Role of NRLP3 inflammasome and AMPK signaling in inflammation induced skeletal muscle atrophy
Responsable de l’encadrement : Benoit Viollet
Tél : 0144412401 E-mail: email@example.com
Résumé du Projet de Stage
Skeletal muscle atrophy is a serious health problem. However, the mechanisms of skeletal muscle atrophy that has been clarified at present are insufficient, and a therapeutic method against skeletal muscle atrophy has not been established. Systemic inflammation has been associated with skeletal muscle atrophy and the current challenge is to elucidate the molecular determinants linking inflammation and maintenance of muscle mass. Recent evidence suggested an association between an innate immune component, the NLRP3 inflammasome, and inflammation-induced morphological alterations in skeletal muscle. Although the NLRP3 inflammasome is known mainly to contribute to cytokine production by immune cells, its specific role in skeletal muscle and specifically within myofibers remains poorly studied and understood. The main objective of this thesis is to reveal new fundamental function and regulation of NLRP3 inflammasome in skeletal muscle atrophy by using in various in vitro and in vivo models of inflammation-induced muscle atrophy. A key unresolved question is the nature of the factors that control inflammation in skeletal muscle and that participate in the development of muscle wasting. We hypothesize a crosstalk between AMPK signaling and activation of inflammasome that could provide the ground for finding new targets to treat neuromuscular diseases. We will investigate the role of AMPactivated protein kinase (AMPK), a critical player in metabolic regulation shown to control NLRP3 inflammasome activation during innate immune cell activation, in the muscle remodeling cycle to maintain muscle mass. We will combine molecular and functional analyses of primary myotubes culture and mouse models in response to inflammasome activators/ inhibitors in the context of inflammationinduced muscle atrophy. Our first aim is to examine the role of AMPK in the regulation of NLRP3, inflammasome activation specifically in skeletal muscle/ myofibers using in vitro and in vivo AMPKdeficient models. Our second aim is to determine how AMPK affects the NLRP3, inflammasome activation through the regulation of the phosphorylation of inflammasome components. Our third aim is to study the effects of pharmacological AMPK activation on inflammasome regulation in an in vivo model of denervation-induced skeletal muscle atrophy. We expect to better understand the contribution of inflammasome in the pathogenesis of neuromuscular diseases and to propose new therapeutic targets to treat inflammation-mediated skeletal muscle wasting during acute and chronic diseases.
Dernières Publications en lien avec le projet :
Kjøbsted R, Hingst JR, Fentz J, Foretz M, Sanz MN, Pehmøller C, Shum M, Marette A, Mounier R, Treebak JT, Wojtaszewski JFP, Viollet B, Lantier L. AMPK in skeletal muscle function and metabolism. FASEB J. 2018 Apr;32(4):1741-1777.
Ce projet s’inscrit dans la perspective d’une thèse
Ecole Doctorale de rattachement : BioSPC ED562
Laboratoire d’accueil :
Nom du Responsable de l’Unité : Florence Niedergang
Nom du Responsable de l’Équipe : Benoit Viollet
Institut cochin 24 rue du faubourg Saint Jacques 75014 Paris