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.
|Original language||English (US)|
|Number of pages||10|
|Journal||Current Therapeutic Research - Clinical and Experimental|
|State||Published - Nov 1 2014|
Bibliographical noteFunding Information:
The authors would like to a thank Wenhua Liu and Evelyn Ralston for their assistance with the analysis of microtubular network structure. The authors would also like to acknowledge Dr. Jeffrey Chamberlain for the adbn −/− mice used in these studies. This work was funded by grants K08 HL102066 and R01 HL114832 from the National Institutes of Health and the Greg Marzolf Jr. Foundation .
- Duchenne muscular dystrophy