Autophagy-regulating TP53INP2 mediates muscle wasting and is repressed in diabetes

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• dc.contributor.author Sala, Davidca
• dc.contributor.author Ivanova, Saskaca
• dc.contributor.author Plana, Natàliaca
• dc.contributor.author Ribas, Vicentca
• dc.contributor.author Duran, Jordica
• dc.contributor.author Bach, Danielca
• dc.contributor.author Turkseven, Saadetca
• dc.contributor.author Laville, Martineca
• dc.contributor.author Vidal, Hubertca
• dc.contributor.author Karczewska-Kupczewska, Monikaca
• dc.contributor.author Kowalska, Irinaca
• dc.contributor.author Straczkowski, Marekca
• dc.contributor.author Testar, Xavierca
• dc.contributor.author Palacín Mateo, Manuelca
• dc.contributor.author Sandri, Marcoca
• dc.contributor.author Serrano, Antonio L.ca
• dc.contributor.author Zorzano, Antonioca
• dc.date.accessioned 2015-06-15T07:18:45Z
• dc.date.available 2015-06-15T07:18:45Z
• dc.date.issued 2014ca
• dc.description.abstract A precise balance between protein degradation and synthesis is essential to preserve skeletal muscle mass. Here, we found that TP53INP2, a homolog of the Drosophila melanogaster DOR protein that regulates autophagy in cellular models, has a direct impact on skeletal muscle mass in vivo. Using different transgenic mouse models, we demonstrated that muscle-specific overexpression of Tp53inp2 reduced muscle mass, while deletion of Tp53inp2 resulted in muscle hypertrophy. TP53INP2 activated basal autophagy in skeletal muscle and sustained p62-independent autophagic degradation of ubiquitinated proteins. Animals with muscle-specific overexpression of Tp53inp2 exhibited enhanced muscle wasting in streptozotocin-induced diabetes that was dependent on autophagy; however, TP53INP2 ablation mitigated experimental diabetes-associated muscle loss. The overexpression or absence of TP53INP2 did not affect muscle wasting in response to denervation, a condition in which autophagy is blocked, further indicating that TP53INP2 alters muscle mass by activating autophagy. Moreover, TP53INP2 expression was markedly repressed in muscle from patients with type 2 diabetes and in murine models of diabetes. Our results indicate that TP53INP2 negatively regulates skeletal muscle mass through activation of autophagy. Furthermore, we propose that TP53INP2 repression is part of an adaptive mechanism aimed at preserving muscle mass under conditions in which insulin action is deficient.en
• dc.description.sponsorship We thank the Advanced Digital Microscopy Facility (IRB Barcelona), the Biostatistics/Bioinformatics Unit (IRB Barcelona), the Functional Genomics Facility (IRB Barcelona), the Unit of Electron Cryo-Microscopy (Scientific and Technological Centers, Universitat de Barcelona), V. Lukesova, J.M. Seco, I. Castrillón, and J.C. Monasterio for technological assistance. D. Sala was the recipient of a FPU fellowship from the “Ministerio de Educación y Cultura,” Spain. V. Ribas was supported by a postdoctoral fellowship from the Instituto de Salud Carlos III (Ministerio de Economía y Competitividad, Spain). This study was supported by research grants from the MINECO (SAF2008-03803), grant 2009SGR915 from the “Generalitat de Catalunya,” CIBERDEM (“Instituto de Salud Carlos III”), FIS-PS09/01267 and FIS-PI13/025 from “Instituto de Salud Carlos III,” Spain, SB/CP2013-0167/16642 from Association Française contre les Myopathies (AFM), Interreg IV-B-Sudoe-Feder (DIOMED, SOE1/P1/E178), and UDA-POIG.01.03.01-00-128/08 from the Innovative Economy Program 2007-2013, partially financed by the European Union within the European Regional Development Fund. A. Zorzano was the recipient of a Science Intensification Award from the University of Barcelona.en
• dc.format.mimetype application/pdfca
• dc.identifier.citation Sala D, Ivanova S, Plana N, Ribas V, Duran J, Bach D et al. Autophagy-regulating TP53INP2 mediates muscle wasting and is repressed in diabetes. J Clin Invest. 2014;124(5):1914-27. DOI: 10.1172/JCI72327ca
• dc.identifier.doi http://dx.doi.org/10.1172/JCI72327
• dc.identifier.issn 0021-9738ca
• dc.identifier.uri http://hdl.handle.net/10230/23814
• dc.language.iso engca
• dc.publisher American Society for Clinical Investigationca
• dc.relation.ispartof Journal of Clinical Investigation. 2014;124(5):1914-27
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/SAF2008-03803
• dc.rights © American Society for Clinical Investigationca
• dc.rights.accessRights info:eu-repo/semantics/openAccessca
• dc.subject.other Diabetis -- Complicacionsca
• dc.subject.other Músculs -- Malaltiesca
• dc.title Autophagy-regulating TP53INP2 mediates muscle wasting and is repressed in diabetesen
• dc.type info:eu-repo/semantics/articleca
• dc.type.version info:eu-repo/semantics/publishedVersionca