SIRT3, a mitochondrial NAD⁺-dependent deacetylase, is involved in the regulation of myoblast differentiation

Sirtuin 3 (SIRT3), one of the seven mammalian sirtuins, is a mitochondrial NAD+-dependent deacetylase known to control key metabolic pathways. SIRT3 deacetylases and activates a large number of mitochondrial enzymes involved in the respiratory chain, in ATP production, and in both the citric acid an...

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Bibliographic Details
Published in:	PloS one 2014-12, Vol.9 (12), p.e114388-e114388
Main Authors:	Abdel Khalek, Waed, Cortade, Fabienne, Ollendorff, Vincent, Lapasset, Laure, Tintignac, Lionel, Chabi, Béatrice, Wrutniak-Cabello, Chantal
Format:	Article
Language:	eng
Subjects:	Animals Biology and life sciences Biosynthesis Calcium-binding protein Cell Differentiation Cell Line Citric acid Dehydrogenases Differentiation Down-Regulation Electron transport Enzymes Gene expression Gene Knockdown Techniques Manganese Metabolic pathways Metabolism Mice Mitochondria Mitochondria - enzymology Mitochondria - metabolism Musculoskeletal system Myoblasts Myoblasts - cytology MyoD protein MyoD Protein - genetics Myogenesis Myogenin NAD NAD - metabolism Oxidation Oxygen Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha Proteins Reactive oxygen species Reactive Oxygen Species - metabolism Regulation Ribonucleic acid RNA RNA, Small Interfering - genetics Rodents Sirtuin 3 - deficiency Sirtuin 3 - genetics Sirtuin 3 - metabolism Sirtuins Superoxide dismutase Transcription Factors - metabolism Troponin Troponin T Urea
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Summary:	Sirtuin 3 (SIRT3), one of the seven mammalian sirtuins, is a mitochondrial NAD+-dependent deacetylase known to control key metabolic pathways. SIRT3 deacetylases and activates a large number of mitochondrial enzymes involved in the respiratory chain, in ATP production, and in both the citric acid and urea cycles. We have previously shown that the regulation of myoblast differentiation is tightly linked to mitochondrial activity. Since SIRT3 modulates mitochondrial activity, we decide to address its role during myoblast differentiation. For this purpose, we first investigated the expression of endogenous SIRT3 during C2C12 myoblast differentiation. We further studied the impact of SIRT3 silencing on both the myogenic potential and the mitochondrial activity of C2C12 cells. We showed that SIRT3 protein expression peaked at the onset of myoblast differentiation. The inhibition of SIRT3 expression mediated by the stable integration of SIRT3 short inhibitory RNA (SIRT3shRNA) in C2C12 myoblasts, resulted in: 1) abrogation of terminal differentiation - as evidenced by a marked decrease in the myoblast fusion index and a significant reduction of Myogenin, MyoD, Sirtuin 1 and Troponin T protein expression - restored upon MyoD overexpression; 2) a decrease in peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and citrate synthase protein expression reflecting an alteration of mitochondrial density; and 3) an increased production of reactive oxygen species (ROS) mirrored by the decreased activity of manganese superoxide dismutase (MnSOD). Altogether our data demonstrate that SIRT3 mainly regulates myoblast differentiation via its influence on mitochondrial activity.
ISSN:	1932-6203 1932-6203