Abstract
Absence of the protein dystrophin causes Duchenne muscular dystrophy. Dystrophin directly binds to microtubules in vitro, and its absence in vivo correlates with disorganization of the subsarcolemmal microtubule lattice, increased detyrosination of α-tubulin, and altered redox signaling. We previously demonstrated that the dystrophin homologue utrophin neither binds microtubules in vitro nor rescues microtubule lattice organization when overexpressed in muscles of dystrophin-deficient mdx mice. Here, we fine-mapped the dystrophin domain necessary for microtubule binding to spectrin-like repeats 20-22. We show that transgenic mdx mice expressing a full-length dystrophin/utrophin chimera completely lacking microtubule binding activity are surprisingly rescued for all measured dystrophic phenotypes, including full restoration of microtubule lattice organization. Conversely, despite the presence of dystrophin at the sarcolemma, β-sarcoglycan-deficient skeletal muscle presents with a disorganized and densified microtubule lattice. Finally, we show that the levels of α-tubulin detyrosination remain significantly elevated to that of mdx levels in transgenic mdx mice expressing nearly full-length dystrophin. Our results demonstrate that the microtubule-associated perturbations of mdx muscle are distinct, separable, and can vary independently from other parameters previously ascribed to dystrophin deficiency.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 4951-4961 |
| Number of pages | 11 |
| Journal | Human molecular genetics |
| Volume | 25 |
| Issue number | 22 |
| DOIs | |
| State | Published - Nov 15 2016 |
Bibliographical note
Funding Information:The authors would like to thank Drs. Wenhua Liu and Evelyn Ralston (National Institute of Arthritis and Musculoskeletal and Skin Diseases) for providing the directionality analysis program and Dr. DeWayne Townsend (University of Minnesota) for a breeding pair of Sgcb-/- mice. The study was supported by National Institute of Arthritis and Musculoskeletal and Skin Diseases grant to J.M.E. [RO1 AR042423]. J.J.B. and J.T.O. were supported by the National Institutes of Health Training Program in Muscle Research [AR007612]. J.J.B. was also supported by a University of Minnesota Doctoral Dissertation Fellowship. J.T.O., T.L.M. and D.M.N. were each supported by fellowships from the National Institute on Aging Training Program for Functional Proteomics of Aging [T32 AG029796]. D.M.T. was supported by an American Heart Association Predoctoral Fellowship [12PRE12040402].
Publisher Copyright:
© The Author 2016. Published by Oxford University Press. All rights reserved.