Microtubules Underlie Dysfunction in Duchenne Muscular Dystrophy

作者：Ramzi J. Khairallah, Guoli Shi, Francesca Sbrana, Benjamin L. Prosser, Carlos Borroto, Mark J. Mazaitis, Eric P. Hoffman, Anup Mahurkar, Fredrick Sachs, Yezhou Sun, Yiwen Chen, Roberto Raiteri, W. Jonathan Lederer, Susan G. Dorsey, Christopher W. Ward · 发表于：Science Signaling · 年份：2012 · DOI：10.1126/scisignal.2002829 · 被引用次数：268 · 研究领域：Muscle Physiology and Disorders、Genetic Neurodegenerative Diseases、Mitochondrial Function and Pathology

Duchenne muscular dystrophy (DMD) is a fatal X-linked degenerative muscle disease caused by the absence of the microtubule-associated protein dystrophin, which results in a disorganized and denser microtubule cytoskeleton. In addition, mechanotransduction-dependent activation of calcium (Ca(2+)) and reactive oxygen species (ROS) signaling underpins muscle degeneration in DMD. We show that in muscle from adult mdx mice, a model of DMD, a brief physiologic stretch elicited microtubule-dependent activation of NADPH (reduced-form nicotinamide adenine dinucleotide phosphate) oxidase-dependent production of ROS, termed X-ROS. Further, X-ROS amplified Ca(2+) influx through stretch-activated channels in mdx muscle. Consistent with the importance of the microtubules to the dysfunction in mdx muscle, muscle cells with dense microtubule structure, such as those from adult mdx mice or from young wild-type mice treated with Taxol, showed increased X-ROS production and Ca(2+) influx, whereas cells with a less dense microtubule network, such as young mdx or adult mdx muscle treated with colchicine or nocodazole, showed little ROS production or Ca(2+) influx. In vivo treatments that disrupted the microtubule network or inhibited NADPH oxidase 2 reduced contraction-induced injury in adult mdx mice. Furthermore, transcriptome analysis identified increased expression of X-ROS-related genes in human DMD skeletal muscle. Together, these data show that microtubules are the proximate element respon...