howlett-geneticreductionofthe-2020.pdf (2.82 MB)
Genetic reduction of the extracellular matrix protein versican attenuates inflammatory cell infiltration and improves contractile function in dystrophic mdx diaphragm muscles
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posted on 2020-07-06, 00:00 authored by N L McRae, A B Addinsall, Kirsten HowlettKirsten Howlett, Bryony McneillBryony Mcneill, D R Mcculloch, N StupkaThere is a persistent, aberrant accumulation of V0/V1 versican in skeletal muscles from patients with Duchenne muscular dystrophy and in diaphragm muscles from mdx mice. Versican is a provisional matrix protein implicated in fibrosis and inflammation in various disease states, yet its role in the pathogenesis of muscular dystrophy is not known. Here, female mdx and male hdf mice (haploinsufficient for the versican allele) were bred. In the resulting F1 mdx-hdf male pups, V0/V1 versican expression in diaphragm muscles was decreased by 50% compared to mdx littermates at 20–26 weeks of age. In mdx-hdf mice, spontaneous physical activity increased by 17% and there was a concomitant decrease in total energy expenditure and whole-body glucose oxidation. Versican reduction improved the ex vivo strength and endurance of diaphragm muscle strips. These changes in diaphragm contractile properties in mdx-hdf mice were associated with decreased monocyte and macrophage infiltration and a reduction in the proportion of fibres expressing the slow type I myosin heavy chain isoform. Given the high metabolic cost of inflammation in dystrophy, an attenuated inflammatory response may contribute to the effects of versican reduction on whole-body metabolism. Altogether, versican reduction ameliorates the dystrophic pathology of mdx-hdf mice as evidenced by improved diaphragm contractile function and increased physical activity.
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Journal
Scientific ReportsVolume
10Issue
1Article number
11080Pagination
1 - 19Publisher
Nature ResearchLocation
Berlin, GermanyPublisher DOI
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eISSN
2045-2322Language
engPublication classification
C1 Refereed article in a scholarly journalCopyright notice
2020, The Author(s)Usage metrics
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