Detyrosinated microtubules modulate mechanotransduction in heart and skeletal muscle

Nat Commun. 2015 Oct 8;6:8526. doi: 10.1038/ncomms9526.

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 Ca(2+) signalling in healthy muscle, but in diseases such as Duchenne muscular dystrophy (DMD), microtubule alterations drive elevated X-ROS, disrupting Ca(2+) 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 Ca(2+) 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomechanical Phenomena
  • Calcium
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred mdx
  • Microscopy, Atomic Force
  • Microtubules / physiology*
  • Muscle Fibers, Skeletal / physiology*
  • Myocytes, Cardiac / physiology*
  • Rats
  • Rats, Sprague-Dawley

Substances

  • Calcium