Adipogenesis and myogenesisdifferentiation programs determined by the ghrelin/GHSR1a and obestatin/GPR39 systems

Resumo

Ghrelin and obestatin are two "brother" peptide hormones responsible for various physiological processes and therefore with broad relevance in many diseases such as obesity and muscle disorders, respectively. Obesity is a chronic disease of multifactorial origin, which is characterized by excessive accumulation of fat or general adipose tissue hypertrophy in the body; Overweight and obesity are the fifth major risk factor of human death in the world. On the other hand, there are many diseases that can affect the muscles and consequently, they lead to problems in locomotion and the proper functioning of the organism through the presence of weakness, pain or even paralysis. Some known causes are: Overuse and sports injuries, genetic causes such as muscular dystrophy, cancer, inflammation and infections, nerve diseases affecting muscles as amyotrophic lateral sclerosis or spinal muscular atrophy. Considering that all these diseases are multifactorial disorders it is necessary to understand that the best option for the treatment of such disorders is to carry out a compendium of strategies: genetic, molecular and metabolic approaches, cell therapies and pharmacologic studies are necessary to make a complete analysis of the problem and achieve successful treatments. Based on it, the main objective of this work is to explore and validate new signaling pathways involved in the adipogenic program triggered by ghrelin/GHRS1a system and in the myogenic program triggered by obestatin/GPR39 system. In the first case, the β-arrestin-dependent signaling mechanism, responsible for regulation of adipogenesis, was validated. We found that β-arrestin 1 and 2 are essential molecules for adipocyte differentiation. In the second case, the obestatin/GPR39 system is described as an autocrine/paracrine factor on human myogenesis. We further determinate that scaffolding proteins β-arrestin 1 and 2 are essential for the activation of cell cycle exit and differentiation through the transactivation of the epidermal growth factor receptor (EGFR). In addition to the well-established role in the control of muscle regeneration, we found that regulates the specification of muscle fiber identity. Obestatin induces skeletal muscle remodeling toward an oxidative phenotype leading enhanced muscle strength. Moreover, another aim of this Thesis was to delinate the role of obestatin/GPR39 system on the motility and migratory capacity of immortalized human myoblasts. Our results show that obestatin comtrols the Dvl2 pathaway to induce migration of human myoblasts. Finally, in order to test the effectiveness of the obestatin/GPR39 system to improve human myoblast transplantation, weevaluated this signaling in xenografts transplantion. Our work shows thatactivation of the obestatin/GPR39 system regulates cell proliferation and migration giving rise to enhanced engraftment of human cells. These results provide a potential pharmacological target to improve the outcome of cell therapy for several muscle diseases.