Metabolic regulation of reciprocal signalling between skeletal muscle cell types

Informations projet

MUSIC

N° de convention de subvention: 896544

DOI

10.3030/896544

Projet clôturé

Date de signature de la CE 28 Mars 2020

Date de début 1 Septembre 2020

Date de fin 31 Août 2022

Financé au titre de

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Coût total

€ 184 707,84

Contribution de l’UE

€ 184 707,84

Coordonné par

UNIVERSITE LYON 1 CLAUDE BERNARD
France

Periodic Reporting for period 1 - MUSIC (Metabolic regulation of reciprocal signalling between skeletal muscle cell types)

Période du rapport: 2020-09-01 au 2022-08-31

Résumé du contexte et des objectifs généraux du projet

Maintenance of skeletal muscle quantity and quality is crucial for healthy aging, and is facilitated by a remarkable tissue plasticity. Muscle-resident stem cells (MuSC) provide an important contribution to this plasticity by differentiation and subsequent fusion with the myofiber – a process called myonuclear accretion. The progression of this process is characterised by distinct MuSC metabolic requirements, and seems to depend on the myofiber metabolic state. We therefore anticipated a role of metabolism – and specifically, the metabolic regulator AMPKalpha2 – in myofiber to the MuSC signalling, directing MuSC fate towards myonuclear accretion. A better understanding of the process of myonuclear accretion and its regulation will be important to better understand disease aetiology and pathophysiology and will contribute to a better treatment (e.g. by AMPK activators) of patients with patient with (metabolic) diseases leading to muscle pathology that may be caused by impaired myonuclear accretion. The overall objectives of the project constitute a ‘proof of principle’, ‘target identification’, and ‘target validation’.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

We found that AMPKa2 specifically regulates myonuclear accretion in a MuSC-instrinsic manner both in vitro and in vivo. Specifically, co-cultures studies between in vitro generated myofibers and EdU-labeled MuSC-derived myocytes was decreased if AMPKa2 was absent from the myocytes. In line, we found a problem with skeletal muscle regeneration in vivo after CTX-induced injury if AMPKa2 was inactive, and observed a MuSC-intrinsic role during myonuclear accretion after neuromuscular electrical stimulation (NMES). We identified BAIAP2 as the target of AMPKa2 that mediates this effect in vitro. These results were presented at several international scientific meetings and will be part of a manuscript that is currently under development.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

The tools generated and approaches used to study myonuclear accretion in this project can be implemented in other projects and by other teams with relative ease. This will contribute to the knowledge development regarding the role and regulation of myonuclear accretion in divers physiological and pathological contexts. The results so far, and the further developed knowledge will contribute to a better understanding of skeletal muscle maintenance in the context of health and disease, and will potentially contribute to their prevention and treatment.

Myonuclear accretion in vivo