Society of Inherited Metabolic Disorders 2018 poster presentation

Background: Barth syndrome (BTHS) is an X-linked multisystem disorder caused by TAZ (G4.5) mutation. BTHS is associated with dilated cardiomyopathy, neutropenia, sudden cardiac death, skeletal muscle weakness, recurrent bacterial infection, and growth delay. There is a lack of effective specific therapies for Barth Syndrome cardiac manifestation due to the limited understanding of cellular pathophysiology and myocardial metabolism in human. Unraveling TAZ mutations impact in the heart at the metabolic and molecular levels is significantly hampered due to difficulties in obtaining and culturing human cardiac samples. Here, we used pluripotent stem cells-derived cardiomyocytes (iPS-CM) as a cellular model of Barth Syndrome to define metabolic and molecular changes associated with TAZ mutation.

Methods: TAZ and isogenic control iPS-CMs were generated on matrigel coated flasks through small molecules protocol that induces differentiation to cardiomyocytes through modulation of Wnt/β-Catenin pathway. For metabolic and molecular studies of TAZ and control iPS-CMs, we used stable isotopic tracers, mass spectrometry assays and targeted gene expression analysis.

Results: iPS-CMs expressed cardiac-specific markers and exhibit regularly beating. We found metabolic alterations in key metabolites linked to mitochondrial energy production and identified significant changes in expression of genes involved in calcium homeostasis and fatty acid metabolism.

Conclusions: Our findings reveal new therapeutic targets to rescue TAZ associated metabolic phenotype. The study of cardiac manifestation in disorder such as Barth Syndrome lays a foundation to explore metabolic and molecular remodeling in the heart at the cellular level and by extension, provides insight into other types of metabolic cardiomyopathies.