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Sci. Signal., 7 August 2012
Vol. 5, Issue 236, p. ra56
[DOI: 10.1126/scisignal.2002829]


Microtubules Underlie Dysfunction in Duchenne Muscular Dystrophy

Ramzi J. Khairallah1, Guoli Shi2, Francesca Sbrana3,4, Benjamin L. Prosser1, Carlos Borroto2, Mark J. Mazaitis5, Eric P. Hoffman6,7, Anup Mahurkar5, Fredrick Sachs8, Yezhou Sun5, Yi-Wen Chen6,7, Roberto Raiteri3, W. Jonathan Lederer1, Susan G. Dorsey2*, and Christopher W. Ward2*

1 Center for Biomedical Engineering and Technology and Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
2 University of Maryland School of Nursing, Baltimore, MD 21201, USA.
3 Department of Biophysical and Electronic Engineering, Università di Genova, Genova 12126, Italy.
4 Biophysics Institute, National Research Council, Genova 16149, Italy.
5 Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
6 Research Center for Genetic Medicine, Children’s National Medical Center, George Washington University, Washington, DC 20010, USA.
7 Department of Integrative Systems Biology, George Washington University, Washington, DC 20010, USA.
8 Center for Single Molecule Studies, University of Buffalo and Tonus Therapeutics, Buffalo, NY 14260, USA.

Abstract: 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 (Ca2+) 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 Ca2+ 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 Ca2+ 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 Ca2+ 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 responsible for the dysfunction in Ca2+ and ROS signaling in DMD and could be effective therapeutic targets for intervention.

* To whom correspondence should be addressed. E-mail: ward{at} (C.W.W.); sdorsey{at} (S.G.D., regarding the transcriptome analysis).

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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