Microtubules Underlie Dysfunction in Duchenne Muscular Dystrophy

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

Microtubules Underlie Dysfunction in Duchenne Muscular Dystrophy

  1. Ramzi J. Khairallah1,
  2. Guoli Shi2,
  3. Francesca Sbrana3,4,
  4. Benjamin L. Prosser1,
  5. Carlos Borroto2,
  6. Mark J. Mazaitis5,
  7. Eric P. Hoffman6,7,
  8. Anup Mahurkar5,
  9. Fredrick Sachs8,
  10. Yezhou Sun5,
  11. Yi-Wen Chen6,7,
  12. Roberto Raiteri3,
  13. W. Jonathan Lederer1,
  14. Susan G. Dorsey2,*, and
  15. Christopher W. Ward2,*
  1. 1Center for Biomedical Engineering and Technology and Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
  2. 2University of Maryland School of Nursing, Baltimore, MD 21201, USA.
  3. 3Department of Biophysical and Electronic Engineering, Università di Genova, Genova 12126, Italy.
  4. 4Biophysics Institute, National Research Council, Genova 16149, Italy.
  5. 5Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
  6. 6Research Center for Genetic Medicine, Children’s National Medical Center, George Washington University, Washington, DC 20010, USA.
  7. 7Department of Integrative Systems Biology, George Washington University, Washington, DC 20010, USA.
  8. 8Center for Single Molecule Studies, University of Buffalo and Tonus Therapeutics, Buffalo, NY 14260, USA.
  1. *To whom correspondence should be addressed. E-mail: ward{at}son.umaryland.edu (C.W.W.); sdorsey{at}son.umaryland.edu (S.G.D., regarding the transcriptome analysis).

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.

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, and C. W. Ward, Microtubules Underlie Dysfunction in Duchenne Muscular Dystrophy. Sci. Signal. 5, ra56 (2012).

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Science Signaling Podcast: 7 August 2012
C. W. Ward, R. J. Khairallah, E. P. Hoffman, and A. M. VanHook
Sci Signal 5, pc18-pc18 (7 August 2012)

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