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 o...
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| Format: | Article |
| Language: | English |
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Springer Nature
2017-04-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201607096 |
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| author | Helene Tronchere Mathieu Cinato Andrei Timotin Laurie Guitou Camille Villedieu Helene Thibault Delphine Baetz Bernard Payrastre Philippe Valet Angelo Parini Oksana Kunduzova Frederic Boal |
| author_facet | Helene Tronchere Mathieu Cinato Andrei Timotin Laurie Guitou Camille Villedieu Helene Thibault Delphine Baetz Bernard Payrastre Philippe Valet Angelo Parini Oksana Kunduzova Frederic Boal |
| author_sort | Helene Tronchere |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-ffde4b6b99b64e4fbcf721fdde0f4a1e |
| institution | DOAJ |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2017-04-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-ffde4b6b99b64e4fbcf721fdde0f4a1e2025-08-20T03:06:00ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842017-04-019677078510.15252/emmm.201607096Inhibition of PIKfyve prevents myocardial apoptosis and hypertrophy through activation of SIRT3 in obese miceHelene Tronchere0Mathieu Cinato1Andrei Timotin2Laurie Guitou3Camille Villedieu4Helene Thibault5Delphine Baetz6Bernard Payrastre7Philippe Valet8Angelo Parini9Oksana Kunduzova10Frederic Boal11INSERM U1048 I2MCINSERM U1048 I2MCINSERM U1048 I2MCINSERM U1048 I2MCCarMeN Laboratory, Inserm U1060, Univ‐Lyon, Université Claude Bernard Lyon 1CarMeN Laboratory, Inserm U1060, Univ‐Lyon, Université Claude Bernard Lyon 1CarMeN Laboratory, Inserm U1060, Univ‐Lyon, Université Claude Bernard Lyon 1INSERM U1048 I2MCINSERM U1048 I2MCINSERM U1048 I2MCINSERM U1048 I2MCINSERM U1048 I2MCAbstract 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.https://doi.org/10.15252/emmm.201607096apoptosiscardiac hypertrophymitochondriaPIKfyveSIRT3 |
| spellingShingle | Helene Tronchere Mathieu Cinato Andrei Timotin Laurie Guitou Camille Villedieu Helene Thibault Delphine Baetz Bernard Payrastre Philippe Valet Angelo Parini Oksana Kunduzova Frederic Boal Inhibition of PIKfyve prevents myocardial apoptosis and hypertrophy through activation of SIRT3 in obese mice EMBO Molecular Medicine apoptosis cardiac hypertrophy mitochondria PIKfyve SIRT3 |
| title | Inhibition of PIKfyve prevents myocardial apoptosis and hypertrophy through activation of SIRT3 in obese mice |
| title_full | Inhibition of PIKfyve prevents myocardial apoptosis and hypertrophy through activation of SIRT3 in obese mice |
| title_fullStr | Inhibition of PIKfyve prevents myocardial apoptosis and hypertrophy through activation of SIRT3 in obese mice |
| title_full_unstemmed | Inhibition of PIKfyve prevents myocardial apoptosis and hypertrophy through activation of SIRT3 in obese mice |
| title_short | Inhibition of PIKfyve prevents myocardial apoptosis and hypertrophy through activation of SIRT3 in obese mice |
| title_sort | inhibition of pikfyve prevents myocardial apoptosis and hypertrophy through activation of sirt3 in obese mice |
| topic | apoptosis cardiac hypertrophy mitochondria PIKfyve SIRT3 |
| url | https://doi.org/10.15252/emmm.201607096 |
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