lindsay-variablerescueof-2018.pdf (1.4 MB)
Variable rescue of microtubule and physiological phenotypes in mdx muscle expressing different miniaturized dystrophins
journal contribution
posted on 2018-06-01, 00:00 authored by D M Nelson, Angus Lindsay, L M Judge, D Duan, J S Chamberlain, D A Lowe, J M ErvastiDelivery 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
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Journal
Human Molecular GeneticsVolume
27Issue
12Pagination
2090 - 2100Publisher
Oxford University PressLocation
Oxford, Eng.Publisher DOI
ISSN
0964-6906eISSN
1460-2083Language
engPublication classification
C1 Refereed article in a scholarly journalUsage metrics
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