Unravelling the Metabolic Regulation of Myonuclear Accretion – Myo-Add

Skeletal muscle function is supported by the excitability and contractility of the myofibers, which are highly metabolically active syncytia composed of hundreds of post-mitotic nuclei. Due to the post-mitotic nature of myofibers, muscle stem cells (MuSCs) are essential for adult muscle maintenance. They not only contribute to muscle maintenance through the well-studied process of fusion among differentiated MuSCs, they also support the response to physiological and pathological stimuli by fusion of MuSCs with pre-existing myofibers (i.e., myonuclear accretion). This project studies, for the first time, the physiological processes that regulate myonuclear accretion.
Due to the localization of MuSC in a specialized niche between the myofiber sarcolemma and the surrounding extracellular matrix, MuSCs and myofibers share their metabolic environment. We thus anticipate a cross-talk between these two cell types, connecting myofiber-metabolic modifications with the regulation of MuSC fate. 5’-AMP-activated protein kinase (AMPK?2) acts as a metabolic checkpoint and is progressively expressed during myogenic fate progression, we therefore hypothesize that AMPK?2 is as an important regulator of myonuclear accretion by coordinating the cross-talk between myofiber-metabolic alterations and MuSC fate.
To this end, we will 1) test the causal role of AMPK?2 in the myofiber versus the MuSC using novel methods to assess myonuclear accretion; 2) unravel the mechanistic and metabolic targets of AMPK?2 in the myofiber and the MuSC using integrative metabolomics and phosphoproteomics analyses; 3) assess the pathophysiological relevance of the identified AMPK?2 axis in the regulation of myonuclear accretion using MuSCs derived from patients with metabolic dysregulation.
Thereby, we will provide the first direct evidence of signalling from the myofiber to the MuSC through metabolism, and demonstrate the pathophysiological relevance of this axis in the regulation of myonuclear accretion.