ROLE OF GHRELIN IN SKELETAL MUSCLE DIFFERENTIATION AND HYPERTROPHY: CHARACTERIZATION OF ITS BIOLOGIC ACTIVITY IN VITRO, IDENTIFICATION OF THE RECEPTOR AND IN VIVO PATHO-PHYSIOLOGICAL IMPLICATION

Muscular dystrophies are extremely invalidant and often fatal diseases. They are characterized by a progressive wasting of skeletal muscles which causes the deterioration of movements, and, in the worst cases, the complete paralysis and death. Examples are the Duchenne muscular dystrophy (DMD) and limb girdle muscular dystrophies. Most of these diseases, in which the molecular deficit has been identified, are caused by mutations affecting proteins linking the contractile cytoskeleton of the muscle fibers with the extracellular environment. Degeneration of the muscle fibers is the consequence of the mechanical stress associated to the contraction of the myofibers affected by the absence/loss of function of these proteins. Ghrelin, a circulating gastric peptide hormone, which induces growth hormone (GH) release, increases food uptake and adiposity, acting on the hypothalamus and pituitary. Moreover, in animal models ghrelin protects from cardiac injury and is particularly efficient in preventing cachexia, i.e. skeletal muscle wasting, associated to cardiac heart failure (CHF). In our laboratory, we have shown for the first time a mechanism through which the major circulating ghrelin form can exert its protective effect, acting on a new, still unindentified, receptor. Preliminary experiments show that ghrelin is a potent in vitro differentiating factor. In this project we want i) to show that ghrelin induces skeletal muscle differentiation in vitro, ii) to identify and clone the receptor responsible for this effect, and iii) to investigate the in vivo role of ghrelin in the mechanisms promoting muscle regeneration in different models of muscular dystrophy and other kind of injury.