Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2017 Mar 9;12(1):49.
doi: 10.1186/s13023-017-0605-5.

The PPAR pan-agonist bezafibrate ameliorates cardiomyopathy in a mouse model of Barth syndrome

Yan Huang  1 , Corey Powers  1 , Victoria Moore  1 , Caitlin Schafer  1 , Mindong Ren  2 , Colin K L Phoon  3 , Jeanne F James  1 , Alexander V Glukhov  4 , Sabzali Javadov  5 , Frédéric M Vaz  6 , John L Jefferies  1 , Arnold W Strauss  1 , Zaza Khuchua  7
Affiliations

The PPAR pan-agonist bezafibrate ameliorates cardiomyopathy in a mouse model of Barth syndrome

Yan Huang et al. Orphanet J Rare Dis. .

Abstract

Background: The PGC-1α/PPAR axis has been proposed as a potential therapeutic target for several metabolic disorders. The aim was to evaluate the efficacy of the pan-PPAR agonist, bezafibrate, in tafazzin knockdown mice (TazKD), a mouse model of Barth syndrome that exhibits age-dependent dilated cardiomyopathy with left ventricular (LV) dysfunction.

Results: The effect of bezafibrate on cardiac function was evaluated by echocardiography in TazKD mice with or without beta-adrenergic stress. Adrenergic stress by chronic isoproterenol infusion exacerbates the cardiac phenotype in TazKD mice, significantly depressing LV systolic function by 4.5 months of age. Bezafibrate intake over 2 months substantially ameliorates the development of LV systolic dysfunction in isoproterenol-stressed TazKD mice. Without beta-adrenergic stress, TazKD mice develop dilated cardiomyopathy by 7 months of age. Prolonged treatment with suprapharmacological dose of bezafibrate (0.5% in rodent diet) over a 4-month period effectively prevented LV dilation in mice isoproterenol treatment. Bezafibrate increased mitochondrial biogenesis, however also promoted oxidative stress in cardiomyocytes. Surprisingly, improvement of systolic function in bezafibrate-treated mice was accompanied with simultaneous reduction of cardiolipin content and increase of monolysocardiolipin levels in cardiac muscle.

Conclusions: Thus, we demonstrate that bezafibrate has a potent therapeutic effect on preventing cardiac dysfunction in a mouse model of Barth syndrome with obvious implications for treating the human disease. Additional studies are needed to assess the potential benefits of PPAR agonists in humans with Barth syndrome.

Keywords: Barth syndrome; Cardiolipin; Cardiomyopathy; Fibrates; Mitochondria; Systolic dysfunction.

PubMed Disclaimer

Figures

Fig. 1
Fig. 1
Isoproterenol (iso) exacerbates systolic dysfunction in TazKD mice. Fractional shortening (FS) and ejection fraction (EF) indices in 4.5-5 month-old isoflurane-sedated WT and TazKD mice (open and black bars, respectively). Numbers in the bars represent the sample size for the corresponding data. Data are presented as means ± standard deviation. Asterisks (*) depict statistical significance (p < 0.05) between groups
Fig. 2
Fig. 2
Bezafibrate (BF) ameliorates systolic function in TazKD mice. a Representative M-mode echocardiographic recordings of 4.5 months old iso-treated TazKD mice fed a diet with or without BF. b–d Effects of BF on (b) LV fractional shortening (LV FS), (c) ejection fraction (LV EF) and (d) end-diastolic interventricular wall thicknesses (IVS;d) in 4.5-month-old iso-treated WT (open bars) and TazKD (black bars) mice. e and f LV FS and LV EF indices are shown for 2.5, 4.5 and 7 months old WT (dashed line) and TazKD (solid line) mice. g and h Effects of BF on LV FS and LV EF in 7 months old WT (open bars) and TazKD mice (black bars). Mice were maintained on a diet with or without 0.5% BF during the 2 months between 2.5 and 4.5 months of age (a-d), or 4 months between 3 and 7 months of age (g and h). Numbers in the bars represent the sample size for the corresponding data. Data are presented as means ± standard deviation. Asterisks (*) depict statistical significance (p < 0.05) between groups
Fig. 3
Fig. 3
Analysis of cardiolipin (CL) molecular species in hearts of 7-month-old WT and TazKD mice fed a diet with or without 0.5% BF. a Molecular forms of CL in 7 months old WT mouse heart. Relative distribution of molecular forms of CL as a percentage of total CL content is shown. b Relative expression of Taz in cardiac muscles of WT and TazKD mice with and without BF treatment. c Changes of absolute values of CL in cardiac muscles of WT and TazKD mice with and without BF treatment. d Monolysocardiolipin (MLCL) to CL ratios in cardiac muscles of WT and TazKD mice with and without BF treatment. Numbers in the bars on panels b-d represent the sample size for the corresponding data. e Relative changes of major molecular forms of CL in WT and TazKD mice with and without BF treatment. Data are presented as means ± standard deviation. Sample sizes are shown. Statistically significant differences (p < 0.05) are indicated: *, between untreated and BF-treated WT mice; #, between WT and TazKD mice without BF treatment; ‡, between untreated and BF-treated TazKD mice
Fig. 4
Fig. 4
Effects of BF on mitochondria. a Mitochondrial DNA (mtDNA) copy numbers were analyzed with qPCR of total DNA from cardiac tissues and normalized to nuclear DNA (nDNA) content. b Citrate synthase (CS) activities were measured in cardiac homogenates and normalized to protein concentrations. Data are depicted as fold changes relative to WT controls. c Enzymatic activity of RC segment I-III in mitochondria from 7 month-old WT and TazKD mice with and without BF treatment. Values are normalized to CS activity and are shown as fold-changes relative to WT controls. d Western blot. 20 μg protein samples from 7 month-old untreated WT, untreated TazKD, and BF-treated TazKD mouse hearts were analyzed. A cocktail of monoclonal antibodies specific to selected polypeptides of the RC complexes were used. Signal intensities were normalized relative to mitochondrial malate dehydrogenase (mMDH) and plotted for each marker
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Acehan D, Vaz F, Houtkooper RH, James J, Moore V, Tokunaga C, Kulik W, Wansapura J, Toth MJ, Strauss A, et al. Cardiac and skeletal muscle defects in a mouse model of human Barth syndrome. J Biol Chem. 2011 - PMC - PubMed
    1. Clarke SL, Bowron A, Gonzalez IL, Groves SJ, Newbury-Ecob R, Clayton N, Martin RP, Tsai-Goodman B, Garratt V, Ashworth M, et al. Barth syndrome. Orphanet J Rare Dis. 2013 - PMC - PubMed
    1. Huang Y, Powers C, Madala SK, Greis KD, Haffey WD, Towbin JA, Purevjav E, Javadov S, Strauss AW, Khuchua Z. Cardiac metabolic pathways affected in the mouse model of barth syndrome. PLoS ONE. 2015 - PMC - PubMed
    1. Powers C, Huang Y, Strauss A, Khuchua Z. Diminished exercise capacity and mitochondrial bc1 complex deficiency in tafazzin-knockdown mice. Front Physiol. 2013 - PMC - PubMed
    1. Jang S, Lewis TS, Powers C, Khuchua Z, Baines CP, Wipf P, Javadov S. Elucidating mitochondrial electron transport chain supercomplexes in the heart during ischemia-reperfusion. Antioxid Redox Signal. 2016 - PMC - PubMed

Publication types