The effects of low levels of dystrophin on mouse muscle function and pathology.

PloS One
Maaike van PuttenAnnemieke Aartsma-Rus

Abstract

Duchenne muscular dystrophy (DMD) is a severe progressive muscular disorder caused by reading frame disrupting mutations in the DMD gene, preventing the synthesis of functional dystrophin. As dystrophin provides muscle fiber stability during contractions, dystrophin negative fibers are prone to exercise-induced damage. Upon exhaustion of the regenerative capacity, fibers will be replaced by fibrotic and fat tissue resulting in a progressive loss of function eventually leading to death in the early thirties. With several promising approaches for the treatment of DMD aiming at dystrophin restoration in clinical trials, there is an increasing need to determine more precisely which dystrophin levels are sufficient to restore muscle fiber integrity, protect against muscle damage and improve muscle function.To address this we generated a new mouse model (mdx-Xist(Δhs)) with varying, low dystrophin levels (3-47%, mean 22.7%, stdev 12.1, n = 24) due to skewed X-inactivation. Longitudinal sections revealed that within individual fibers, some nuclei did and some did not express dystrophin, resulting in a random, mosaic pattern of dystrophin expression within fibers.Mdx-Xist(Δhs), mdx and wild type females underwent a 12 week functional t...Continue Reading

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Methods Mentioned

BETA
antisense oligonucleotide
PCR
protein assay
chip

Software Mentioned

Odyssey
R
Mayachitra Imago
Xist
NMD
ImageJ
LinREgPCR
Leica IM50
mdx
TREAT

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