Unacylated Ghrelin Enhances Satellite Cell Function and Relieves the Dystrophic Phenotype in Duchenne Muscular Dystrophy mdx Model

Abstract

Muscle regeneration depends on satellite cells (SCs), quiescent precursors that, in consequence of injury or in 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. Unacylated ghrelin (UnAG) is a circulating hormone that protects muscle from atrophy, promotes myoblast differentiation, and enhances ischemia-induced muscle regeneration. Here we show that UnAG increases SC activity and stimulates Par polarity complex/p38-mediated asymmetric division, fostering both SC self-renewal and myoblast differentiation. Because of those activities on different steps of muscle regeneration, we hypothesized a beneficial effect of UnAG in mdx dystrophic mice, in which the absence of dystrophin leads to chronic muscle degeneration, defective muscle regeneration, fibrosis, and, at later stages of the pathology, SC pool exhaustion. Upregulation of UnAG levels in mdx mice reduces muscle degeneration, improves muscle function, and increases dystrophin-null SC self-renewal, maintaining the SC pool. Our results suggest that UnAG has significant therapeutic potential for preserving the muscles in dystrophies. Stem Cells 2017;35:1733-1746.

Metabolic Alterations in a Slow‐Paced Model of Pancreatic Cancer‐Induced Wasting

“…Remarkably, despite the absence of overt signs of cachexia, skeletal muscle functionality, checked by rotarod evaluation twice a week (not shown), was drastically affected, but only at week 5, the week of the sacrifice. Accordingly, tumor-bearing mice showed reduced muscle performance, as assessed by the hanging-wire test [ 12 ] ( Figure 1(f) ), suggesting muscle deterioration in tumor-bearing animals. Along with reduced performance in stamina-related assays, mice displayed as well a reduction in grip strength, indicating also that the maximal force developed was reduced ( Figure 1(g) ).…”

“…A wire-hanging test was used to assess whole-body muscle strength and endurance. The test was performed as previously described [ 12 ]. Briefly, mice were subjected to a 180-second hanging test on a wire, during which “falling” and “reaching” scores were recorded.…”

HIF-1α Directly Controls WNT7A Expression During Myogenesis

“…Histological analysis was performed as previously reported (Reano et al, 2017). Briefly, TA muscles were frozen in liquid nitrogen-cooled isopentane and mounted in Killik embedding medium (Bio-optica).…”

The Homeostatic Force of Ghrelin

“…Desacyl ghrelin promotes cell-cycle entry in satellite cells via modulation of the superoxide dismutase-2 (SOD-2)-miR-221/222-p57 kip2 pathway ( Figure 4E). In concert, desacyl ghrelin enhances self-renewal of satellite cells, facilitates myoblast differentiation, and ameliorates the dystrophic phenotype in mdx mice, a model of Duchenne muscular dystrophy (Reano et al, 2017).…”