Le maintien de la quantité et de la qualité des muscles squelettiques est crucial pour un vieillissement en bonne santé, et est facilité par une bonne plasticité tissulaire. Les cellules souches musculaires (MuSC) apportent une contribution importante à cette plasticité à travers la différenciation et subséquente fusion avec la myofibre, un processus appelé accrétion myonucléaire. La progression de ce processus est caractérisée par des besoins métaboliques distincts du MuSC et semble dépendre de l'état métabolique de la myofibre. Ce projet souhaite comprendre rôle du métabolisme et, plus précisément, du régulateur métabolique AMPKalpha2, dans la myofibre vers la signalisation MuSC, orientant le destin du MuSC vers l'accrétion myonucléaire.

 

Key information / Informations

•   Programme de financement: H2020 MSCA-IF-ST-2020
•    Coordinateur: Université Claude Bernard Lyon 1 - France
•    Subvention : 184.707 €
•    Début – Fin : 09/2020 – 08/2022


Context / Contexte


Skeletal muscle is one of the most abundant tissues in the human body, and powers all if its movements. Both a sufficient amount and quality of skeletal muscle therefore constitute a vital prerequisite for locomotion, exercise, and performing daily tasks. The importance of skeletal muscle health becomes particularly evident upon the development of musculoskeletal conditions such as the loss of skeletal muscle mass and function. The World Health Organization recognizes the impact of musculoskeletal conditions and emphasizes the need for multimodal interventions with exercise as a key component to reduce mobility loss. However, while exercise has well-established beneficial effects on average, there is a large inter-individual variability in the response to exercise. This variability may be partially overcome by a multimodal approach, but it also calls for the implementation of individualized treatment programs, for which a comprehensive understanding of underlying cellular and molecular processes is indispensable.

Objectives / Objectifs


In the proposed project, we will explore the role of metabolism in the reciprocal signalling between the myofiber and the MuSC, during myogenesis facilitating myofiber plasticity. To do this, we will focus on the role of the metabolic regulator AMPKalpha2, in directing MuSC fate towards myonuclear accretion. Specifically, the research objectives are:
1)    Testing the causal role of AMPKalpha2 in the myofiber and MuSC, respectively, in the regulation of myonuclear accretion. Demonstrating an altered response to the induction of myonuclear accretion in absence of AMPKalpha2 would provide the first direct evidence for reciprocal signalling between the myofiber and the MuSC through metabolism (i.e., system validation).
2)    Unravelling the mechanistic and metabolic targets of AMPKalpha2 in the myofiber and MuSC during myonuclear accretion, using integrative metabolomics and phosphoproteomics analyses (i.e., target identification).
3)    Testing the causal role of identified AMPKalpha2 targets in the regulation of myonuclear accretion. Demonstrating a causal role for specific metabolic targets in the coordination of myonuclear accretion would provide a mechanistic insight in the role of metabolism in the reciprocal signalling between the myofiber and MuSC (i.e., target validation).

Expected impact and results / Impact et résultats attendus


MSCA IF aim to support the career development and training of researchers through international and intersectoral mobility. The impact of the fellowship will be both on the individual competence in terms of skill acquisition through advanced training (transferable skills and technical skills) and on the scientific project.
Concerning the research, this study is the first to directly address the metabolic cross-talk between the myofiber and MuSC. The main impact of the project will therefore be a revised theoretical model that will have important implications for both the understanding of the MuSC response to exercise, and the role of MuSC in the exercise-induced metabolic adaptations of the myofiber.

LIP’s contribution / Rôle de LIP :

LIP a accompagné le porteur de projet dans toute la phase de montage. LIP est en charge du suivi administratif, juridique et financier de ce projet.