Duchenne muscular dystrophy is a fatal progressive disease of both cardiac and skeletal muscle resulting from the mutations in the DMD gene and loss of the protein dystrophin. Alpha-dystrobrevin (α-DB) tightly associates with dystrophin but significance of this interaction within cardiac myocytes is poorly understood. In the current study the functional role of α-DB in cardiomyocytes and its implications for dystrophin function are examined. Cardiac stress testing demonstrated significant heart disease in α-DB null (adbn−/−) mice, which displayed mortality and lesion sizes that were equivalent to those seen in the dystrophin-deficient mdx mouse. Despite normal expression and subcellular localization of dystrophin in the adbn−/− heart, there is a significant decrease in the strength of dystrophin's interaction with the membrane-bound dystrophin-associated glycoprotein complex (DGC). A similar weakening of the dystrophin-membrane interface was observed in mice lacking the sarcoglycan complex. Cardiomyocytes from adbn−/− mice were smaller and responded less to adrenergic receptor induced hypertrophy. The basal decrease in size could not be attributed to aberrant Akt activation. In addition, the organization of the microtubule network was significantly altered in adbn−/− cardiac myocytes, while the total expression of tubulin was unchanged in the adbn−/− hearts. These studies demonstrate that α-DB is a multifunctional protein that increases dystrophin's binding to the dystrophin-glycoprotein complex, and is critical for the full functionality of dystrophin.
The C‐terminal region of dystrophin is highly conserved across vertebrates, but its function is largely unknown. α‐Dystrobrevin (DB) is one of several proteins that bind to this region of dystrophin. Mice lacking α‐DB demonstrate a mild myopathy in skeletal muscle, but the phenotype of the heart has not been fully characterized. Here we demonstrate that the loss of α‐DB significantly weakens the association of cardiac dystrophin with membrane glycoproteins. In the absence of α‐DB, wheat germ agglutinin pull down assay reveals a dystrophin:α‐dystroglycan ratio only 13% of that observed in wildtype mice. The physiological importance of the disruption of this interaction is evident in the marked pathology induced by chronic isoproterenol administration. This challenge protocol results in significant myocardial damage and mortality >60% in mice lacking α‐DB, in contrast wild type mice survived with minimal injury. The lesions and mortality observed in the α‐DB null mice were not different from mice lacking dystrophin. These findings have significant implications on the design of truncated dystrophin constructs suitable for delivery via gene therapy, as many of these constructs lack the binding domain for α‐DB.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.