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Detyrosinated microtubules modulate mechanotransduction in heart and skeletal muscle

Author

Listed:
  • 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
    Center for Biomedical Engineering and Technology (BioMET), University of Maryland School of Medicine)

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.

Suggested Citation

  • 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 & Ch, 2015. "Detyrosinated microtubules modulate mechanotransduction in heart and skeletal muscle," Nature Communications, Nature, vol. 6(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9526
    DOI: 10.1038/ncomms9526
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    Cited by:

    1. Caroline Dour & Maria Chatzifrangkeskou & Coline Macquart & Maria M. Magiera & Cécile Peccate & Charlène Jouve & Laura Virtanen & Tiina Heliö & Katriina Aalto-Setälä & Silvia Crasto & Bruno Cadot & Dé, 2022. "Actin-microtubule cytoskeletal interplay mediated by MRTF-A/SRF signaling promotes dilated cardiomyopathy caused by LMNA mutations," Nature Communications, Nature, vol. 13(1), pages 1-21, December.
    2. Takema Sasaki & Kei Saito & Daisuke Inoue & Henrik Serk & Yuki Sugiyama & Edouard Pesquet & Yuta Shimamoto & Yoshihisa Oda, 2023. "Confined-microtubule assembly shapes three-dimensional cell wall structures in xylem vessels," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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