Variable rescue of microtubule and physiological phenotypes in mdx muscle expressing different miniaturized dystrophins

D'anna M. Nelson, Angus Lindsay, Luke M. Judge, Dongsheng Duan, Jeffrey S. Chamberlain, Dawn A Lowe, James M Ervasti

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Delivery of miniaturized dystrophin genes via adeno-associated viral vectors is one leading approach in development to treat Duchenne muscular dystrophy. Here we directly compared the functionality of five mini- and micro-dystrophins via skeletal muscle-specific transgenic expression in dystrophin-deficient mdx mice. We evaluated their ability to rescue defects in the microtubule network, passive stiffness and contractility of skeletal muscle. Transgenic mdx mice expressing the short dystrophin isoform Dp116 served as a negative control. All mini- and micro-dystrophins restored elevated detyrosinated α-tubulin and microtubule density of mdx muscle to values not different from C57BL/10, however, only mini-dystrophins restored the transverse component of the microtubule lattice back to C57BL/10. Passive stiffness values in mdx muscles expressing mini- or micro-dystrophins were not different from C57BL/10. While all mini- and micro-dystrophins conferred significant protection from eccentric contraction-induced force loss in vivo and ex vivo compared to mdx, removal of repeats two and three resulted in less protection from force drop caused by eccentric contraction ex vivo. Our data reveal subtle yet significant differences in the relative functionalities for different therapeutic constructs of miniaturized dystrophin in terms of protection from ex vivo eccentric contraction-induced force loss and restoration of an organized microtubule lattice.

Original languageEnglish (US)
Pages (from-to)2090-2100
Number of pages11
JournalHuman molecular genetics
Volume27
Issue number12
DOIs
StatePublished - Jun 15 2018

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Dystrophin
Microtubules
Phenotype
Muscles
Inbred mdx Mouse
Skeletal Muscle
Duchenne Muscular Dystrophy
Tubulin
Transgenic Mice
Protein Isoforms

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

Cite this

Variable rescue of microtubule and physiological phenotypes in mdx muscle expressing different miniaturized dystrophins. / Nelson, D'anna M.; Lindsay, Angus; Judge, Luke M.; Duan, Dongsheng; Chamberlain, Jeffrey S.; Lowe, Dawn A; Ervasti, James M.

In: Human molecular genetics, Vol. 27, No. 12, 15.06.2018, p. 2090-2100.

Research output: Contribution to journalArticle

Nelson, D'anna M. ; Lindsay, Angus ; Judge, Luke M. ; Duan, Dongsheng ; Chamberlain, Jeffrey S. ; Lowe, Dawn A ; Ervasti, James M. / Variable rescue of microtubule and physiological phenotypes in mdx muscle expressing different miniaturized dystrophins. In: Human molecular genetics. 2018 ; Vol. 27, No. 12. pp. 2090-2100.
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