Ghrelin and its analogs in muscle diseases

Acylated and unacylated ghrelin (AG and UnAG) are circulating peptide hormones generated by the ghrelin gene mainly in the stomach in consequence of fasting or caloric restriction. AG, through binding to growth hormone secretagogue receptor type 1a (GHSR1a), induces strong release of growth hormone (GH) and other central and peripheral activities. UnAG is not able to bind and activate GHSR1a but features several biological functions, such as improvement of insulin sensitivity in skeletal muscle and enhancement of skeletal muscle regeneration induced by hindlimb ischemia. Moreover, it has been demonstrated that both peptides share common activities, mediated by an unknown receptor, on skeletal muscle where they protect against atrophy and promote proliferation and fusion of myoblast. Giving the multiple activities of this hormone on skeletal muscle, we assessed involvement of ghrelin in muscle regeneration, cachexia and sarcopenia. We showed that UnAG enhances SCs function and stimulates Par polarity complex/P38-mediated asymmetric division, sustaining both SCs self-renewal and myoblast differentiation. We also showed that upregulation of plasmatic levels of UnAG results in an improvement of pathologic phenotype and in the ablation of self-renewal defect of dystrophin-null SCs with a consequent preservation of SCs pool in the later stage of the pathology. Moreover, we show that ghrelin analogs recognize the alternative receptor and protect against cytokines-induced skeletal muscle atrophy. We demonstrate that anamorelin protects against fasting-induced adipose tissue loss without inhibiting muscle wasting in WT mice. Finally, preliminary data show that upregulation of UnAG improves muscle functionality and slightly protects against muscle atrophy and intramyocellular fat deposition. Surprisingly, deletion of ghrelin gene differently affects muscle function, weight, food intake and glucose metabolism, indicating an important role of ghrelin during the aging process.