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International audience; Background: A therapeutic approach for the treatment of glucocorticoid‐induced skeletal muscle atrophy should be based on the knowledge of the molecular mechanisms determining the unbalance between anabolic and catabolic processes and how to re‐establish this balance. Here, we investigated whether the obestatin/GPR39 system, an autocrine signalling system acting on myogenesis and with anabolic effects on the skeletal muscle, could protect against chronic glucocorticoid‐induced muscle atrophy.Methods: In this study, we used an in vivo model of muscle atrophy induced by the synthetic glucocorticoid dexamethasone to examine the liaison molecules that define the interaction between the glucocorticoid receptor and the obestatin/GPR39 systems. The findings were extended to in vitro effects on human atrophy using human KM155C25 myotubes.Results: KLF15 and FoxO transcription factors were identified as direct targets of obestatin signalling in the control of proteostasis in skeletal muscle. The KLF15‐triggered gene expression program, including atrogenes and FoxOs, was regulated via KLF15 ubiquitination by the E3 ubiquitin ligase NEDD4. Additionally, a specific pattern of FoxO post‐translational modification, including FoxO4 phosphorylation by Akt pathway, was critical in the regulation of the ubiquitin–proteasome system. The functional cooperativity between Akt and NEDD4 in the regulation of FoxO and KLF15 provides integrated cues to counteract muscle proteostasis and re‐establish protein synthesis.Conclusions: The effective control of FoxO activity in response to glucocorticoid is critical to counteract muscle‐related pathologies. These results highlight the potential of the obestatin/GPR39 system to fine‐tune the effects of glucocorticoids on skeletal muscle wasting.

Background. Injuries to the peripheral nerve system are common conditions, with broad spectrum of symptoms depending on the impaired nerves and severity of damage. Although peripheral nervous system retains a remarkable ability for regeneration, it is estimated that less than ten percent of patients fully recover function after nerve injury and the available treatments remain suboptimal. Here, we identify a role for the obestatin/GPR39 system in the regulation of the Schwann cell plasticity as well as in the preservation of neuromuscular synapses in the course of nerve repair. Methods. Utilizing a compression model of sciatic nerve injury, axonotmesis, we assessed the obestatin-related regenerative response in the peripheral nerve system. The role of the obestatin/GPR39 system was further evaluated on immortalized rat Schwann cells, IFRS1, and the model of neuronal differentiation, PC12 cells. The interactions between SCs and neurons was evaluated using a co-culture system that combine the SC cell line IFRS1 and the NGF-primed PC12. Results. Obestatin signaling directs proliferation and migration of Schwann cells that sustain axonal regrowth and later remyelinate regenerated axons. We provide evidence supporting the preservation of skeletal muscle by the maintenance of neuromuscular synapses through the axonal regulation of calpain-calpastatin proteolytic system. This encompasses the control of skeletal muscle homeostasis by regulation of the ubiquitin proteasome system and the autophagy machinery. Conclusions. These results provide important insights into how the obestatin/GPR39 system promotes nerve repair through integration of multiple molecular cues of neuron-Schwann cells crosstalk aimed to promote axon growth and guide axons back to their targets.

// Begona O. Alen 1, 2 , Saul Leal-Lopez 1, 2 , Maria Otero Alen 3, 4 , Patricia Viano 3, 4 , Victoria Garcia-Castro 4 , Carlos S. Mosteiro 1, 2 , Andres Beiras 3, 4, 5 , Felipe F. Casanueva 1, 2, 6 , Rosalia Gallego 2, 3, 5 , Tomas Garcia-Caballero 3, 4, 5 , Jesus P. Camina 1, 2 , Yolanda Pazos 1, 2 1 Area de Endocrinologia Molecular y Celular, Instituto de Investigacion Sanitaria de Santiago (IDIS), Complejo Hospitalario Universitario de Santiago (CHUS), Servicio Gallego de Salud (SERGAS), Santiago de Compostela, Spain 2 CIBER Fisiopatologia de la Obesidad y Nutricion, Santiago de Compostela, Spain 3 IDIS, CHUS, Santiago de Compostela, Spain 4 Servicio de Anatomia Patologica, CHUS, SERGAS, Santiago de Compostela, Spain 5 Departamento de Ciencias Morfologicas, Universidad de Santiago de Compostela (USC), Santiago de Compostela, Spain 6 Departamento de Medicina, USC, Santiago de Compostela, Spain Correspondence to: Yolanda Pazos, e-mail: yolanda.pazos.randulfe@sergas.es Keywords: GPR39, obestatin, stomach, adenocarcinoma Received: July 29, 2015 Accepted: November 25, 2015 Published: December 22, 2015 ABSTRACT Obestatin, a 23-amino acid peptide encoded by the ghrelin gene, and the GPR39 receptor were reported to be involved in the control of mitogenesis of gastric cancer cell lines; however, the relationship between the obestatin/GPR39 system and gastric cancer progression remains unknown. In the present study, we determined the expression levels of the obestatin/GPR39 system in human gastric adenocarcinomas and explored their potential functional roles. Twenty-eight patients with gastric adenocarcinomas were retrospectively studied, and clinical data were obtained. The role of obestatin/GPR39 in gastric cancer progression was studied in vitro using the human gastric adenocarcinoma AGS cell line. Obestatin exogenous administration in these GPR39-bearing cells deregulated the expression of several hallmarks of the epithelial-mesenchymal transition (EMT) and angiogenesis. Moreover, obestatin signaling promoted phenotypic changes via GPR39, increasingly impacting on the cell morphology, proliferation, migration and invasion of these cells. In healthy human stomachs, obestatin expression was observed in the neuroendocrine cells and GPR39 expression was localized mainly in the chief cells of the oxyntic glands. In human gastric adenocarcinomas, no obestatin expression was found; however, an aberrant pattern of GPR39 expression was discovered, correlating to the dedifferentiation of the tumor. Altogether, our data strongly suggest the involvement of the obestatin/GPR39 system in the pathogenesis and/or clinical outcome of human gastric adenocarcinomas and highlight the potential usefulness of GPR39 as a prognostic marker in gastric cancer.