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 () and Christopher W. Ward ()
Additional contact information
Jaclyn P. Kerr: University of Maryland School of Medicine
Patrick Robison: Pennsylvania Muscle Institute, Perelman School of Medicine, University of Pennsylvania
Guoli Shi: University of Maryland School of Medicine
Alexey I. Bogush: Pennsylvania Muscle Institute, Perelman School of Medicine, University of Pennsylvania
Aaron M. Kempema: College of Pharmacy, University of Minnesota
Joseph K. Hexum: College of Pharmacy, University of Minnesota
Natalia Becerra: Bioengineering, Robotics and System Engineering, University of Genova
Daniel A. Harki: College of Pharmacy, University of Minnesota
Stuart S. Martin: Marlene and Stuart Greenebaum National Cancer Institute Cancer Center, University of Maryland School of Medicine
Roberto Raiteri: Bioengineering, Robotics and System Engineering, University of Genova
Benjamin L. Prosser: Pennsylvania Muscle Institute, Perelman School of Medicine, University of Pennsylvania
Christopher W. Ward: University of Maryland School of Medicine

Nature Communications, 2015, vol. 6, issue 1, 1-14

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms9526

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