Periodic Reporting for period 1 - MUSIC (Metabolic regulation of reciprocal signalling between skeletal muscle cell types)
Período documentado: 2020-09-01 hasta 2022-08-31
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’.
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.
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.