Ghrelin knockout mice display defective skeletal muscle regeneration and impaired satellite cell self-renewal

Elia Angelino, Simone Reano, Alessandro Bollo, Michele Ferrara, Marilisa De Feudis, Hana Sustova, Emanuela Agosti, Sara Clerici, Flavia Prodam, Catherine-Laure Tomasetto, Andrea Graziani, Nicoletta Filigheddu

Muscle regeneration depends on satellite cells (SCs), quiescent precursors that, in consequence of injury or pathological states such as muscular dystrophies, activate, proliferate, and differentiate to repair the damaged tissue. A subset of SCs undergoes self-renewal, thus preserving the SC pool and its regenerative potential. The peptides produced by the ghrelin gene, i.e., acylated ghrelin (AG), unacylated ghrelin (UnAG), and obestatin (Ob), affect skeletal muscle biology in several ways, not always with overlapping effects. In particular, UnAG and Ob promote SC self-renewal and myoblast differentiation, thus fostering muscle regeneration. To delineate the endogenous contribution of preproghrelin in muscle regeneration, we evaluated the repair process in Ghrl -/- mice upon CTX-induced injury. Although muscles from Ghrl -/- mice do not visibly differ from WT muscles in term of weight, structure, and SCs content, muscle regeneration after CTX-induced injury is impaired in Ghrl -/- mice, indicating that ghrelin-derived peptides actively participate in muscle repair. Remarkably, the lack of ghrelin gene impacts SC self-renewal during regeneration. Although we cannot discern the specific Ghrl-derived peptide responsible for such activities, these data indicate that Ghrl contributes to a proper muscle regeneration.