Santos-Zas Icía, Gurriarán-Rodríguez Uxía, Cid-Díaz Tania, Figueroa Gabriela, González-Sánchez Jessica, Bouzo-Lorenzo Mónica, Mosteiro Carlos S, Señarís José, Casanueva Felipe F, Casabiell Xesús, Gallego Rosalía, Pazos Yolanda, Mouly Vincent, Camiña Jesús P
Área de Endocrinología Molecular y Celular, Instituto de Investigación Sanitaria de Santiago (IDIS), Complejo Hospitalario Universitario de Santiago (CHUS), Servicio Gallego de Salud (SERGAS), Santiago de Compostela, Spain.
CIBER Fisiopatología de la Obesidad y Nutrición, Santiago de Compostela, Spain.
Cell Mol Life Sci. 2016 Feb;73(3):617-35. doi: 10.1007/s00018-015-1994-z. Epub 2015 Jul 27.
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.
胃饥饿素/胃动素受体39（Obestatin/GPR39）信号通路通过诱导卫星干细胞的扩增以及肌纤维肥大来刺激骨骼肌修复。在此，我们描述了Obestatin/GPR39系统在人类肌生成过程中作为自分泌/旁分泌因子发挥作用。胃饥饿素调节肌生成的多个步骤：成肌细胞增殖、细胞周期退出、分化以及募集融合形成多核肥大肌管。胃饥饿素诱导的促有丝分裂作用由细胞外信号调节激酶1/2（ERK1/2）和JunD活性介导，由一种G依赖性机制精心调控。在肌生成的后期阶段，支架蛋白β抑制蛋白1和2对于通过表皮生长因子受体（EGFR）的反式激活来激活细胞周期退出和分化至关重要。在胃饥饿素刺激下，β抑制蛋白被募集到细胞膜，在那里它们与GPR39发生功能性相互作用，导致Src激活并形成信号复合物，进而通过基质金属蛋白酶实现EGFR的反式激活。该信号复合物通过p21和p57的表达调节有丝分裂停滞，并通过JNK/c-Jun、钙/钙调蛋白依赖性蛋白激酶II（CAMKII）、蛋白激酶B（Akt）和p38信号通路调节分化的中晚期阶段。这一发现不仅首次揭示了β抑制蛋白在肌生成中的功能活性，还通过触发参与肌生成的GPR39信号通路的特定信号臂，确定了潜在的治疗靶点。
