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Metabolic switch from fatty acid oxidation to glycolysis in knock-in mouse model of Barth Syndrome.

ABSTRACT: Mitochondria are central for cellular metabolism and energy supply. Barth Syndrome (BTHS) is a severe disorder, due to dysfunction of the mitochondrial cardiolipin acyl transferase tafazzin. Altered cardiolipin remodeling affects mitochondrial inner membrane organization and function of membrane proteins such as transporters and the oxidative phosphorylation (OXPHOS) system. Here, we describe a mouse model that carries a G197V exchange in tafazzin, corresponding to BTHS patient. TAZG197V mice recapitulate disease-specific pathology including cardiac dysfunction and reduced oxidative phosphorylation. We show that mutant mitochondria display defective fatty acid driven oxidative phosphorylation due to reduced levels of carnitine palmitoyl transferases. A metabolic switch in ATP production from OXPHOS to glycolysis is apparent in mouse heart and patient iPSC cell-derived cardiomyocytes. An increase in glycolytic ATP production inactivates AMPK causing altered metabolic signaling in TAZG197V. Treatment of mutant cells with AMPK activator reestablishes fatty acid driven OXPHOS and protects mice against cardiac failure.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Peter Rehling

PROVIDER: MSV000092116 | MassIVE | Wed Jun 07 02:59:00 BST 2023

SECONDARY ACCESSION(S): PXD042788

REPOSITORIES: MassIVE

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Project description:Objective: To explore the protective effects of exercise-derived β-aminoisobutyric (BAIBA) on apoptosis and energy metabolism in rats with heart failure. Methods: A rat model of heart failure after myocardial infarction (MI) was started by ligating the left anterior descending branch of the coronary artery, the anterior descending branch of the rats in the SHAM group was only threaded and not ligated. Exercise intervention was given to rats with heart failure. The possible mechanisms by which exercise affected cardiac remodeling after MI were investigated using color ultrasound, HE, Masson, and TUNEL staining, and the detection of apoptosis-associated factors in cardiac tissue. High-throughput sequencing and mass spectrometry were used to measure the production of BAIBA and to explore its protective effects and molecular mechanisms. An in vitro model of apoptosis was created by the application of H2O2 to induce mitochondrial dysfunction. This was then transfected with miR-208b analogue and miR-208b-inhibitor. Apoptosis-related proteins were detected by Western blotting (WB), and ATP production was also assessed. After intervention with BAIBA and compound C, assessments were made of apoptosis, mitochondrial function, lipid uptake, utilization of related proteins, ATP changes, alterations in membrane potential (δψm), and changes in reactive oxygen species (ROS). Results: Compared with the control heart failure (HF) group, exercise improved the function of mitochondria, reversed the expression of apoptosis-related proteins, and increased ATP production. In both the normal and heart failure groups, exercise significantly increased the production of BAIBA. It was shown that BAIBA played a similar role to exercise in ameliorating heart failure. Transcriptome analysis confirmed that the expression of miR-208b was increased after BAIBA intervention, and transfection with miR-208b analogue increased both the expression of apoptosis-related proteins and energy metabolism in H9C2 cells induced by H2O2. Combined analysis of the transcriptome and metabolome identified AMPK as a target for BAIBA to improve metabolic stress. Cell experiments further confirmed that BAIBA increased AMPK phosphorylation and had a protective effect on downstream fatty acid uptake, oxidative efficiency, and mitochondrial function, which could be counteracted by the AMPK inhibitor compound C. Conclusion: Exercise-induced BAIBA can reduce the metabolic stress and apoptosis induced by mitochondrial dysfunction through the miR-208b/AMPK pathway.

Project description:OBJECTIVE: To explore the cardioprotective effects of exercise-derived β-aminoisobutyric (BAIBA) on cardiomyocyte apoptosis and energy metabolism in a rat model of heart failure (HF).METHODS: In male Sprague-Dawley rats (8-week-old), myocardial infarction (MI) was used to induce HF by ligating the left anterior descending branch of the coronary artery. In the Sham group, the coronary artery was threaded but not ligated. After HF development, Sham and HF rats were exercised 60 min daily, 5 days per week on a treadmill for 8 weeks (50-60% maximal intensity) and exercise-induced cardiac remodeling after MI were assessed using echocardiography, hematoxylin and eosin (H&E), Masson’s Trichrome and TUNEL staining for the detection of apoptosis-associated factors in cardiac tissue. High-throughput sequencing and mass spectrometry were used to measure BAIBA production and to explore its cardioprotective effects and molecular actions. To further characterize the cardioprotective effects of BAIBA, an in vitro model of apoptosis was generated by applying H2O2 to H9C2 cells to induce mitochondrial dysfunction. In addition, cells were transfected with either a miR-208b analogue or a miR-208b inhibitor. Apoptosis-related proteins were detected by Western Blotting (WB). ATP production was also assessed by luminometry. After administration of BAIBA and Compound C, the expression of proteins related to apoptosis, mitochondrial function, lipid uptake and β-oxidative were determined. Changes in the levels of reactive oxygen species (ROS) were assessed by fluorescence microscopy. In addition, alterations in membrane potential (δψm) were obtained by confocal microscopy.RESULTS: Rats with HF after MI are accompanied by mitochondrial dysfunction, metabolic stress and apoptosis. Reduced expression of apoptosis-related proteins was observed, together with increased ATP production and reduced mitochondrial dysfunction in the exercised compared with the Sham (non-exercised) HF group. Importantly, exercise increased the production of BAIBA, irrespective of the presence of HF. To assess whether BAIBA had similar effects to exercise in ameliorating HF-induced adverse cardiac remodeling, rats were treated with 75 mg/kg/day of BAIBA and we found BAIBA had a similar cardioprotective effect. Transcriptomic analyses found that the expression of miR-208b was increased after BAIBA administration, and subsequent transfection with an miR-208b analogue ameliorated both the expression of apoptosis-related proteins and energy metabolism in H2O2-treated H9C2 cells. In combining transcriptomic with metabolomic analyses, we identified AMPK as a downstream target for BAIBA in attenuating metabolic stress in HF. Further cell experiments confirmed that BAIBA increased AMPK phosphorylation and had a cardioprotective effect on downstream fatty acid uptake, oxidative efficiency and mitochondrial function, which was prevented by the AMPK inhibitor Compound C.CONCLUSION: Exercise-generated BAIBA can reduce cardiomyocyte metabolic stress and apoptosis induced by mitochondrial dysfunction through the miR-208b/AMPK pathway.

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Metabolic switch from fatty acid oxidation to glycolysis in knock-in mouse model of Barth Syndrome.

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