Impaired cardiac and skeletal muscle bioenergetics in children, adolescents, and young adults with Barth syndrome

Adil Bashir, Kathryn L Bohnert, Dominic N Reeds, Linda R Peterson, Adam J Bittel, Lisa de Las Fuentes, Christina A Pacak, Barry J Byrne, W Todd Cade, Adil Bashir, Kathryn L Bohnert, Dominic N Reeds, Linda R Peterson, Adam J Bittel, Lisa de Las Fuentes, Christina A Pacak, Barry J Byrne, W Todd Cade

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 (VO2peak) 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 (τPCr) 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.

Keywords: Barth syndrome; energetics; exercise; mitochondria; muscle.

© 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

Figures

Figure 1
Figure 1
Reference images of the heart. Location of saturation band and approximate sensitive region of the RF coil is also shown (A) Spectrum from a healthy control (B) and a participant with Barth syndrome (C) detailing the peaks of PCr, ATP, PDE, and 2,3 DPG. PCr resonance amplitude is reduced in spectrum from Barth participant with similar ATP amplitudes. The red dashed lines provide a visual cue of changes in PCr and ATP peaks. β‐ATP resonance in the spectra is diminished due to the bandwidth limitations of the adiabatic RF pulse. DPG, 2,3‐diphosphoglycerate; PDE, phosphodiester.
Figure 2
Figure 2
Typical postexercise PCr recovery data. PCr amplitude (normalized to resting condition) for all participants (A) Adults, (B) Children/Adolescents). Error bars represent standard error. Representative PCr recovery data from adults (C) and children/adolescents (D) showing example of signal exponential fit.
Figure 3
Figure 3
Scatterplots of VO 2peak and (A) τPCR, (B) Vi, C) Qmax‐lin, and (D) Qmax‐ADP during 60‐sec exercise.

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