Sirtuin3 dysfunction is the key determinant of skeletal muscle insulin resistance by angiotensin II

Daniela Macconi, Luca Perico, Lorena Longaretti, Marina Morigi, Paola Cassis, Simona Buelli, Norberto Perico, Giuseppe Remuzzi, Ariela Benigni

Research output: Contribution to journalArticle

Abstract

Background: Angiotensin II promotes insulin resistance. The mechanism underlying this abnormality, however, is still poorly defined. In a different setting, skeletal muscle metabolism and insulin signaling are regulated by Sirtuin3. Objective: Here, we investigate whether angiotensin II-induced insulin resistance in skeletal muscle is associated with Sirtuin3 dysregulation and whether pharmacological manipulation of Sirtuin3 confers protection. Study Design: Parental and GLUT4-myc L6 rat skeletal muscle cells exposed to angiotensin II are used as in vitro models of insulin resistance. GLUT4 translocation, glucose uptake, intracellular molecular signals such as mitochondrial reactive oxygen species, Sirtuin3 protein expression and activity, along with its downstream targets and upstream regulators, are analyzed both in the absence and presence of acetyl-L-carnitine. The role of Sirtuin3 in GLUT4 translocation and intracellular molecular signaling is also studied in Sirtuin3-silenced as well as overexpressing cells. Results: Angiotensin II promotes insulin resistance in skeletal muscle cells via mitochondrial oxidative stress, resulting in a two-fold increase in superoxide generation. In this context, reactive oxygen species open the mitochondrial permeability transition pore and significantly lower Sirtuin3 levels and activity impairing the cell antioxidant defense. Angiotensin II-induced Sirtuin3 dysfunction leads to the impairment of AMP-activated protein kinase/nicotinamide phosphoribosyltransferase signaling. Acetyl-L-carnitine, by lowering angiotensin II-induced mitochondrial superoxide formation, prevents Sirtuin3 dysfunction. This phenomenon implies the restoration of manganese superoxide dismutase antioxidant activity and AMP-activated protein kinase activation. Acetyl-L-carnitine protection is abrogated by specific Sirtuin3 siRNA. Conclusions: Our data demonstrate that angiotensin II-induced insulin resistance fosters mitochondrial superoxide generation, in turn leading to Sirtuin3 dysfunction. The present results also high-light Sirtuin3 as a therapeutic target for the insulin-sensitizing effects of acetyl-L-carnitine.

Original languageEnglish
Article numbere0127172
JournalPLoS One
Volume10
Issue number5
DOIs
Publication statusPublished - May 19 2015

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angiotensin II
insulin resistance
Angiotensin II
Muscle
skeletal muscle
Insulin Resistance
Skeletal Muscle
Acetylcarnitine
Insulin
carnitine
Superoxides
superoxide anion
AMP-activated protein kinase
AMP-Activated Protein Kinases
myocytes
Muscle Cells
reactive oxygen species
Reactive Oxygen Species
nicotinamide phosphoribosyltransferase
insulin

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Sirtuin3 dysfunction is the key determinant of skeletal muscle insulin resistance by angiotensin II. / Macconi, Daniela; Perico, Luca; Longaretti, Lorena; Morigi, Marina; Cassis, Paola; Buelli, Simona; Perico, Norberto; Remuzzi, Giuseppe; Benigni, Ariela.

In: PLoS One, Vol. 10, No. 5, e0127172, 19.05.2015.

Research output: Contribution to journalArticle

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AU - Perico, Luca

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AU - Morigi, Marina

AU - Cassis, Paola

AU - Buelli, Simona

AU - Perico, Norberto

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