AUTHOR=Shafaati Tanin , Greenwell Amanda A. , Saed Christina T. , Tabatabaei Dakhili Seyed Amirhossein , Chan Jordan S. F. , Dong Linyue , Stenlund Magnus J. , Ferrari Sally R. , Han Ruth , Kruger Jennifer , Eaton Farah , Gopal Keshav , Davidge Sandra T. , Oudit Gavin Y. , Ussher John R. 

TITLE=Pharmacological increases in circulating ketones fail to alleviate the hypertrophic cardiomyopathy present in the Tafazzin knockdown mouse model of Barth syndrome

JOURNAL=Journal of Pharmacy & Pharmaceutical Sciences

VOLUME=Volume 28 - 2025

YEAR=2025

URL=https://www.frontierspartnerships.org/journals/journal-of-pharmacy-pharmaceutical-sciences/articles/10.3389/jpps.2025.15688

DOI=10.3389/jpps.2025.15688

ISSN=1482-1826

ABSTRACT=ObjectiveMutations in the tafazzin gene lead to impaired remodeling of cardiolipin, thereby impairing mitochondrial function and causing Barth syndrome (BTHS), a rare X-linked genetic disorder characterized by cardiomyopathy. Previous studies in a mouse model of BTHS, secondary to knockdown of Tafazzin (TazKD mice), also observed perturbations in mitochondrial substrate metabolism and a hypertrophic cardiomyopathy. BTHS may be characterized by increased cardiac ketone metabolism, as myocardial protein expression of the ketolytic enzyme, β-hydroxybutyrate dehydrogenase 1 (BDH1), was markedly increased in TazKD mice. We therefore determined whether increasing ketone supply in TazKD mice may have therapeutic utility against their cardiac abnormalities.MethodsWe treated TazKD mice and their wild-type littermates with either the sodium-glucose cotransporter-2 inhibitor, empagliflozin (10 mg/kg), or a ketone ester (KE; 1719 mg/kg) once daily for 7-week, and performed ultrasound echocardiography to assess cardiac structure and function.ResultsTreatment of TazKD mice with either empagliflozin or a KE increased circulating ketone levels. However, neither approach proved capable of alleviating the cardiac hypertrophy present in TazKD mice, as their increased left ventricular wall thickness and decreased left ventricular diameter remained comparable to that observed in vehicle control treated animals. We also observed that empagliflozin and KE treatment did not impact key markers of cardiac hypertrophy in TazKD mice.ConclusionIncreasing circulating ketone levels did not alleviate the cardiac hypertrophy in TazKD mice, suggesting that such an approach would not improve outcomes in BTHS.