The Effects of PPAR Stimulation on Cardiac Metabolic Pathways in Barth Syndrome Mice

Abstract

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.

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].…”

Effect of statin therapy on plasma C-type Natriuretic Peptides and Endothelin-1 in males with and without symptomatic coronary artery disease

“…Recent work showing that the clearance receptor NPR3 is down regulated after hypoxic or ischaemic insults in a wide range of cardiac tissues, and remains reduced in established heart failure 41 , provides a plausible mechanism. Alternatively upregulation of osteocrin -a peptide expressed and secreted by the failing human heart 42 and which has anti-inflammatory actions reducing cardiac remodelling in experimental animals 43 -could mediate the changes by displacing CNP from NPR3 44 as shown recently in transgenic mice 45 . Future study of temporal responses of plasma osteocrin in subjects presenting with ACS, and plasma levels of microRNA-100 and miRNA-143 (proven negative regulators of Npr3 expression in cardiac tissue 41,46 , can be expected to clarify these observations and contribute to our understanding of the adaptive responses to cardiac injury in humans.…”

Myocardial Energy Metabolism in Non-ischemic Cardiomyopathy

“…To date, few studies have examined whether correcting defects in myocardial energy metabolism can reduce the risk for cardiomyopathy in people with BTHS. Intriguingly, treatment of 3-month-old TazKD mice with the pan-PPAR agonist (primarily PPARα), bezafibrate, via supplementation in the diet (0.05% weight/weight) for 4 months, prevented the development of dilated cardiomyopathy and systolic dysfunction (Schafer et al, 2018). Despite myocardial energy metabolism not being directly assessed, gene-ontology analysis revealed that bezafibrate treatment resulted in increased expression of genes involved in multiple intermediary energy metabolism pathways, and the actions of PPAR agonists to increase fatty acid oxidation are well documented (Lopaschuk et al, 2010).…”