Detyrosinated microtubules modulate mechanotransduction in heart and skeletal muscle

Jaclyn P. Kerr, Patrick Robison, Guoli Shi, Alexey I. Bogush, Aaron M. Kempema, Joseph K. Hexum, Natalia Becerra, Daniel A. Harki, Stuart S. Martin, Roberto Raiteri, Benjamin L. Prosser, Christopher W. Ward

Research output: Contribution to journalArticlepeer-review

161 Scopus citations

Abstract

In striated muscle, X-ROS is the mechanotransduction pathway by which mechanical stress transduced by the microtubule network elicits reactive oxygen species. X-ROS tunes Ca2+ signalling in healthy muscle, but in diseases such as Duchenne muscular dystrophy (DMD), microtubule alterations drive elevated X-ROS, disrupting Ca2+ homeostasis and impairing function. Here we show that detyrosination, a post-translational modification of α-tubulin, influences X-ROS signalling, contraction speed and cytoskeletal mechanics. In the mdx mouse model of DMD, the pharmacological reduction of detyrosination in vitro ablates aberrant X-ROS and Ca2+ signalling, and in vivo it protects against hallmarks of DMD, including workload-induced arrhythmias and contraction-induced injury in skeletal muscle. We conclude that detyrosinated microtubules increase cytoskeletal stiffness and mechanotransduction in striated muscle and that targeting this post-translational modification may have broad therapeutic potential in muscular dystrophies.

Original languageEnglish (US)
Article number8526
JournalNature communications
Volume6
DOIs
StatePublished - Oct 8 2015

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© 2015 Macmillan Publishers Limited. All rights reserved.

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