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β-Arrestin scaffolds and signaling elements essential for the obestatin/GPR39 system that determine the myogenic program in human myoblast cells

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Abstract

Obestatin/GPR39 signaling stimulates skeletal muscle repair by inducing the expansion of satellite stem cells as well as myofiber hypertrophy. Here, we describe that the obestatin/GPR39 system acts as autocrine/paracrine factor on human myogenesis. Obestatin regulated multiple steps of myogenesis: myoblast proliferation, cell cycle exit, differentiation and recruitment to fuse and form multinucleated hypertrophic myotubes. Obestatin-induced mitogenic action was mediated by ERK1/2 and JunD activity, being orchestrated by a G-dependent mechanism. At a later stage of myogenesis, scaffolding proteins β-arrestin 1 and 2 were essential for the activation of cell cycle exit and differentiation through the transactivation of the epidermal growth factor receptor (EGFR). Upon obestatin stimulus, β-arrestins are recruited to the membrane, where they functionally interact with GPR39 leading to Src activation and signalplex formation to EGFR transactivation by matrix metalloproteinases. This signalplex regulated the mitotic arrest by p21 and p57 expression and the mid- to late stages of differentiation through JNK/c-Jun, CAMKII, Akt and p38 pathways. This finding not only provides the first functional activity for β-arrestins in myogenesis but also identify potential targets for therapeutic approaches by triggering specific signaling arms of the GPR39 signaling involved in myogenesis.

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Acknowledgments

Marta Picado Barreiro is greatly acknowledged for assistance with the confocal microscope experiments. The platform for immortalization of human cells of the Center of research in Myology is acknowledged, particularly K. Mamchaoui. This work was supported by grants from Instituto de Salud Carlos III (ISCIII; MINECO, Spain; PS12/02388) and cofinanced by ERDF funding, Asociación Duchenne Parent Project España and Association Française contre les Myopathies (AFM). The work of JP Camina and Y Pazos are funded by the ISCIII and SERGAS through a research-staff stabilization contract. Xunta de Galicia funds J González-Sánchez through a pre-doctorate research scholarship. IDIS funds T Cid-Diaz through a pre-doctorate research scholarship. ISCIII funds M Bouzo-Lorenzo through a pre-doctorate research scholarship.

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Correspondence to Jesús P. Camiña.

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Santos-Zas, I., Gurriarán-Rodríguez, U., Cid-Díaz, T. et al. β-Arrestin scaffolds and signaling elements essential for the obestatin/GPR39 system that determine the myogenic program in human myoblast cells. Cell. Mol. Life Sci. 73, 617–635 (2016). https://doi.org/10.1007/s00018-015-1994-z

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