Variable rescue of microtubule and physiological phenotypes in mdx muscle expressing different miniaturized dystrophins
| Autor: | Angus Lindsay, D'anna M. Nelson, Dongsheng Duan, James M. Ervasti, Jeffrey S. Chamberlain, Luke M. Judge, Dawn A. Lowe |
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| Rok vydání: | 2018 |
| Předmět: |
musculoskeletal diseases
0301 basic medicine medicine.medical_specialty congenital hereditary and neonatal diseases and abnormalities Duchenne muscular dystrophy Mice Transgenic Biology Microtubules Dystrophin Mice 03 medical and health sciences 0302 clinical medicine Tubulin Microtubule In vivo Molecular genetics Genetics medicine Animals Humans Eccentric Muscular dystrophy Muscle Skeletal Molecular Biology Genetics (clinical) Skeletal muscle Articles Genetic Therapy General Medicine musculoskeletal system medicine.disease Phenotype Cell biology Muscular Dystrophy Duchenne Disease Models Animal 030104 developmental biology medicine.anatomical_structure HMG-CoA reductase Mice Inbred mdx biology.protein Erratum 030217 neurology & neurosurgery Ex vivo Muscle Contraction |
| Zdroj: | Human Molecular Genetics. 27:2090-2100 |
| ISSN: | 1460-2083 0964-6906 |
| DOI: | 10.1093/hmg/ddy113 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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