The Effects of PPAR Stimulation on Cardiac Metabolic Pathways in Barth Syndrome Mice
Aim: Tafazzin knockdown (TazKD) in mice is widely used to create an experimental model of Barth syndrome (BTHS) that exhibits dilated cardiomyopathy and impaired exercise capacity. Peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor proteins that play essential roles...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-04-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fphar.2018.00318/full |
| _version_ | 1811324546588868608 |
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| author | Caitlin Schafer Vicky Moore Nupur Dasgupta Sabzali Javadov Jeanne F. James Jeanne F. James Alexander I. Glukhov Alexander I. Glukhov Arnold W. Strauss Zaza Khuchua Zaza Khuchua |
| author_facet | Caitlin Schafer Vicky Moore Nupur Dasgupta Sabzali Javadov Jeanne F. James Jeanne F. James Alexander I. Glukhov Alexander I. Glukhov Arnold W. Strauss Zaza Khuchua Zaza Khuchua |
| author_sort | Caitlin Schafer |
| collection | DOAJ |
| description | Aim: Tafazzin knockdown (TazKD) in mice is widely used to create an experimental model of Barth syndrome (BTHS) that exhibits dilated cardiomyopathy and impaired exercise capacity. Peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor proteins that play essential roles as transcription factors in the regulation of carbohydrate, lipid, and protein metabolism. We hypothesized that the activation of PPAR signaling with PPAR agonist bezafibrate (BF) may ameliorate impaired cardiac and skeletal muscle function in TazKD mice. This study examined the effects of BF on cardiac function, exercise capacity, and metabolic status in the heart of TazKD mice. Additionally, we elucidated the impact of PPAR activation on molecular pathways in TazKD hearts.Methods: BF (0.05% w/w) was given to TazKD mice with rodent chow. Cardiac function in wild type-, TazKD-, and BF-treated TazKD mice was evaluated by echocardiography. Exercise capacity was evaluated by exercising mice on the treadmill until exhaustion. The impact of BF on metabolic pathways was evaluated by analyzing the total transcriptome of the heart by RNA sequencing.Results: The uptake of BF during a 4-month period at a clinically relevant dose effectively protected the cardiac left ventricular systolic function in TazKD mice. BF alone did not improve the exercise capacity however, in combination with everyday voluntary running on the running wheel BF significantly ameliorated the impaired exercise capacity in TazKD mice. Analysis of cardiac transcriptome revealed that BF upregulated PPAR downstream target genes involved in a wide spectrum of metabolic (energy and protein) pathways as well as chromatin modification and RNA processing. In addition, the Ostn gene, which encodes the metabolic hormone musclin, is highly induced in TazKD myocardium and human failing hearts, likely as a compensatory response to diminished bioenergetic homeostasis in cardiomyocytes.Conclusion: The PPAR agonist BF at a clinically relevant dose has the therapeutic potential to attenuate cardiac dysfunction, and possibly exercise intolerance in BTHS. The role of musclin in the failing heart should be further investigated. |
| first_indexed | 2024-04-13T14:16:17Z |
| format | Article |
| id | doaj.art-4c75ebf4b16a4f1cb7b3fc68f4434c4e |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-13T14:16:17Z |
| publishDate | 2018-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-4c75ebf4b16a4f1cb7b3fc68f4434c4e2022-12-22T02:43:38ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122018-04-01910.3389/fphar.2018.00318353638The Effects of PPAR Stimulation on Cardiac Metabolic Pathways in Barth Syndrome MiceCaitlin Schafer0Vicky Moore1Nupur Dasgupta2Sabzali Javadov3Jeanne F. James4Jeanne F. James5Alexander I. Glukhov6Alexander I. Glukhov7Arnold W. Strauss8Zaza Khuchua9Zaza Khuchua10The Heart Institute, Cincinnati Children’s Research Foundation, Cincinnati, OH, United StatesThe Heart Institute, Cincinnati Children’s Research Foundation, Cincinnati, OH, United StatesThe Division of Human Genetics, Department of Pediatrics, University of Cincinnati College of Medicine and Cincinnati Children’s Research Foundation, Cincinnati, OH, United