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

Abstract
Data availability
Article and author information
Metrics

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

(2020) NAD+ enhances ribitol and ribose rescue of α-dystroglycan functional glycosylation in human FKRP-mutant myotubes
Dryad Digital Repository, doi:10.5061/dryad.x3ffbg7hx.

http://dx.doi.org/10.5061/dryad.x3ffbg7hx

The following previously published data sets were used

1. Kuwabara
2. N.
(2020) Crystal structure of FKRP in complex with Ba ion, CDP-ribtol, and sugar acceptor
PDB, 6KAM.

https://www.rcsb.org/structure/6KAM

Article and author information

Author details

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.

"This ORCID iD identifies the author of this article:" 0000-0001-6953-0366
Alessandro Magli

Lillehei Heart Institute, University of Minnesota, Minneapolis, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-3874-2838
Neha Dhoke

Lillehei Heart Institute, Department of Medicine, University of Minnesota, Minneapolis, United States

Competing interests
The authors declare that no competing interests exist.
Taylor Kuebler

Bioinformatics and Computational Biology Program, University of Minnesota, Minneapolis, United States

Competing interests
The authors declare that no competing interests exist.
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.
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.
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.
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.
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.

"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.

Copyright

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.