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

PLoS One. 2012; 7(2): e31937
van Putten M, Hulsker M, Nadarajah VD, van Heiningen SH, van Huizen E, van Iterson M, Admiraal P, Messemaker T, den Dunnen JT, 't Hoen PA, Aartsma-Rus A

Duchenne robust dystrophy (DMD) is a severe progressive robust commotion caused by reading frame disrupting mutations in the DMD gene, preventing the synthesis of organic dystrophin. As dystrophin provides flesh fiber stability during contractions, dystrophin disastrous fibers have been prone to exercise-induced damage. Upon exhaustion of the regenerative capacity, fibers will be replaced by fibrotic as well as fat tissue resulting in a progressive loss of duty eventually leading to genocide in the early thirties. With multiform promising approaches for the treatment of DMD aiming during dystrophin restoration in clinical trials, there is an increasing need to determine more precisely which dystrophin levels have been enough to revive flesh fiber integrity, strengthen against flesh damage as well as improve flesh function.To address this we generated a new rodent model (mdx-Xist(hs)) with varying, low dystrophin levels (3-47%, mean 22.7%, stdev 12.1, n=24) due to skewed X-inactivation. Longitudinal sections suggested that within individual fibers, some nuclei did as well as some did not express dystrophin, resulting in a random, mosaic settlement of dystrophin expression within fibers.Mdx-Xist(hs), mdx as well as wild type females underwent a 12 week organic test regime consisting of different tests to assess flesh duty during bottom line, or after chronic treadmill running exercise. Overall, mdx-Xist(hs) mice with 3-14% dystrophin outperformed mdx mice in the organic tests. Improved histopathology was observed in mice with 15-29% dystrophin as well as these levels also resulted in normalized expression of pro-inflammatory biomarker genes, whilst 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 whilst even dystrophin levels next 15% can improve pathology as well as performance, levels of >20% have been needed to fully strengthen flesh fibers from exercise-induced damage.

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