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

82 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

Bibliographical note

Funding Information:
Support was provided by the NIH (R01-AR062554 to CWW; R00 HL114879 to BLP; T32-AR07592 to J.P.K.; T32-AR053461 to PR), Hyundai Hope on Wheels (Hope Grant award to D.A.H.) and The V Foundation for Cancer Research (V Scholar award to D.A.H.). We thank Brunella Tedesco for her assistance with the AFM measurements. Assistance with the instrumentation and reagents for the myofibre stretch studies was kindly provided by IonOptix LLC and Aurora Scientific Inc. We thank E. Michael Ostap for careful review of the manuscript.

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