NAD+ enhances ribitol and ribose rescue of α-dystroglycan functional glycosylation in human FKRP-mutant myotubes

  1. Carolina Ortiz Cordero
  2. Alessandro Magli
  3. Neha Dhoke
  4. Taylor Kuebler
  5. Nelio AJ Oliveira
  6. Haowen Zhou
  7. Yuk Y Sham
  8. Anne G Bang
  9. Rita CR Perlingeiro  Is a corresponding author
  1. University of Minnesota, United States
  2. Sanford Burnham Prebys Medical Discovery Institute, United States

Abstract

Mutations in the fukutin-related protein (FKRP) cause Walker-Warburg Syndrome (WWS), a severe form of congenital muscular dystrophy. Here we established a WWS human induced pluripotent stem cell-derived myogenic model that recapitulates hallmarks of WWS pathology. We used this model to investigate the therapeutic effect of metabolites of the pentose phosphate pathway in human WWS. We show that functional recovery of WWS myotubes is promoted not only by ribitol but also its precursor ribose. Moreover, we found that the combination of each of these metabolites with NAD+ results in a synergistic effect, as demonstrated by rescue of α-dystroglycan glycosylation and laminin binding capacity. Mechanistically, we find that FKRP residual enzymatic capacity, characteristic of many recessive FKRP mutations, is required for rescue as supported by functional and structural mutational analysis. These findings provide the rationale for testing ribose/ribitol in combination with NAD+ to treat WWS and other diseases associated with FKRP mutations.

Data availability

Complete Images for blots and analyzed data is available at Dryad, Dataset, (https://doi.org/10.5061/dryad.x3ffbg7hx).

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Carolina Ortiz Cordero

    Department of Integrative Biology and Physiology and Lillehei Heart Institute, Department of Medicine, University of Minnesota, Minneapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6953-0366
  2. Alessandro Magli

    Lillehei Heart Institute, University of Minnesota, Minneapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3874-2838
  3. Neha Dhoke

    Lillehei Heart Institute, Department of Medicine, University of Minnesota, Minneapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Taylor Kuebler

    Bioinformatics and Computational Biology Program, University of Minnesota, Minneapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Nelio AJ Oliveira

    Lillehei Heart Institute, Department of Medicine, University of Minnesota, Minneapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Haowen Zhou

    Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Yuk Y Sham

    Department of Integrative Biology and Bioinformatics and Computational Biology Program, University of Minnesota, Minneapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Anne G Bang

    Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Rita CR Perlingeiro

    Lillehei Heart Institute, Department of Medicine, University of Minnesota, Minneapolis, United States
    For correspondence
    perli032@umn.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9412-1118

Funding

National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR055299)

  • Rita CR Perlingeiro

National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR071439)

  • Rita CR Perlingeiro

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

Ethics

Animal experimentation: Animal experiments were carried out according to protocols (protocol ID: 2002-37833A) approved by the University of Minnesota Institutional Animal Care and Use Committee.

Reviewing Editor

  1. Christopher Cardozo

Publication history

  1. Received: December 4, 2020
  2. Accepted: January 28, 2021
  3. Accepted Manuscript published: January 29, 2021 (version 1)
  4. Version of Record published: March 2, 2021 (version 2)

Copyright

© 2021, Ortiz Cordero 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. Carolina Ortiz Cordero
  2. Alessandro Magli
  3. Neha Dhoke
  4. Taylor Kuebler
  5. Nelio AJ Oliveira
  6. Haowen Zhou
  7. Yuk Y Sham
  8. Anne G Bang
  9. Rita CR Perlingeiro
(2021)
NAD+ enhances ribitol and ribose rescue of α-dystroglycan functional glycosylation in human FKRP-mutant myotubes
eLife 10:e65443.
https://doi.org/10.7554/eLife.65443

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