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

Abstract

BackgroundThe 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.ResultsThe 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.ConclusionsThus, 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.

Barth Syndrome: Exploring Cardiac Metabolism with Induced Pluripotent Stem Cell-Derived Cardiomyocytes

“…Other studies involved cellular models such as fibroblasts [35], lymphoblasts [36], neutrophils [37], neonatal ventricular fibroblasts [38], and cardiac myocytes [39]. Later, mouse models were generated and revealed multiple cardiac and muscle dysfunctions [40,41] and disruption of the interactions between the electron transport chain (ETC) and some fatty acid oxidation enzymes [42].…”

Metabolic Alterations in Inherited Cardiomyopathies

“…PPAR regulates a large number of genes involved in energy conversion and FA metabolism. Studies in mice indicate a benefit in cardiac function and in exercise capacity in BTHS mice treated with bezafibrate [182,183] In summary, CL deficiency in BTHS has severe impact on many mitochondrial functions, hindering ATP production and inducing oxidative stress. Moreover, mitochondria are also a central hub for cellular signaling pathways [184].…”

Mitochondrial dysfunctions in barth syndrome

“…Indeed, Xu et al were able to demonstrate an increase in supercomplex assembly in patient B‐lymphoblasts and, interestingly, the increase in supercomplex levels was accompanied by a reduced turnover of CL and a decrease in MLCL . In an in vivo study, bezafibrate was found effective in substantially ameliorating the development of left ventricular systolic dysfunction in TAZ‐KD mice that were exposed to beta‐adrenergic stress . Without beta‐adrenergic stress, TAZ‐KD mice develop dilated cardiomyopathy much later in life, around the age of 7 months.…”

“…A promising strategy emerged from the finding that supramolecular assembly of MRC complexes can be stimulated by bezafibrate treatment in a mouse model of BTHS . Indeed, Xu et al were able to demonstrate an increase in supercomplex assembly in patient B‐lymphoblasts and, interestingly, the increase in supercomplex levels was accompanied by a reduced turnover of CL and a decrease in MLCL .…”

“…Surprisingly, these positive outcomes of bezafibrate treatment were associated with increased oxidative stress in cardiomyocytes. Moreover, improvement of systolic function in bezafibrate‐treated mice was accompanied with simultaneous reduction of CL content and increase of MLCL levels in cardiac muscle . Therefore, at this moment, it is difficult to realize the therapeutic potential of bezafibrate in ameliorating mitochondrial pathophysiology in BTHS patients.…”