Human Molecular Genetics, 2002, Vol. 11, No. 9 1095-1105
© 2002 Oxford University Press
Expression of Dp260 in muscle tethers the actin cytoskeleton to the dystrophin–glycoprotein complex and partially prevents dystrophy
1Department of Neurology, University of Washington, Seattle, WA 98195, USA and 2Department of Physiology, University of Wisconsin, Madison, WI 53706, USA
Dystrophin forms a mechanical link between the actin cytoskeleton and the extracellular matrix in muscle that helps maintain sarcolemmal integrity. Two regions of dystrophin have been shown to bind actin: the N-terminal domain and rod domain repeats 11–17. To better understand the roles of these two domains and whether the rod domain actin-binding domain alone can support a mechanically functional link with actin, we constructed transgenic mice expressing Dp260 in skeletal muscle. Dp260, the retinal isoform of dystrophin, lacks the N-terminal domain and a significant portion of the rod domain, but retains the rod domain actin-binding domain. Our results indicate that Dp260 expression restores a stable association between costameric actin and the sarcolemma, assembles the dystrophin–glycoprotein complex, and significantly slows the progression of the dystrophy in the dystrophin-deficient mdx mouse. We assessed the functional integrity of the mechanical link in Dp260 transgenic mdx mice and found that Dp260 muscles showed normal resistance to contraction-induced injury, but dramatic reductions in force generation similar to those found with mdx muscles. Morphologically, Dp260 muscles displayed reduced amounts of inflammation and fibrosis, but still showed a significant, albeit reduced, amount of degeneration/regeneration. These data demonstrate that protection from contraction-induced injury can dramatically ameliorate, but not completely halt, the dystrophic process. We suggest that a non-mechanical defect, attributed to the loss of the N terminus of dystrophin, is likely responsible for the residual dystrophy observed.
* To whom correspondence should be addressed at: Department of Neurology, University of Washington, 1959 NE Pacific Street, Room K243B HSB, Box 357720, Seattle, WA 98195-7720, USA. Tel: +1 206 221 5363; Fax: +1 206 616 8272; Email: JSC5{at}u.washington.edu
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  M. R. Stone, A. O'Neill, R. M. Lovering, J. Strong, W. G. Resneck, P. W. Reed, D. M. Toivola, J. A. Ursitti, M. B. Omary, and R. J. Bloch Absence of keratin 19 in mice causes skeletal myopathy with mitochondrial and sarcolemmal reorganization J. Cell Sci., November 15, 2007; 120(22): 3999 - 4008. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. B. Banks, P. Gregorevic, J. M. Allen, E. E. Finn, and J. S. Chamberlain Functional capacity of dystrophins carrying deletions in the N-terminal actin-binding domain Hum. Mol. Genet., September 1, 2007; 16(17): 2105 - 2113. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. G. Tidball and M. Wehling-Henricks The role of free radicals in the pathophysiology of muscular dystrophy J Appl Physiol, April 1, 2007; 102(4): 1677 - 1686. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Duan Challenges and opportunities in dystrophin-deficient cardiomyopathy gene therapy Hum. Mol. Genet., October 15, 2006; 15(suppl_2): R253 - R261. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. M. Judge, M. Haraguchiln, and J. S. Chamberlain Dissecting the signaling and mechanical functions of the dystrophin-glycoprotein complex J. Cell Sci., April 15, 2006; 119(8): 1537 - 1546. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. M. Hanft, I. N. Rybakova, J. R. Patel, J. A. Rafael-Fortney, and J. M. Ervasti Cytoplasmic {gamma}-actin contributes to a compensatory remodeling response in dystrophin-deficient muscle PNAS, April 4, 2006; 103(14): 5385 - 5390. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Assereto, S. Stringara, F. Sotgia, G. Bonuccelli, A. Broccolini, M. Pedemonte, M. Traverso, R. Biancheri, F. Zara, C. Bruno, et al. Pharmacological rescue of the dystrophin-glycoprotein complex in Duchenne and Becker skeletal muscle explants by proteasome inhibitor treatment Am J Physiol Cell Physiol, February 1, 2006; 290(2): C577 - C582. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. R. Stone, A. O'Neill, D. Catino, and R. J. Bloch Specific Interaction of the Actin-binding Domain of Dystrophin with Intermediate Filaments Containing Keratin 19 Mol. Biol. Cell, September 1, 2005; 16(9): 4280 - 4293. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Ishikawa-Sakurai, M. Yoshida, M. Imamura, K. E. Davies, and E. Ozawa ZZ domain is essentially required for the physiological binding of dystrophin and utrophin to {beta}-dystroglycan Hum. Mol. Genet., April 1, 2004; 13(7): 693 - 702. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Abmayr, R.W. Crawford, and J.S. Chamberlain Characterization of ARC, apoptosis repressor interacting with CARD, in normal and dystrophin-deficient skeletal muscle Hum. Mol. Genet., January 15, 2004; 13(2): 213 - 221. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Ervasti Costameres: the Achilles' Heel of Herculean Muscle J. Biol. Chem., April 11, 2003; 278(16): 13591 - 13594. [Full Text] [PDF]
|
|
|
|
|
|
J. S. Chamberlain Gene therapy of muscular dystrophy Hum. Mol. Genet., October 1, 2002; 11(20): 2355 - 2362. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Q. Harper, R. W. Crawford, C. DelloRusso, and J. S. Chamberlain Spectrin-like repeats from dystrophin and {alpha}-actinin-2 are not functionally interchangeable Hum. Mol. Genet., August 1, 2002; 11(16): 1807 - 1815. [Abstract] [Full Text] [PDF]
|
|