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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 \u03b1-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.<\/jats:p>","DOI":"10.7554\/elife.65443","type":"journal-article","created":{"date-parts":[[2021,1,29]],"date-time":"2021-01-29T12:00:50Z","timestamp":1611921650000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.65443","source":"Crossref","is-referenced-by-count":15,"title":["NAD+ enhances ribitol and ribose rescue of \u03b1-dystroglycan functional glycosylation in human FKRP-mutant myotubes"],"prefix":"10.7554","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6953-0366","authenticated-orcid":true,"given":"Carolina","family":"Ortiz-Cordero","sequence":"first","affiliation":[{"name":"Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, United States"},{"name":"Lillehei Heart Institute, Department of Medicine, University of Minnesota, Minneapolis, United States"},{"name":"Stem Cell 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