Feeding the starving heart in Barth Syndrome  

Adam J. Chicco, PhD; Colorado State University  

Barth syndrome (BTHS) is an X-linked genetic disorder that results from mutations in the TAFAZZIN (a.k.a. TAZ) gene, which encodes a phospholipid transacylase responsible for generating the mature form of cardiolipin in inner mitochondrial membranes. BTHS patients develop early-onset cardiomyopathy and a derangement of intermediary metabolism consistent with mitochondrial disease, but the precise alterations in energy metabolism that limit functional capacity and induce cardio-skeletal myopathy are incompletely understood. Last year, we published the first comprehensive analyses of cardiac mitochondrial metabolism in the Taz shRNA knockdown mouse model of BTHS (Le J Biol Chem 295:12485, 2020), which we recently followed up with the first detailed metabolic phenotyping of cardiac tissue from BTHS patients compared to age-matched healthy and idiopathic failing heart samples  (Chatfield J Inherit Metab Dis 2021).  We found a striking alignment of results between species that implicates specific deficiencies in long-chain fatty acid oxidation (LCFAOx) as a primary distinguishing metabolic feature of BTHS cardiomyopathy.  These defects appear to be compensated for by a greater reliance upon the catabolism of ketones, amino acids and glucose to meet cardiac energy demands, which is consistent with in vivo studies of cardiac and whole-body metabolism in BTHS patients by Cade et al. (J Nucl Cardiol 2019, J Inherit Metab Dis 2013).  Unfortunately, these fuels are evidently insufficient to fully support cardiac energy demands in humans, likely contributing to reduced functional capacity and perhaps the development of cardiomyopathy in BTHS patients.  Studies in the proposal aim to leverage these lessons learned from humans and mice to test the hypothesis that providing BTHS patients with alternative metabolic substrates that bypass defects in LCFAOx will improve exercise tolerance and cardiac functional capacity.  To address this, we will utilize the Taz shRNA mouse model to establish the pre-clinical utility of dietary supplementation with triheptanoin (a C7 medium-chain triglyceride recently FDA-approved for treatment of LCFAOx disorders) in the presence and absence of an 8-week light exercise training protocol (treadmill walking). Parallel studies will also be performed in the new Taz knockout mouse model developed by Dr. Strathdee to maximize the potential for translation of these studies to BTHS patients. Effects on exercise tolerance and capacity (graded exercise tests), cardiac function (serial echocardiography and ex vivo hemodynamics), cardiac and serum metabolomics (LC/GC-MS), and mitochondrial metabolism (high resolution respirometry on cardiac and skeletal muscle) will be evaluated as primary outcomes.  If positive, the results of these studies will provide the basis for exploring a clinically feasible and relatively inexpensive metabolic intervention for improving functional capacity and quality of life in BTHS patients while we await more permanent solutions (e.g., gene therapy) to this debilitating disease.