title: Detyrosinated microtubules modulate mechanotransduction in heart and skeletal muscle.
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.
authors.affiliation: Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
authors.forename: Jaclyn P
authors.initials: JP
authors.lastname: Kerr
authors.affiliation: Department of Physiology, Pennsylvania Muscle Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Robison
authors.affiliation: Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
authors.forename: Guoli
authors.initials: G
authors.lastname: Shi
authors.affiliation: Department of Physiology, Pennsylvania Muscle Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Alexey I
authors.initials: AI
authors.lastname: Bogush
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Kempema
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: Joseph K
authors.initials: JK
authors.lastname: Hexum
authors.affiliation: Department of Informatics, Bioengineering, Robotics and System Engineering, University of Genova, Genova 16146, Italy.
authors.forename: Natalia
authors.initials: N
authors.lastname: Becerra
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Harki
authors.affiliation: Marlene and Stuart Greenebaum National Cancer Institute Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
authors.forename: Stuart S
authors.initials: SS
authors.lastname: Martin
authors.affiliation: Department of Informatics, Bioengineering, Robotics and System Engineering, University of Genova, Genova 16146, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Raiteri
authors.affiliation: Department of Physiology, Pennsylvania Muscle Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Prosser
authors.affiliation: Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.|Center for Biomedical Engineering and Technology (BioMET), University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Ward
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D002118:Calcium; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D018625:Microscopy, Atomic Force; D008870:Microtubules / Q000502:physiology*; D018485:Muscle Fibers, Skeletal / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002118:Calcium