Description of the thesis topic

Skeletal muscle is essential for locomotion, posture, and overall metabolism. It is composed of muscle fibers that contract under the control of motor neurons, forming a finely regulated neuromuscular system. Dysfunctions in this regulation can lead to severe pathologies, such as muscular dystrophies or myopathies. Complex molecular signaling pathways, involving various actors like protein kinases, are implicated in coordinating muscle and nerve functions. Among them, the AMPK-related protein kinase family plays a potential yet still poorly understood role in muscle function.

This PhD project aims to investigate the specific role of several AMPK-related protein kinases in the regulation of neuromuscular function by using transgenic knockout (KO) mouse models for genes encoding these protein kinases, specifically in skeletal muscles.

The project is structured into four major parts: (1) Characterization of KO mice for the targeted protein kinases specifically in skeletal muscles. These transgenic models will be validated through a series of analyses to ensure the specificity and efficiency of the targeted kinase knockouts in muscle tissue. Histological, biochemical, and cell biology analyses will be conducted to determine the impact of kinase invalidation on muscle structure, cell signaling, and other factors. (2) Functional and morphological phenotyping: In-depth analysis of muscle performance through strength, endurance, and electromyography tests. The impact of the absence of these kinases on myofiber typology and the morphology of neuromuscular junctions will be studied using imaging techniques (fluorescence microscopy, histology). (3) Study of molecular mechanisms: Evaluation of alterations in downstream signaling pathways resulting from the deletion of the kinases using transcriptomic, proteomic, and western blot approaches to understand the mechanisms affecting contractility and neuromuscular transmission. (4) Consequences on muscle regeneration: KO mice will be subjected to muscle injury models to analyze the impact of these kinases on regeneration and repair processes. This project will contribute to a better understanding of the roles of AMPK-related protein kinases in neuromuscular pathophysiology, with potential implications for diseases such as muscular dystrophies.

Work Context

The selected candidate will join a research group at the Institut Cochin, composed of researchers, lecturers, and PhD students. He/she will benefit from excellent supervision and a stimulating research environment within the Institut Cochin.

Constraints and risks

No specific constraints or risks, aside from those related to working in biological research laboratories (ethics, scientific rigor, confidentiality, etc.).