sedentary rats. This percentage increased to about 30% in runners, but not if they were treated with TrkB or A2A specific receptor antagonists. Moreover, sedentary controls administered with specific TrkB or A2A agonists showed an increase similar to that obtained under running conditions. These findings show a primary role of adenosine in intramuscular motor nerve sprouting and strongly suggest that the adenosine action through A2A receptors by gating the TrkB signaling might be the underlying mechanism.