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

Data:	2016
Resum:	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.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Publicat a:	Molecular Therapy. Methods & Clinical Development, Vol. 5 (november 2016) , p. 16072, ISSN 2329-0501

DOI: 10.1038/mtm.2016.72
PMID: 27909699

9 p, 2.2 MB

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