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

Abstract

Although we cannot discern the specific Ghrl-derived peptide responsible for such activities, these data indicate that Ghrl contributes to a proper muscle regeneration.

Physiological Effect of Ghrelin on Body Systems

“…Des-acyl ghrelin fosters muscle regeneration by promoting myoblast differentiation and regeneration [228].…”

“…Both ghrelin and des-acyl ghrelin stimulate proliferating C2C12 skeletal myoblasts [229]. Ghrelin is also important for skeletal muscle cell regeneration following injury, which depends on satellite cells, quiescent precursors that activate, proliferate, and differentiate to repair the damaged tissue [228]. Des-acyl ghrelin reduces skeletal muscle mitochondrial ROS generation [230] and ROS-induced cell injuries by inducing the expression of superoxide dismutase-2 in satellite cells resulting in the induction of the myogenic process and reduction of functional impairment [231].…”

Both ghrelin deletion and unacylated ghrelin overexpression preserve muscles in aging mice

“…On the contrary, the finding that old Ghrl KO mice were atrophy-resistant, featuring enhanced physical performance ( Figure 3A , 3B ), lower levels of catabolism-related genes ( Figure 4A – 4C ), and larger myofiber areas than WT mice ( Figure 4E ), was less expected, as we have formerly demonstrated that, upon a traumatic event, muscle regeneration in Ghrl KO mice is reduced, due to an impaired satellite cell self-renewal activity [ 22 ]. Also, old Ghrl KO mice are more susceptible to fasting-induced muscle atrophy likely because of an altered mitochondrial function [ 9 ].…”

“…To address whether ghrelin levels during aging affect sarcopenia development, we examined young (3-month-old), adult (6-month-old), middle-aged (12-month-old), and old (24-month-old) Myh6/ Ghrl transgenic mice characterized by high levels of circulating UnAG, up to 100 times more than WT animals (Tg; [ 7 , 13 ]), their WT littermates, and ghrelin knockout ( Ghrl KO; [ 22 ]) mice, lacking all the gene-derived peptides.…”

“…Analyzing the fiber cross-sectional area distributions of gastrocnemius (GAS) muscles from young adult and old WT mice, it was evident a clear shift toward smaller areas in the latter ( Supplementary Figure 1 ). Since the muscles of young Tg and KO mice, in unstimulated conditions, do not differ from those of WT animals [ 13 , 22 ], the shift towards larger areas in old Tg and Ghrl KO muscles compared to old WT muscles ( Figure 4E ) indicates that both high levels of circulating UnAG and the lack of ghrelin peptides protect against muscle mass loss during aging.…”