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

Detyrosinated microtubules modulate mechanotransduction in heart and skeletal muscle.

Author information

1
Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
2
Department of Physiology, Pennsylvania Muscle Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
3
Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota 55455, USA.
4
Department of Informatics, Bioengineering, Robotics and System Engineering, University of Genova, Genova 16146, Italy.
5
Marlene and Stuart Greenebaum National Cancer Institute Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
6
Center for Biomedical Engineering and Technology (BioMET), University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.

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.

PMID:
26446751
PMCID:
PMC4633818
DOI:
10.1038/ncomms9526
[Indexed for MEDLINE]
Free PMC Article

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