Our team aims to understand, in the model of skeletal muscle fibers, mechanisms controlling genome expression, cytoskeleton rearrangements and nuclear domain establishment and their implication in pathological contexts such as genetic disorders (Emery-Dreifuss Muscular Dystrophy and Centronuclear myopathies) or physiological aging (Sarcopenia). We also aim, in the model of cardiomyocyte, decipher implication of mutations identified in cardiomyopathies such as inherited hypertrophic cardiomyopathies (HCM), Atrial fibrillation (AF) or Arrhythmogenic right ventricular cardiomyopathy (ARVC).
Microtubule proteome and MyoNuclei Domains (MNDs) formation/maintenance during skeletal muscle development
Myonuclei actively position throughout muscular development. Growing evidences support a direct connection between regulation of nuclear positioning/shape, myonuclear domains establishment, microtubule architecture maintenance in muscle fibers and normal function of muscles. Microtubule network is completely redesigned during muscle formation. We hypothesize that differences between proteome associated with microtubules in immature and mature fibers contribute to (1) microtubule reorganization and (2) myonuclei localization. We developed a mass-spectrometry strategy to isolate and analyze those two proteomes using an original in vitro system that allow the formation of pure “mature” muscle fibers. This strategy conducts to the selection of nearly 500 candidates that we are currently investigating using a siRNA screen-approach using both immortalized muscle C2C12 cells and primary murine muscle cells.
Rescue myonuclear domains establishment in centronuclear myopathies with chemical compounds
The incorrect positioning of nuclei in the center of myofibers is a hallmark of a class of muscular diseases called centronuclear myopathies (CNM), which includes myotubular myopathy. We have developed a screening strategy that has the potential to identify new molecules that can rescue nuclear positioning defects observed in centronuclear myopathies. The screening proposed here is expected to lead to novel strategies for the treatment of centronuclear myopathies by reducing muscle weakness caused by central nuclei in diseased muscles.
Mutations identification and implication in the physiopathology of cardiomyopathies
Cardiac arrhythmias are cardiomyopathies that regroup different pathophysiological syndromes such as atrial fibrillation, tachycardia and ventricular fibrillation. Deciphering molecular mechanisms implicated in these cardiomyopathies will help the identification of therapeutics targets and the development of new treatments. We are leading a systematic approach that consists in the identification of mutations in patients with related cardiomyopathies. Using iPSCs (Induced pluripotent stem cells) and CRISPR/Cas9 technology, we are developing cardiomyocytes with identified mutations and decipher in vitro implication of associated genome alterations on the behavior of those cells.