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NADPH oxidase mediates microtubule alterations and diaphragm dysfunction in dystrophic mice

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Cite this article as: eLife 2018;7:e31732 doi: 10.7554/eLife.31732

Abstract

Skeletal muscle from mdx mice is characterized by increased Nox2 ROS, altered microtubule network, increased muscle stiffness, and decreased muscle/respiratory function. While microtubule de-tyrosination has been suggested to increase stiffness and Nox2 ROS production in isolated single myofibers, its role in altering tissue stiffness and muscle function has not been established. Because Nox2 ROS production is upregulated prior to microtubule network alterations and ROS affect microtubule formation, we investigated the role of Nox2 ROS in diaphragm tissue microtubule organization, stiffness and muscle/respiratory function. Eliminating Nox2 ROS prevents microtubule disorganization and reduces fibrosis and muscle stiffness in mdx diaphragm. Fibrosis accounts for the majority of variance in diaphragm stiffness and decreased function, implicating altered extracellular matrix and not microtubule de-tyrosination as a modulator of diaphragm tissue function. Ultimately, inhibiting Nox2 ROS production increased force and respiratory function in dystrophic diaphragm, establishing Nox2 as a potential therapeutic target in Duchenne muscular dystrophy.

Article and author information

Author details

  1. James Anthony Loehr

    Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Shang Wang

    Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9447-719X
  3. Tanya R Cully

    Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Rituraj Pal

    Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Irina V Larina

    Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Kirill V Larin

    Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. George G Rodney

    Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, United States
    For correspondence
    rodney@bcm.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6968-1516

Funding

National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR061370)

  • George G Rodney

National Heart, Lung, and Blood Institute (HL007676)

  • James Anthony Loehr

National Eye Institute (EY022362)

  • Kirill V Larin

American Heart Association (16POST30990070)

  • Shang Wang

Gillson Longenbaugh Foundation

  • George G Rodney

National Heart, Lung, and Blood Institute (HL120140)

  • Irina V Larina
  • Kirill V Larin

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#AN-5829) of Baylor College of Medicine.

Reviewing Editor

  1. Stanley C Froehner

Publication history

  1. Received: September 6, 2017
  2. Accepted: January 20, 2018
  3. Accepted Manuscript published: January 30, 2018 (version 1)
  4. Version of Record published: February 14, 2018 (version 2)

Copyright

© 2018, Loehr et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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