Sci. Signal., 7 August 2012
Microtubules and Muscle DysfunctionDuchenne muscular dystrophy (DMD) is an inherited, progressive, and eventually fatal degenerative muscle disorder that is caused by the absence of the microtubule-associated protein dystrophin. Increased Ca2+ influx and enhanced production of reactive oxygen species (ROS) are detected in DMD muscle, although it is not known how these cellular events are connected to the microtubule network and the pathology of DMD. Khairallah et al. used mice that are a model for DMD (mdx mice). They found that a modest stretch of adult mdx muscle, but not of wild-type or young mdx muscle, stimulated the production of ROS by NADPH oxidase 2 (NOX2) through the dense microtubule network as the mechanotransduction element. This pathway, known as X-ROS, triggered Ca2+ influx through stretch-activated channels. Ca2+ influx, X-ROS production, and contraction-induced muscle injury were decreased in adult mdx muscle by treatments that reduced the density of the microtubule network or that inhibited NOX2. X-ROS production was increased in young mdx muscle by treatments that increased microtubule density. Transcriptome analysis revealed increased expression of X-ROS–related genes in human DMD skeletal muscle, suggesting that drugs that reduce microtubule density or block the activity of NOX2 could slow the progression of DMD.
Citation: R. J. Khairallah, G. Shi, F. Sbrana, B. L. Prosser, C. Borroto, M. J. Mazaitis, E. P. Hoffman, A. Mahurkar, F. Sachs, Y. Sun, Y.-W. Chen, R. Raiteri, W. J. Lederer, S. G. Dorsey, C. W. Ward, Microtubules Underlie Dysfunction in Duchenne Muscular Dystrophy. Sci. Signal. 5, ra56 (2012).
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