title: Inhibition of PIKfyve prevents myocardial apoptosis and hypertrophy through activation of SIRT3 in obese mice.
abstract: PIKfyve is an evolutionarily conserved lipid kinase that regulates pleiotropic cellular functions. Here, we identify PIKfyve as a key regulator of cardiometabolic status and mitochondrial integrity in chronic diet-induced obesity.In vitro, we show that PIKfyve is critical for the control of mitochondrial fragmentation and hypertrophic and apoptotic responses to stress. We also provide evidence that inactivation of PIKfyve by the selective inhibitor STA suppresses excessive mitochondrial ROS production and apoptosis through a SIRT3-dependent pathway in cardiomyoblasts. In addition, we report that chronic STA treatment improves cardiometabolic profile in a mouse model of cardiomyopathy linked to obesity. We provide evidence that PIKfyve inhibition reverses obesity-induced cardiac mitochondrial damage and apoptosis by activating SIRT3. Furthermore, treatment of obese mice with STA improves left ventricular function and attenuates cardiac hypertrophy. In contrast, STA is not able to reduce isoproterenol-induced cardiac hypertrophy in SIRT3.KO mice. Altogether, these results unravel a novel role for PIKfyve in obesity-associated cardiomyopathy and provide a promising therapeutic strategy to combat cardiometabolic complications in obesity.
authors.affiliation: INSERM U1048 I2MC, Toulouse, Cedex 4, France.|Université Paul Sabatier, Toulouse, France.
authors.forename: Helene
authors.initials: H
authors.lastname: Tronchere
authors.affiliation: INSERM U1048 I2MC, Toulouse, Cedex 4, France.|Université Paul Sabatier, Toulouse, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Cinato
authors.affiliation: INSERM U1048 I2MC, Toulouse, Cedex 4, France.|Université Paul Sabatier, Toulouse, France.
authors.forename: Andrei
authors.initials: A
authors.lastname: Timotin
authors.affiliation: INSERM U1048 I2MC, Toulouse, Cedex 4, France.|Université Paul Sabatier, Toulouse, France.
authors.forename: Laurie
authors.initials: L
authors.lastname: Guitou
authors.affiliation: CarMeN Laboratory, Inserm U1060, Univ-Lyon, Université Claude Bernard Lyon 1, Bron, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Villedieu
authors.affiliation: CarMeN Laboratory, Inserm U1060, Univ-Lyon, Université Claude Bernard Lyon 1, Bron, France.
authors.forename: Helene
authors.initials: H
authors.lastname: Thibault
authors.affiliation: CarMeN Laboratory, Inserm U1060, Univ-Lyon, Université Claude Bernard Lyon 1, Bron, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Baetz
authors.affiliation: INSERM U1048 I2MC, Toulouse, Cedex 4, France.|Université Paul Sabatier, Toulouse, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Payrastre
authors.affiliation: INSERM U1048 I2MC, Toulouse, Cedex 4, France.|Université Paul Sabatier, Toulouse, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Valet
authors.affiliation: INSERM U1048 I2MC, Toulouse, Cedex 4, France.|Université Paul Sabatier, Toulouse, France.
authors.forename: Angelo
authors.initials: A
authors.lastname: Parini
authors.affiliation: INSERM U1048 I2MC, Toulouse, Cedex 4, France.|Université Paul Sabatier, Toulouse, France.
authors.forename: Oksana
authors.identifier: 0000-0003-2503-6555
authors.initials: O
authors.lastname: Kunduzova
authors.affiliation: INSERM U1048 I2MC, Toulouse, Cedex 4, France frederic.boal@inserm.fr.|Université Paul Sabatier, Toulouse, France.
authors.forename: Frederic
authors.identifier: 0000-0001-7607-4573
authors.initials: F
authors.lastname: Boal
mesh_terms: D000818:Animals; D017209:Apoptosis; D009202:Cardiomyopathies / Q000473:pathology; D002460:Cell Line; D004195:Disease Models, Animal; D006984:Hypertrophy / Q000473:pathology*; D018345:Mice, Knockout; D008820:Mice, Obese; D009206:Myocardium / Q000473:pathology*; D009765:Obesity / Q000150:complications; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D056566:Sirtuin 3 / Q000378:metabolism*
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D056566:Sirtuin 3; C525046:Sirt3 protein, mouse; C116930:Pikfyve protein, mouse
keywords: PIKfyve; SIRT3; apoptosis; cardiac hypertrophy; mitochondria