Neuromuscular interplay and lncRNAs: a synaptic liaison

Maintaining muscle homeostasis is crucial for the upkeep and repair of adult tissues. Any deviation from the dynamic equilibrium that preserves muscle fibers in a constant state of complexity can lead to various diseases. Recent years have witnessed groundbreaking studies that bring fresh attention to this field by delving into the impact of novel regulators in muscle pathophysiology. Beyond protein factors, innovative high-throughput and biochemical approaches have unveiled the additional and essential contribution of RNA-mediated molecular mechanisms to the regulation of myogenic gene expression. Building upon our unique collection of newly annotated lncRNAs (Ballarino M. et al., Mol Cell Biol 2015) as an invaluable resource for selecting candidate disease-associated genes, we are integrating gene editing, induced pluripotent stem cell technology, and state-of-the-art biochemical approaches. This approach aims to study the contribution of lncRNAs to muscular and neuromuscular physiology and elucidate novel pathways and disease mechanisms. Notably, our investigations include Charme (Taliani V. et al., Elife 2023), previously identified in mice as a myogenic lncRNA, currently under investigation to clarify its role in human skeletal muscle differentiation. A particular emphasis is also placed on the study of muscle-nerve interaction. Within this framework, we examine the function of muscle lncRNAs and motoneuronal lncRNAs, such as nHOTAIRM1 (Tollis P. et al., Cell Death & Dis 2023), in neuromuscular development, NMJ formation, and maturation. This study provides a suitable platform to trace the developmental contribution of lncRNAs to neuromuscular formation and disorders, discover new RNA functions, and advance their application in gene therapy.