Microtubule binding distinguishes dystrophin from utrophin

Joseph J Belanto, Tara L. Mader, Michael D. Eckhoff, Dana M. Strandjord, Glen B. Banks, Melissa K Gardner, Dawn A Lowe, James M Ervasti

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

Dystrophin and utrophin are highly similar proteins that both link cortical actin filaments with a complex of sarcolemmal glycoproteins, yet localize to different subcellular domains within normal muscle cells. In mdx mice and Duchenne muscular dystrophy patients, dystrophin is lacking and utrophin is consequently up-regulated and redistributed to locations normally occupied by dystrophin. Transgenic overexpression of utrophin has been shown to significantly improve aspects of the disease phenotype in the mdx mouse; therefore, utrophin up-regulation is under intense investigation as a potential therapy for Duchenne muscular dystrophy. Here we biochemically compared the previously documented microtubule binding activity of dystrophin with utrophin and analyzed several transgenic mouse models to identify phenotypes of the mdx mouse that remain despite transgenic utrophin overexpression. Our in vitro analyses revealed that dystrophin binds microtubules with high affinity and pauses microtubule polymerization, whereas utrophin has no activity in either assay. We also found that transgenic utrophin overexpression does not correct subsarcolemmal microtubule lattice disorganization, loss of torque production after in vivo eccentric contractions, or physical inactivity after mild exercise. Finally, our data suggest that exerciseinduced inactivity correlates with loss of sarcolemmal neuronal NOS localization in mdx muscle, whereas loss of in vivo torque production after eccentric contraction-induced injury is associated with microtubule lattice disorganization.

Original languageEnglish (US)
Pages (from-to)5723-5728
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number15
DOIs
StatePublished - Apr 15 2014

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Utrophin
Dystrophin
Microtubules
Inbred mdx Mouse
Duchenne Muscular Dystrophy
Torque
Phenotype
Actin Cytoskeleton
Polymerization
Muscle Cells
Transgenic Mice
Glycoproteins
Up-Regulation
Exercise
Muscles

Cite this

Microtubule binding distinguishes dystrophin from utrophin. / Belanto, Joseph J; Mader, Tara L.; Eckhoff, Michael D.; Strandjord, Dana M.; Banks, Glen B.; Gardner, Melissa K; Lowe, Dawn A; Ervasti, James M.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 15, 15.04.2014, p. 5723-5728.

Research output: Contribution to journalArticle

Belanto, Joseph J ; Mader, Tara L. ; Eckhoff, Michael D. ; Strandjord, Dana M. ; Banks, Glen B. ; Gardner, Melissa K ; Lowe, Dawn A ; Ervasti, James M. / Microtubule binding distinguishes dystrophin from utrophin. In: Proceedings of the National Academy of Sciences of the United States of America. 2014 ; Vol. 111, No. 15. pp. 5723-5728.
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