10 páginas, 2 figuras. ; Telomeres—the specialized DNA-protein structures at the ends of eukaryotic chromosomes—are essential for maintaining genome stability and integrity and for extended proliferative life span in both cultured cells and in the whole organism. Telomerase and additional telomere-associated proteins are necessary for preserving telomeric DNA length. Age-dependent telomere shortening in most somatic cells, including vascular endothelial cells, smooth muscle cells, and cardiomyocytes, is thought to impair cellular function and viability of the aged organism. Telomere dysfunction is emerging as an important factor in the pathogenesis of hypertension, atherosclerosis, and heart failure. In this Review, we discuss present studies on telomeres and telomere-associated proteins in cardiovascular pathobiology and their implications for therapeutics. ; Work in the laboratory of V.A. is supported in part by the Ministry of Science and Technology of Spain and Fondo Europeo de Desarrollo Regional (grants SAF2001-2358 and SAF2002-1443) and from Instituto de Salud Carlos III (Red de Centros C03/01). A.L.S. is the recipient of a Marie Curie postdoctoral fellowship from the European Union. ; Peer reviewed
Repair of damaged tissue requires the coordinated action of inflammatory and tissue-specific cells to restore homeostasis, but the underlying regulatory mechanisms are poorly understood. In this paper, we report new roles for MKP-1 (mitogen-activated protein kinase [MAPK] phosphatase-1) in controlling macrophage phenotypic transitions necessary for appropriate muscle stem cell-dependent tissue repair. By restricting p38 MAPK activation, MKP-1 allows the early pro- to antiinflammatory macrophage transition and the later progression into a macrophage exhaustion-like state characterized by cytokine silencing, thereby permitting resolution of inflammation as tissue fully recovers. p38 hyperactivation in macrophages lacking MKP-1 induced the expression of microRNA-21 (miR-21), which in turn reduced PTEN (phosphatase and tensin homologue) levels, thereby extending AKT activation. In the absence of MKP-1, p38-induced AKT activity anticipated the acquisition of the antiinflammatory gene program and final cytokine silencing in macrophages, resulting in impaired tissue healing. Such defects were reversed by temporally controlled p38 inhibition. Conversely, miR-21-AKT interference altered homeostasis during tissue repair. This novel regulatory mechanism involving the appropriate balance of p38, MKP-1, miR-21, and AKT activities may have implications in chronic inflammatory degenerative diseases. ; The authors acknowledge funding from The Ministry of Science and Innovation (PLE2009-0124, SAF2009-09782, FIS-PS09/01267, and SAF2010-21682), Association Française contre les Myopathies, Fundación Marató-TV3/R-Pascual, Muscular Dystrophy Association, and European Union Seventh Framework Programme (Myoage, Optistem, and Endostem). P. Sousa-Victor was supported by a predoctoral fellowship from Fundação para a Ciência e a Tecnologia
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. ; 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.
