Understanding the maintenance of neuromuscular integrity: role of CtBP1 and EZH2 in skeletal muscle response to denervation

Abstract

Loss of functional innervation of skeletal muscles is key in several pathologies, including sarcopenia. Neuromuscular junctions (NMJs) maintenance involves local expression of synaptic genes restricted to sub-synaptic nuclei, and a proper response to spontaneous denervation to re-innervate and preserve muscle functions. We hypothesized that the Akt/mTORC1 signaling pathway acts as a regulatory platform coordinating muscle responses to denervation. During my PhD, I characterized the expression pattern of two candidate targets, C-terminal binding protein 1 (CtBP1) and enhancer of zeste homolog 2 (EZH2) in both innervated and denervated conditions. I also studied the consequences of knocking down and/or overexpressing CtBP1 or EZH2 on synaptic gene expression, NMJ maintenance, muscle histology and metabolism. Lastly, I evaluated the role of Akt/mTORC1 in the regulation of CtBP1 and EZH2 in skeletal muscle, by comparing their expression pattern in control and TSCmKO mice, characterized by Akt/mTORC1 deregulation and used as a model for sarcopenia