Perrine Castets

Muscle and NeuroMuscular Junction

Loss of functional innervation of skeletal muscle is a hallmark of multiple pathological conditions, contributing to the onset and aggravation of muscle dysfunction. Neuromuscular junctions (NMJs) are highly specialized regions allowing the transmission of neural information to muscle and, thereby its contraction. The functioning of the system relies on the accumulation of synaptic proteins in the sub-synaptic muscle region, while their synthesis is shut down in extra-synaptic domains. Neural inactivity (e.g. after nerve injury) triggers major synaptic remodeling in muscle, including a drastic increase in the expression of synaptic proteins in both sub- and extra-junctional regions of muscle fibers. This plasticity determines muscle ability to adapt and prepare for recovery, albeit conditions abrogating nerve/muscle interplays will ultimately cause severe muscle dysfunction. The objectives of the research program are to decipher the molecular mechanisms that sustain functional and plastic connectivity between nerve and skeletal muscle and, to delineate factors liable to compromise muscle / nerve interplays.

In a first research axis, we aim at identifying effectors involved in the regulation of synaptic gene expression and/or in the control of synaptic protein dynamics in sub- and extra-synaptic regions, dependent on neural activity. The second part of our research program focuses on the molecular events triggering synaptic remodeling in muscle fibers, especially upon nerve injury. Lastly, translational, collaborative projects aim at determining the contribution of NMJ perturbations in muscle alterations in specific pathological conditions.

By focusing on the molecular mechanisms supporting or alternatively threatening NMJ maintenance, our overall goal is to better understand the loss of neuromuscular integrity in systemic conditions and neuromuscular diseases, in order to anticipate and prevent the associated muscle dysfunction.