title: Dystrobrevin increases dystrophin's binding to the dystrophin-glycoprotein complex and provides protection during cardiac stress.
abstract: 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 the 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 dystrophin-deficient mdx mice. 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 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.
authors.affiliation: Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Jana
authors.initials: J
authors.lastname: Strakova
authors.affiliation: Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Jon D
authors.initials: JD
authors.lastname: Dean
authors.affiliation: Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Katharine M
authors.initials: KM
authors.lastname: Sharpe
authors.affiliation: Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Tatyana A
authors.initials: TA
authors.lastname: Meyers
authors.affiliation: Department of Neurology, University of Washington, Seattle, WA, USA.
authors.forename: Guy L
authors.initials: GL
authors.lastname: Odom
authors.affiliation: Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN, USA. Electronic address: town0045@umn.edu.
authors.forename: DeWayne
authors.initials: D
authors.lastname: Townsend
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016189:Dystrophin / Q000378:metabolism*; D049029:Dystrophin-Associated Proteins / Q000502:physiology*; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008870:Microtubules / Q000378:metabolism; D020388:Muscular Dystrophy, Duchenne / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D011485:Protein Binding; D049031:Sarcoglycans / Q000378:metabolism*; D013312:Stress, Physiological
chemical_list: D016189:Dystrophin; D049029:Dystrophin-Associated Proteins; D049031:Sarcoglycans; C098885:dystrobrevin
keywords: Alpha-dystrobrevin; Duchenne muscular dystrophy; Dystrophin; Tubulin