StatesDepartment of Physiology, School of Medicine, University of Puerto Rico, San Juan, Puerto RicoThe Heart Institute, Cincinnati Children’s Research Foundation, Cincinnati, OH, United StatesMedical College of Wisconsin, Milwaukee, WI, United StatesDepartment of Biochemistry, I.M. Sechenov First Moscow State Medical University, Moscow, RussiaFaculty of Biology, Lomonosov Moscow State University, Moscow, RussiaThe Heart Institute, Cincinnati Children’s Research Foundation, Cincinnati, OH, United StatesThe Heart Institute, Cincinnati Children’s Research Foundation, Cincinnati, OH, United StatesDepartment of Biochemistry, I.M. Sechenov First Moscow State Medical University, Moscow, RussiaAim: Tafazzin knockdown (TazKD) in mice is widely used to create an experimental model of Barth syndrome (BTHS) that exhibits dilated cardiomyopathy and impaired exercise capacity. Peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor proteins that play essential roles as transcription factors in the regulation of carbohydrate, lipid, and protein metabolism. We hypothesized that the activation of PPAR signaling with PPAR agonist bezafibrate (BF) may ameliorate impaired cardiac and skeletal muscle function in TazKD mice. This study examined the effects of BF on cardiac function, exercise capacity, and metabolic status in the heart of TazKD mice. Additionally, we elucidated the impact of PPAR activation on molecular pathways in TazKD hearts.Methods: BF (0.05% w/w) was given to TazKD mice with rodent chow. Cardiac function in wild type-, TazKD-, and BF-treated TazKD mice was evaluated by echocardiography. Exercise capacity was evaluated by exercising mice on the treadmill until exhaustion. The impact of BF on metabolic pathways was evaluated by analyzing the total transcriptome of the heart by RNA sequencing.Results: The uptake of BF during a 4-month period at a clinically relevant dose effectively protected the cardiac left ventricular systolic function in TazKD mice. BF alone did not improve the exercise capacity however, in combination with everyday voluntary running on the running wheel BF significantly ameliorated the impaired exercise capacity in TazKD mice. Analysis of cardiac transcriptome revealed that BF upregulated PPAR downstream target genes involved in a wide spectrum of metabolic (energy and protein) pathways as well as chromatin modification and RNA processing. In addition, the Ostn gene, which encodes the metabolic hormone musclin, is highly induced in TazKD myocardium and human failing hearts, likely as a compensatory response to diminished bioenergetic homeostasis in cardiomyocytes.Conclusion: The PPAR agonist BF at a clinically relevant dose has the therapeutic potential to attenuate cardiac dysfunction, and possibly exercise intolerance in BTHS. The role of musclin in the failing heart should be further investigated.http://journal.frontiersin.org/article/10.3389/fphar.2018.00318/fullPPAR agonistbezafibratecardiomyopathyOstnmusclinBarth syndrome |
| spellingShingle | Caitlin Schafer Vicky Moore Nupur Dasgupta Sabzali Javadov Jeanne F. James Jeanne F. James Alexander I. Glukhov Alexander I. Glukhov Arnold W. Strauss Zaza Khuchua Zaza Khuchua The Effects of PPAR Stimulation on Cardiac Metabolic Pathways in Barth Syndrome Mice Frontiers in Pharmacology PPAR agonist bezafibrate cardiomyopathy Ostn musclin Barth syndrome |
| title | The Effects of PPAR Stimulation on Cardiac Metabolic Pathways in Barth Syndrome Mice |
| title_full | The Effects of PPAR Stimulation on Cardiac Metabolic Pathways in Barth Syndrome Mice |
| title_fullStr | The Effects of PPAR Stimulation on Cardiac Metabolic Pathways in Barth Syndrome Mice |
| title_full_unstemmed | The Effects of PPAR Stimulation on Cardiac Metabolic Pathways in Barth Syndrome Mice |
| title_short | The Effects of PPAR Stimulation on Cardiac Metabolic Pathways in Barth Syndrome Mice |
| title_sort | effects of ppar stimulation on cardiac metabolic pathways in barth syndrome mice |
| topic | PPAR agonist bezafibrate cardiomyopathy Ostn musclin Barth syndrome |
| url | http://journal.frontiersin.org/article/10.3389/fphar.2018.00318/full |
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