N-terminal domain on dystroglycan enables LARGE1 to extend matriglycan on α-dystroglycan and prevents muscular dystrophy

  1. Hidehiko Okuma
  2. Jeffrey M Hord
  3. Ishita Chandel
  4. David Venzke
  5. Mary E Anderson
  6. Ameya S Walimbe
  7. Soumya Joseph
  8. Zeita Gastel
  9. Yuji Hara
  10. Fumiaki Saito
  11. Kiichiro Matsumura
  12. Kevin P Campbell  Is a corresponding author
  1. Howard Hughes Medical Institute, University of Iowa, United States
  2. University of Shizuoka, Japan
  3. Teikyo University, Japan

Abstract

Dystroglycan (DG) requires extensive post-translational processing and O-glycosylation to function as a receptor for extracellular matrix (ECM) proteins containing laminin-G-like (LG) domains. Matriglycan is an elongated polysaccharide of alternating xylose (Xyl) and glucuronic acid (GlcA) that binds with high-affinity to ECM proteins with LG-domains and is uniquely synthesized on α-dystroglycan (α-DG) by like-acetylglucosaminyltransferase-1 (LARGE1). Defects in the post-translational processing or O-glycosylation of α-DG that result in a shorter form of matriglycan reduce the size of α-DG and decrease laminin binding, leading to various forms of muscular dystrophy. Previously, we demonstrated that Protein O-Mannose Kinase (POMK) is required for LARGE1 to generate full-length matriglycan on α-DG (~150-250 kDa) (Walimbe et al., 2020). Here, we show that LARGE1 can only synthesize a short, non-elongated form of matriglycan in mouse skeletal muscle that lacks the DG N-terminus (α-DGN), resulting in a ~100-125 kDa α-DG. This smaller form of α-DG binds laminin and maintains specific force but does not prevent muscle pathophysiology, including reduced force production after eccentric contractions or abnormalities in the neuromuscular junctions. Collectively, our study demonstrates that α-DGN, like POMK, is required for LARGE1 to extend matriglycan to its full mature length on α-DG and thus prevent muscle pathophysiology.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided for Figures 2C, 5C, 6B, 7B, Figure 2-figure supplement 1, Figure 2-figure supplement 2, Figure 5-figure supplement 1B, and Figure 6-figure supplement 1.

Article and author information

Author details

  1. Hidehiko Okuma

    Department of Molecular Physiology and Biophysics, Howard Hughes Medical Institute, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2749-9855
  2. Jeffrey M Hord

    Department of Molecular Physiology and Biophysics, Howard Hughes Medical Institute, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Ishita Chandel

    Department of Molecular Physiology and Biophysics, Howard Hughes Medical Institute, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. David Venzke

    Department of Department of Molecular Physiology and BiophysicsPhysiology and Biophysics, Howard Hughes Medical Institute, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8180-9562
  5. Mary E Anderson

    Department of Molecular Physiology and Biophysics, Howard Hughes Medical Institute, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Ameya S Walimbe

    Department of Molecular Physiology and Biophysics, Howard Hughes Medical Institute, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Soumya Joseph

    Department of Molecular Physiology and Biophysics, Howard Hughes Medical Institute, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Zeita Gastel

    Department of Molecular Physiology and Biophysics, Howard Hughes Medical Institute, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Yuji Hara

    Department Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
    Competing interests
    The authors declare that no competing interests exist.
  10. Fumiaki Saito

    Department of Neurology, Teikyo University, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  11. Kiichiro Matsumura

    Department of Neurology, Teikyo University, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  12. Kevin P Campbell

    Department of Molecular Physiology and Biophysics, Howard Hughes Medical Institute, University of Iowa, Iowa City, United States
    For correspondence
    kevin-campbell@uiowa.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2066-5889

Funding

Paul D. Wellstone Muscular Dystrophy Specialized Research Center (1U54NS053672)

  • Kevin P Campbell

Howard Hughes Medical Institute

  • Kevin P Campbell

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

Reviewing Editor

  1. Joseph G Gleeson, University of California, San Diego, United States

Ethics

Animal experimentation: 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 animal experiments were approved by the Institutional Animal Care and Use Committee (IACUC) protocols of the University of Iowa (#0081122).

Version history

  1. Preprint posted: August 9, 2022 (view preprint)
  2. Received: August 25, 2022
  3. Accepted: January 31, 2023
  4. Accepted Manuscript published: February 1, 2023 (version 1)
  5. Version of Record published: February 10, 2023 (version 2)

Copyright

© 2023, Okuma 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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  1. Hidehiko Okuma
  2. Jeffrey M Hord
  3. Ishita Chandel
  4. David Venzke
  5. Mary E Anderson
  6. Ameya S Walimbe
  7. Soumya Joseph
  8. Zeita Gastel
  9. Yuji Hara
  10. Fumiaki Saito
  11. Kiichiro Matsumura
  12. Kevin P Campbell
(2023)
N-terminal domain on dystroglycan enables LARGE1 to extend matriglycan on α-dystroglycan and prevents muscular dystrophy
eLife 12:e82811.
https://doi.org/10.7554/eLife.82811

Share this article

https://doi.org/10.7554/eLife.82811

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