Blunted Fat Oxidation upon Submaximal Exercise is Partially Compensated by Enhanced Glucose Metabolism in Children, Adolescents and Young Adults with Barth Syndrome.

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 66H2 glucose and U-C-13 palmitate and indirect calorimetry during rest, 30-minutes of moderate exercise (50% V O2peak), and recovery. Cardiac function, cardioskeletal mitochondrial energetics, and exercise capacity were examined via echocardiography, P-31 magnetic resonance spectroscopy, and peak exercise testing, respectively. The glucose turnover rate was significantly higher in individuals with BTHS during rest (33.29.8 vs 27.2 +/- 8.1 mol/kgFFM/min, P<.01) and exercise (34.7 +/- 11.2 vs 29.5 +/- 8.8 mol/kgFFM/min, P<.05) and tended to be higher postexercise (33.7 +/- 10.2 vs 28.8 +/- 8.0 mol/kgFFM/min, P<.06) compared to controls. Increases in total fat (-3.9 +/- 7.5 vs 10.5 +/- 8.4 mol/kgFFM/min, P<.0001) and plasma fatty acid oxidation rates (0.0 +/- 1.8 vs 5.1 +/- 3.9 mol/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.