Blunted fat oxidation upon submaximal exercise is partially compensated by enhanced glucose metabolism in children, adolescents, and young adults with Barth syndrome

William Todd Cade, Kathryn L. Bohnert, Linda R. Peterson, Bruce W. Patterson, Adam J. Bittel, Adewole L. Okunade, Lisa de las Fuentes, Karen Steger-May, Adil Bashir, George G. Schweitzer, Shaji K. Chacko, Ronald J. Wanders, Christina A. Pacak, Barry J. Byrne, Dominic N. Reeds

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Barth syndrome (BTHS) is a rare X-linked condition resulting in abnormal mitochondria, cardioskeletal myopathy, and growth delay; however, the effects of BTHS on substrate metabolism regulation and their relationships with tissue function in humans are unknown. We sought to characterize glucose and fat metabolism during rest, submaximal exercise, and postexercise rest in children, adolescents, and young adults with BTHS and unaffected controls and examine their relationships with cardioskeletal energetics and function. Children/adolescents and young adults with BTHS (n = 29) and children/adolescent and young adult control participants (n = 28, total n = 57) underwent an infusion of 6′6′H2 glucose and U-13C palmitate and indirect calorimetry during rest, 30-minutes of moderate exercise (50% (Formula presented.)), and recovery. Cardiac function, cardioskeletal mitochondrial energetics, and exercise capacity were examined via echocardiography, 31P magnetic resonance spectroscopy, and peak exercise testing, respectively. The glucose turnover rate was significantly higher in individuals with BTHS during rest (33.2 ± 9.8 vs 27.2 ± 8.1 μmol/kgFFM/min, P <.01) and exercise (34.7 ± 11.2 vs 29.5 ± 8.8 μmol/kgFFM/min, P <.05) and tended to be higher postexercise (33.7 ± 10.2 vs 28.8 ± 8.0 μmol/kgFFM/min, P <.06) compared to controls. Increases in total fat (−3.9 ± 7.5 vs 10.5 ± 8.4 μmol/kgFFM/min, P <.0001) and plasma fatty acid oxidation rates (0.0 ± 1.8 vs 5.1 ± 3.9 μmol/kgFFM/min, P <.0001) from rest to exercise were severely blunted in BTHS compared to controls. Conclusion: An inability to upregulate fat metabolism during moderate intensity exercise appears to be partially compensated by elevations in glucose metabolism. Derangements in fat and glucose metabolism are characteristic of the pathophysiology of BTHS. A severely blunted ability to upregulate fat metabolism during a modest level of physical activity is a defining pathophysiologic characteristic in children, adolescents, and young adults with BTHS.

Original languageEnglish (US)
Pages (from-to)480-493
Number of pages14
JournalJournal of Inherited Metabolic Disease
Volume42
Issue number3
DOIs
StatePublished - May 2019
Externally publishedYes

Bibliographical note

Funding Information:
information Foundation for the National Institutes of Health, Grant/Award Numbers: R01HL107406-01, K01EB010171, P30DK056341, P30DK020579, HD007434, UL1TR000448We thank the nursing staff at the Washington University Institute for Clinical and Translational Sciences Clinical Research Unit for their hard work and altruism. We also thank Freida Custodio and Jennifer Shew for their assistance in sample processing. Finally, we thank the participants and their families for their dedication and effort to travel to St. Louis and participate in this study. This work was supported by the National Institutes of Health R01HL107406-01, K01EB010171, P30DK056341, P30DK020579, HD007434, and UL1TR000448 from the National Center for Research Resources and NIH Roadmap for Medical Research. Clinical Trials #: NCT01625663.

Funding Information:
We thank the nursing staff at the Washington University Institute for Clinical and Translational Sciences Clinical Research Unit for their hard work and altruism. We also thank Freida Custodio and Jennifer Shew for their assistance in sample processing. Finally, we thank the participants and their families for their dedication and effort to travel to St. Louis and participate in this study. This work was supported by the National Institutes of Health R01HL107406-01, K01EB010171, P30DK056341, P30DK020579, HD007434, and UL1TR000448 from the National Center for Research Resources and NIH Roadmap for Medical Research. Clinical Trials #: NCT01625663.

Publisher Copyright:
© 2019 SSIEM

Keywords

  • Barth syndrome
  • exercise
  • fatty acid
  • mitochondria

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