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 test regime consisting of different tests to assess muscle function at base line, or after chronic treadmill running exercise. Overall, mdx-Xist Δhs mice with 3–14% dystrophin outperformed mdx mice in the functional tests. Improved histopathology was observed in mice with 15–29% dystrophin and these levels also resulted in normalized expression of pro-inflammatory biomarker genes, while for other parameters >30% of dystrophin was needed. Chronic exercise clearly worsened pathology, which needed dystrophin levels >20% for protection. Based on these findings, we conclude that while even dystrophin levels below 15% can improve pathology and performance, levels of >20% are needed to fully protect muscle fibers from exercise-induced damage.
Highlights
Duchenne Muscular Dystrophy (DMD) is an X-linked recessive disorder affecting 1:3500 new born boys
Mdx-XistDhs mice express varying levels of dystrophin To study whether low dystrophin levels reduce the dystrophic pathology of mdx mice, mdx-XistDhs mice carrying a wide range of low dystrophin levels based on non-random X-inactivation were bred (Figure 1A)
Longitudinal sections of the quadriceps revealed that dystrophin expression along a single whole fiber was patchy, with nuclei either expressing dystrophin or not (Figure 1E). This indicates that dystrophin proteins cannot freely diffuse along the muscle fiber and that nuclei where the normal DMD gene is not inactivated serve only certain regional domains in the muscle fiber
Summary
Duchenne Muscular Dystrophy (DMD) is an X-linked recessive disorder affecting 1:3500 new born boys. There is no cure for DMD, but many potential therapeutic compounds currently tested in clinical trials aim at restoration of (a BMD like) dystrophin [5,6,7,8,9,10,11,12] These trials at best resulted in the synthesis of low levels of dystrophin protein. It is not yet known how these levels will affect disease pathology, and which levels are needed to maintain muscle fiber integrity, to prevent against exercise-induced damage, or to improve muscle function. In perspective of further optimization of currently tested potential therapeutic compounds, detailed studies in this direction are necessary
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