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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 Ghrlcontributes to a proper muscle regeneration.

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. StemCells2017;35:1733–1746 (A): Unacylated ghrelin (UnAG) induces the asymmetric co‐segregation of atypical PKCλ/ι and phospho‐p38 within satellite cells (CD34+) on floating myofibers. Scale bar, 50 µm. (B): The segregation of PKCλ/ι and phospho‐p38 MAPK results in the asymmetric division of satellite cells, giving rise to quiescent stem cells (Pax7+/MyoD–) and cells committed to differentiation (Pax7+/MyoD+). Scale bar, 20 µm.

Muscle wasting is a comorbidity often associated with a wide range of disorders that severely affects patient prognosis and quality of life. Ghrelin, through its receptor GHSR-1a, stimulates appetite and growth hormone (GH) release. Several studies indicate that ghrelin administration is a valid treatment for cachexia because it improves muscle mass and function, likely by restoring a positive energy balance.

STIM and ORAI proteins play a fundamental role in calcium signaling, allowing for calcium influx through the plasma membrane upon depletion of intracellular stores, in a process known as store-operated Ca2+ entry. Point mutations that lead to gain-of-function activity of either STIM1 or ORAI1 are responsible for a cluster of ultra-rare syndromes characterized by motor disturbances and platelet dysfunction. The prevalence of these disorders is at present unknown. In this study, we describe the generation and characterization of a knock-in mouse model (KI-STIM1I115F) that bears a clinically relevant mutation located in one of the two calcium-sensing EF-hand motifs of STIM1. The mouse colony is viable and fertile. Myotubes from these mice show an increased store-operated Ca2+ entry, as predicted. This most likely causes the dystrophic muscle phenotype observed, which worsens with age. Such histological features are not accompanied by a significant increase in creatine kinase. However, animals have significantly worse performance in rotarod and treadmill tests, showing increased susceptibility to fatigue, in analogy to the human disease. The mice also show increased bleeding time and thrombocytopenia, as well as an unexpected defect in the myeloid lineage and in natural killer cells. The present model, together with recently described models bearing the R304W mutation (located on the coiled-coil domain in the cytosolic side of STIM1), represents an ideal platform to characterize the disorder and test therapeutic strategies for patients with STIM1 mutations, currently without therapeutic solutions. This article has an associated First Person interview with Celia Cordero-Sanchez, co-first author of the paper.