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AAV-mediated Sirt1 overexpression in skeletal muscle activates oxidative capacity but does not prevent insulin resistance
Vilà, Laia (CIBER de Diabetes y Enfermedades Metabólicas Asociadas)
Roca, Carles (CIBER de Diabetes y Enfermedades Metabólicas Asociadas)
Elias, Ivet (CIBER de Diabetes y Enfermedades Metabólicas Asociadas)
Casellas, Alba (CIBER de Diabetes y Enfermedades Metabólicas Asociadas)
Lage, Ricardo (Universitat Autònoma de Barcelona. Departament de Bioquímica i Biologica Molecular)
Franckhauser, Sylvie (CIBER de Diabetes y Enfermedades Metabólicas Asociadas)
Bosch i Tubert, Fàtima (CIBER de Diabetes y Enfermedades Metabólicas Asociadas)

Fecha: 2016
Resumen: Type 2 diabetes is characterized by triglyceride accumulation and reduced lipid oxidation capacity in skeletal muscle. SIRT1 is a key protein in the regulation of lipid oxidation and its expression is reduced in the skeletal muscle of insulin resistant mice. In this tissue, Sirt1 up-regulates the expression of genes involved in oxidative metabolism and improves mitochondrial function mainly through PPARGC1 deacetylation. Here we examined whether Sirt1 overexpression mediated by adeno-associated viral vectors of serotype 1 (AAV1) specifically in skeletal muscle can counteract the development of insulin resistance induced by a high fat diet in mice. AAV1- Sirt1 -treated mice showed up-regulated expression of key genes related to β-oxidation together with increased levels of phosphorylated AMP protein kinase. Moreover, SIRT1 overexpression in skeletal muscle also increased basal phosphorylated levels of AKT. However, AAV1- Sirt1 treatment was not enough to prevent high fat diet-induced obesity and insulin resistance. Although Sirt1 gene transfer to skeletal muscle induced changes at the muscular level related with lipid and glucose homeostasis, our data indicate that overexpression of SIRT1 in skeletal muscle is not enough to improve whole-body insulin resistance and that suggests that SIRT1 has to be increased in other metabolic tissues to prevent insulin resistance.
Derechos: This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit https://creativecommons.org/licenses/by-nc-nd/4.0/ Creative Commons
Lengua: Anglès.
Documento: article ; recerca ; publishedVersion
Publicado en: Molecular Therapy. Methods & Clinical Development, Vol. 5 (november 2016) , p. 16072, ISSN 2329-0501

PMID: 27909699
DOI: 10.1038/mtm.2016.72

9 p, 2.2 MB

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