Skeletal muscle is composed of a large and heterogeneous variety of cell populations that interact with each other to maintain muscle homeostasis and orchestrate regeneration. On the other hand, the participation of those cell populations in the neuron-muscle interaction remains understudied. In neuromuscular disorders, such as Amyotrophic Lateral Sclerosis (ALS), a disruption of the neuron-muscle interaction leads to muscle denervation, muscle atrophy and loss of function, with devastating consequences to the patient’s health and often with invariably fatal outcome.

We recently observed that muscle resident cells are sensitive to muscle denervation and activate an alternative gene expression program. Preliminary data reveal a muscle resident cell population characterized by the activation of a potent neurotrophic program in response to loss of innervation. Indeed, few days after denervation expression of neurotrophic genes such as sonic hedgehog (Shh) and Glial Cell Derived Neurotrophic Factor (Gdnf) are strongly induced in those cells. Finally, functional experiment indicate that those cells promote neurite growth and elongation in-vitro.  The aim of this study is to analyse the ability of those cell population in the neuromuscular junction maintenance in physiological and pathological conditions.

To tackle this unexplored facet muscle biology, we will use next generation Single-Cell RNA-sequencing, in-vitro and in-vivo studies. The elucidation of the molecular players that drive muscle innervation maintenance will allow the identification of novel therapeutic targets to counteract neurodegenerative diseases.