Metabolic Alterations in Cardiomyocytes of Patients with Duchenne and Becker Muscular Dystrophies

Abstract

Duchenne and Becker muscular dystrophies (DMD/BMD) result in progressive weakness of skeletal and cardiac muscles due to the deficiency of functional dystrophin. Respiratory failure is a leading cause of mortality in DMD patients; however, improved management of the respiratory symptoms have increased patients’ life expectancy, thereby also increasing the clinical relevance of heart disease. In fact, the prevalence of cardiomyopathy, which significantly contributes to mortality in DMD patients, increases with age and disease progression, so that over 95% of adult patients has cardiomyopathy signs. We here review the current literature featuring the metabolic alterations observed in the dystrophic heart of the mdx mouse, i.e., the best-studied animal model of the disease, and discuss their pathophysiological role in the DMD heart. It is well assessed that dystrophin deficiency is associated with pathological alterations of lipid metabolism, intracellular calcium levels, neuronal nitric oxide (NO) synthase localization, and NO and reactive oxygen species production. These metabolic stressors contribute to impair the function of the cardiac mitochondrial bulk, which has a relevant pathophysiological role in the development of cardiomyopathy. In fact, mitochondrial dysfunction becomes more severe as the dystrophic process progresses, thereby indicating it may be both the cause and the consequence of the dystrophic process in the DMD heart.

Cardiomyocyte depolarization triggers NOS-dependent NO transient after calcium release, reducing the subsequent calcium transient

“…According to the genotype, the source (isoform) of diastolic NO production varied, suggesting that all three isoforms contribute to basal NO production. In comparison to WT cardiomyocytes, dystrophic cardiomyocytes produced significantly lower amounts of NO during diastole, supporting previous reports of mdx cardiomyocytes producing lower levels of NO [ 23 , 82 ]. Interestingly, there was no difference in NO production during diastole between WT and mdx cardiomyocytes, as both genotypes exhibited reduced NO production after treatment with 1400 W and increased NO production after treatment with L-NIO.…”

Metformin Reverses the Enhanced Myocardial SR/ER–Mitochondria Interaction and Impaired Complex I-Driven Respiration in Dystrophin-Deficient Mice

“…Myocardial metabolic and mitochondrial impairments as well as mitochondrial and cellular Ca 2+ handling have been extensively studied in DMD during the last decade. All the studies agree that these disorders, which precede the onset of structural remodeling and deterioration of myocardial macroscopic function, play a central role in the progression of the pathology to heart failure (for review: Esposito and Carsana, 2019 ). Here, for the first time, our data suggests that the enhancement of SR/ER–mitochondria contact points and increasing mitochondrial Ca 2+ uptake and content would enhance glycolytic flux and complex I respiration.…”

Muscle metabolic remodelling patterns in Duchenne muscular dystrophy revealed by ultra-high-resolution mass spectrometry imaging

“…Defective dystrophin is known to be the main alteration in the DMD etiology, however, metabolic impairment has been reported in several tissues such as the skeletal and cardiac muscles, liver and brain 27 . Here, we explored the differential metabolic patterns of muscle biopsies from DMD patients and control samples using a hypothesis-free strategy based on MSI.…”