Metabolic Adaptations During Progression of Duchenne Cardiomyopathy

All articles of this category (opens in new window) Background: Duchenne muscular dystrophy (DMD) leads to progressive skeletal and cardiac muscle degeneration, with cardiomyopathy being a major determinant of mortality. The contribution of mitochondrial dysfunction to disease progression remains poorly understood. We aimed to characterize age-dependent cardiac remodeling and mitochondrial function in mdx mice to define the temporal relationship between mitochondrial alterations and cardiomyopathy development. Methods: Male mdx (C57BL/10ScSn-Dmdmdx/J) and wildtype (C57BL/10ScSnJ) mice were studied at 3, 6, 9, 12, 15, and 18 months. Echocardiography was performed to assess cardiac function and morphology. Cardiac mitochondria were isolated via enzymatic disruption and differential centrifugation. Citrate synthase activity was quantified, and mitochondrial respiration was measured using a Clark electrode. Results: Mdx mice showed increased heart and ventricular weights from 6 months onward, resulting in significantly elevated heart-to-body weight ratios. Echocardiography demonstrated left ventricular hypertrophy at 3, 9, 12, and 15 months with early hypercontractility, later progressing to diastolic dysfunction. Right-sided involvement was more pronounced, with early right atrial enlargement and significantly reduced TAPSE at 18 months. In cardiac tissue homogenate, citrate synthase activity declined at 12 and 18 months. Isolated cardiac mitochondria revealed impaired oxidative capacity (reduced ADP-stimulated state 3 respiration), decreased ATP synthesis, and uncoupled respiration, particularly at 12 months. In contrast, the ADP/O ratio was increased. Conclusion: Mdx mice develop progressive cardiomyopathy with early right ventricular dysfunction and left ventricular hypertrophy progressing to diastolic impairment. At later stages, cardiac dysfunction is accompanied by reduced ADP-stimulated respiration and an increased ADP/O ratio, indicating a compensatory metabolic shift toward lower capacity but more oxygen-efficient ATP production. These findings highlight a link between mitochondrial dysfunction and disease progression in dystrophin-deficient hearts. Publication History Article published online: 17 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany