Role and mechanism of action of anabolic stimuli on neuromuscular trophicity

Resumo

Accumulating evidence suggests that the synapse between motoneurons and skeletal muscle fibers, the neuromuscular junction (NMJ), plays an integral role not only for muscle contraction but also for superior, metabolic muscle functions. This might be of particular relevance under a series of severe atrophic conditions, including age-related muscle loss (sarcopenia). The principal postsynaptic component is the nicotinic acetylcholine receptor (AChR), whose density in the synaptic membrane and metabolic stability are finely tuned in an activity-dependent manner. While agrin was identified as a factor inducing the clustering of AChR, the extracellular signals that regulate the metabolism of AChR are still elusive. Different lines of evidence indicate that postsynaptic cAMP/PKA-signaling and calpain activity play crucial roles in this process. Our published and preliminary data show that catecholamines as well as the neuropeptide, CGRP, inhibit calpain function via cAMP/PKA- dependent signaling in skeletal muscle. Furthermore, recent data highlight the beneficial effect of beta-agonists for the treatment of neuromuscular disease, suggesting that there is a direct mechanistic link. Notably, our data further demonstrate that catecholamines and CGRP are also important regulators of muscle protein metabolism indicating an intimate connection between the processes regulating protein turnover in both NMJ and fiber. This project aims to address 1) the role of catecholamines and CGRP under basal and catabolic conditions for the maintenance of the NMJ, 2) the mechanisms that underlie such function, and 3) whether the processes regulating protein turnover in the fiber are similar to those in the NMJ. To that end, the Brazilian and German groups will synergize with their respective expertises on muscle metabolism, in vivo-models and live animal microscopy. (AU)