Abstract
Barth syndrome (BTHS) is an X‐linked condition characterized by altered cardiolipin metabolism and cardioskeletal myopathy. We sought to compare cardiac and skeletal muscle bioenergetics in children, adolescents, and young adults with BTHS and unaffected controls and examine their relationships with cardiac function and exercise capacity. Children/adolescents and young adults with BTHS (n = 20) and children/adolescent and young adult control participants (n = 23, total n = 43) underwent 31P magnetic resonance spectroscopy (31P‐MRS) of the lower extremity (calf) and heart for estimation of skeletal muscle and cardiac bioenergetics. Peak exercise testing (VO 2peak) and resting echocardiography were also performed on all participants. Cardiac PCr/ATP ratio was significantly lower in children/adolescents (BTHS: 1.5 ± 0.2 vs. Control: 2.0 ± 0.3, P < 0.01) and adults (BTHS: 1.9 ± 0.2 vs. Control: 2.3 ± 0.2, P < 0.01) with BTHS compared to Control groups. Adults (BTHS: 76.4 ± 31.6 vs. Control: 35.0 ± 7.4 sec, P < 0.01) and children/adolescents (BTHS: 71.5 ± 21.3 vs. Control: 31.4 ± 7.4 sec, P < 0.01) with BTHS had significantly longer calf PCr recovery (τ PCr) postexercise compared to controls. Maximal calf ATP production through oxidative phosphorylation (Qmax‐lin) was significantly lower in children/adolescents (BTHS: 0.5 ± 0.1 vs. Control: 1.1 ± 0.3 mmol/L per sec, P < 0.01) and adults (BTHS: 0.5 ± 0.2 vs. Control: 1.0 ± 0.2 mmol/L sec, P < 0.01) with BTHS compared to controls. Blunted cardiac and skeletal muscle bioenergetics were associated with lower VO2peak but not resting cardiac function. Cardiac and skeletal muscle bioenergetics are impaired and appear to contribute to exercise intolerance in BTHS.
Highlights
Barth syndrome (BTHS) is a X-linked disorder resulting from mutations in the gene encoding for tafazzin (TAZ) (Bione et al 1996) and is characterized by heart failure, exercise intolerance, fatigue, and premature mortality (Barth et al 1983)
Using near-infrared spectroscopy we found that skeletal muscle oxygen extraction was significantly blunted during exercise in children, adolescents, and young adults with BTHS suggesting impaired mitochondrial energetics in these individuals (Spencer et al 2011)
The principal and novel findings of this study were that skeletal muscle and cardiac bioenergetics, as determined from postexercise PCr recovery kinetics using 31P magnetic resonance spectroscopy (31P-MRS), were impaired in both children/adolescents and young adults with BTHS when compared to unaffected, agematched, sedentary controls
Summary
Barth syndrome (BTHS) is a X-linked disorder resulting from mutations in the gene encoding for tafazzin (TAZ) (Bione et al 1996) and is characterized by heart failure, exercise intolerance, fatigue, and premature mortality (Barth et al 1983). TAZ, a phospholipid-lysophospholipid transacylase, remodels monolysocardiolipin to tetralinoleoyl-cardiolipin which provides inner membrane stability necessary for ATP production by the electron transport chain (Zhang et al 2002). Mutations in TAZ result in an increase in monolysocardiolipin and reduction in tetralinoleoyl-cardiolipin (Schlame et al 2003), smaller and fragmented mitochondria (Wang et al 2014),. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society. Impaired Energetics in Barth Syndrome disruptions in mitochondrial supercomplexes (Xu et al 2016), instability in the mitochondrial inner membrane (Zhang et al 2002), and markedly reduced respiratory capacity (Wang et al 2014)
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