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

Carolina Ortiz Cordero; Alessandro Magli; Neha Dhoke; Taylor Kuebler; Nelio A.J. Oliveira; Haowen Zhou; Yuk Y. Sham; Anne G. Bang; Rita C.R. Perlingeiro

doi:10.7554/eLife.65443

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

Carolina Ortiz Cordero, Alessandro Magli, Neha Dhoke, Taylor Kuebler, Nelio A.J. Oliveira, Haowen Zhou, Yuk Y. Sham, Anne G. Bang, Rita C.R. Perlingeiro

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

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 by 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 found that FKRP residual enzymatic capacity, characteristic of many recessive FKRP mutations, is required for rescue as supported by functional and structural mutational analyses. These findings provide the rationale for testing ribose/ribitol in combination with NAD+ to treat WWS and other diseases associated with FKRP mutations.

Original language	English (US)
Article number	e65443
Pages (from-to)	1-50
Number of pages	50
Journal	eLife
Volume	10
DOIs	https://doi.org/10.7554/eLife.65443
State	Published - Jan 2021

Bibliographical note

Funding Information:
This project was supported by NIH grants R01 AR071439 and AR055299 (R.C.R.P.), the LGMD2I Research Funds (R.C.R.P. and A.G.B.). C.O.C. was supported by PINN MICITT Costa Rica. We are grateful to Jiri Vajsar for providing the WWS patient sample. We thank Lila Habib and James Kiley for their contribution in the generation of FP4 iPS cells and myogenic progenitors, respectively. The monoclonal antibody to MHC and the IIH6 antibody were obtained from the Developmental Studies Hybridoma Bank developed under the auspices of the NICHD and maintained by the University of Iowa. We are thankful to Cynthia Faraday for graphical design.

Funding Information:
This project was supported by NIH grants R01 AR071439 and AR055299 (R.C.R.P.), the

Publisher Copyright:
© 2021, eLife Sciences Publications Ltd. All rights reserved.

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@article{29b95969b0c144659a46f23708b212eb,

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

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 by 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 found that FKRP residual enzymatic capacity, characteristic of many recessive FKRP mutations, is required for rescue as supported by functional and structural mutational analyses. These findings provide the rationale for testing ribose/ribitol in combination with NAD+ to treat WWS and other diseases associated with FKRP mutations.",

author = "{Ortiz Cordero}, Carolina and Alessandro Magli and Neha Dhoke and Taylor Kuebler and Oliveira, {Nelio A.J.} and Haowen Zhou and Sham, {Yuk Y.} and Bang, {Anne G.} and Perlingeiro, {Rita C.R.}",

note = "Funding Information: This project was supported by NIH grants R01 AR071439 and AR055299 (R.C.R.P.), the LGMD2I Research Funds (R.C.R.P. and A.G.B.). C.O.C. was supported by PINN MICITT Costa Rica. We are grateful to Jiri Vajsar for providing the WWS patient sample. We thank Lila Habib and James Kiley for their contribution in the generation of FP4 iPS cells and myogenic progenitors, respectively. The monoclonal antibody to MHC and the IIH6 antibody were obtained from the Developmental Studies Hybridoma Bank developed under the auspices of the NICHD and maintained by the University of Iowa. We are thankful to Cynthia Faraday for graphical design. Funding Information: This project was supported by NIH grants R01 AR071439 and AR055299 (R.C.R.P.), the Publisher Copyright: {\textcopyright} 2021, eLife Sciences Publications Ltd. All rights reserved.",

year = "2021",

month = jan,

doi = "10.7554/eLife.65443",

language = "English (US)",

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AU - Ortiz Cordero, Carolina

AU - Magli, Alessandro

AU - Dhoke, Neha

AU - Kuebler, Taylor

AU - Oliveira, Nelio A.J.

AU - Zhou, Haowen

AU - Sham, Yuk Y.

AU - Bang, Anne G.

AU - Perlingeiro, Rita C.R.

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N2 - 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 by 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 found that FKRP residual enzymatic capacity, characteristic of many recessive FKRP mutations, is required for rescue as supported by functional and structural mutational analyses. These findings provide the rationale for testing ribose/ribitol in combination with NAD+ to treat WWS and other diseases associated with FKRP mutations.

AB - 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 by 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 found that FKRP residual enzymatic capacity, characteristic of many recessive FKRP mutations, is required for rescue as supported by functional and structural mutational analyses. These findings provide the rationale for testing ribose/ribitol in combination with NAD+ to treat WWS and other diseases associated with FKRP mutations.

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

Abstract

Bibliographical note

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