the effects of low levels of dystrophin on mouse muscle function and pathology的影响,低水平的抗肌萎缩蛋白在小鼠肌肉功能和病理.pdf

The Effects of Low Levels of Dystrophin on Mouse Muscle Function and Pathology Maaike van Putten, Margriet Hulsker, Vishna Devi Nadarajah, Sandra H. van Heiningen, Ella van Huizen, Maarten van Iterson, Peter Admiraal, Tobias Messemaker, Johan T. den Dunnen, Peter A. C. ’t Hoen, Annemieke Aartsma-Rus* Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands 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-XistDhs) 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-XistDhs, 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-XistDhs mice with 3–14%