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Background: Barth syndrome (BTHS) is an X-linked mitochondrial lipid disorder caused by mutations in TAFAZZIN ( TAZ). Cardiomyopathy is a major clinical feature in BTHS. Thus far, there is no curative therapy for BTHS. TAZ is an acyltransferase required for remodeling/maturation of cardiolipin (CL), a signature phospholipid of mitochondria. TAZ deficiency causes ineffcient transacylation and maturation of CL. In mammalian heart, the major mature CL species is tetralinoleoyl-CL, containing four linoleic acid (LA) side chains. LA is one of two essential fatty acids that must be obtained through diet. In this study, focus on the investigation of potential therapeutic effects of a safflower oil diet-based LA supplementation on BTHS cardiomyopathy. Hypothesis: Linoleic acid (LA) supplementation could ameliorate BTHS by increasing incorporation of linoleoyl groups into nascent CL towards mature CL composition without requiring the remodeling process. Methods: Taz global (gKO) and cardiomyocyte-specific knockout (cKO) mouse models were fed with high-LA safflower oil diet (LAD) contained 10% LA (LA weight/chow weight; law/cw) and the low-LA palm oil control diet (CD) contained 1% LA (law/cw). Echocardiographic analysis was performed for cardiac function over a full-time course. Lipidomic analysis was performed to determine CL profiles in mutant hearts. Results: Our results clearly revealed that dietary LA supplementation fully prevented cardiomyopathy in Taz gKO and cKO mutants at 4 months of age, with cardiac function of mutants in the LAD group being comparable to that of WT controls, while mutants in the CD group displayed significant dilated cardiomyopathy (DCM) at this age. The beneficial effects of LA supplementation extended to, albeit with diminishing effcacy, at 6 and 8 months of age. In lipidomic analysis, we observed “BTHS-like” CL profiles in Taz cKO hearts both in LAD and CD groups. However, LAD ameliorated the severity of CL abnormalities in Taz cKO hearts. Interesting, beneficial effects of LAD on CL profiles declined at 8 months of age. Conclusion: Our study demonstrated that dietary LA supplementation has potential to delay development of BTHS cardiomyopathy at early stages, but there is a declining effectiveness as the disease progresses, providing important insights into the temporal effects of LA in BTHS therapy. Xi Fang is supported by NIH grants. Sylvia M Evans is supported by NIH grants and the Foundation Leducq (16 CVD 03). Asa B Gustafsson is supported by NIH grants R01HL155281 and R01HL157265. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Zhu et al. (Wed,) studied this question.