Ribitol Dose-dependently Enhances Matriglycan Expression and Improves Muscle Function with Prolonged Life Span in Limb Girdle Muscular Dystrophy 2I Mouse Model

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2022 Dec 1

PMID 36454905

Authors

Bo Wu

Morgan Drains

Sapana N Shah

Pei Juan Lu

Victoria Leroy

Jessalyn Killilee

Raegan Rawls

Jason D Tucker

Anthony Blaeser

Qi Long Lu

Affiliations

Soon will be listed here.

Abstract

Limb Girdle Muscular Dystrophy 2I (LGMDR9) is one of the most common LGMD characterized by defects in glycosylation of α-dystroglycan (matriglycan) resulting from mutations of Fukutin-related protein (FKRP). There is no effective therapy currently available. We recently demonstrated that ribitol supplement increases levels of matriglycan in cells in vitro and in FKRP-P448L (P448L) mutant mouse model through drinking water administration. To be clinically relevant, we have now conducted a dose-escalating efficacy study by gavage in P448L mutant mice. Six months of ribitol treatment daily significantly rescued functions of skeletal, respiratory, and cardiac muscles dose-dependently. This was associated with a dose dependent increase in matriglycan and improvement in muscle pathology with reductions in muscle degeneration, inflammatory infiltration and fibrosis. Importantly, ribitol significantly increased life span and muscle functions of the female animals receiving treatment from 10 months of age. The only observed side effect was gastrointestinal tract bloating with loose stool and this effect is also dose dependent. The results validate the mechanism that ribitol as a pre-substrate of glycosyltransferase is able to compensate for the decreased function of mutant FKRP with restoration of matriglycan expression and provide a guidance for future clinical trial design.

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References

Blaeser A, Awano H, Wu B, Lu Q . Progressive Dystrophic Pathology in Diaphragm and Impairment of Cardiac Function in FKRP P448L Mutant Mice. PLoS One. 2016; 11(10):e0164187. PMC: 5053477. DOI: 10.1371/journal.pone.0164187. View

Tucker J, Lu P, Xiao X, Lu Q . Overexpression of Mutant FKRP Restores Functional Glycosylation and Improves Dystrophic Phenotype in FKRP Mutant Mice. Mol Ther Nucleic Acids. 2018; 11:216-227. PMC: 5992437. DOI: 10.1016/j.omtn.2018.02.008. View

Kanagawa M, Toda T . The genetic and molecular basis of muscular dystrophy: roles of cell-matrix linkage in the pathogenesis. J Hum Genet. 2006; 51(11):915-926. DOI: 10.1007/s10038-006-0056-7. View

Praissman J, Willer T, Sheikh M, Toi A, Chitayat D, Lin Y . The functional O-mannose glycan on α-dystroglycan contains a phospho-ribitol primed for matriglycan addition. Elife. 2016; 5. PMC: 4924997. DOI: 10.7554/eLife.14473. View

Blaeser A, Keramaris E, Chan Y, Sparks S, Cowley D, Xiao X . Mouse models of fukutin-related protein mutations show a wide range of disease phenotypes. Hum Genet. 2013; 132(8):923-34. DOI: 10.1007/s00439-013-1302-7. View

Hinderer C, Katz N, Buza E, Dyer C, Goode T, Bell P . Severe Toxicity in Nonhuman Primates and Piglets Following High-Dose Intravenous Administration of an Adeno-Associated Virus Vector Expressing Human SMN. Hum Gene Ther. 2018; 29(3):285-298. PMC: 5865262. DOI: 10.1089/hum.2018.015. View

Awano H, Blaeser A, Keramaris E, Xu L, Tucker J, Wu B . Restoration of Functional Glycosylation of α-Dystroglycan in FKRP Mutant Mice Is Associated with Muscle Regeneration. Am J Pathol. 2015; 185(7):2025-37. DOI: 10.1016/j.ajpath.2015.03.017. View

Brown S, Torelli S, Brockington M, Yuva Y, Jimenez C, Feng L . Abnormalities in alpha-dystroglycan expression in MDC1C and LGMD2I muscular dystrophies. Am J Pathol. 2004; 164(2):727-37. PMC: 1602276. DOI: 10.1016/s0002-9440(10)63160-4. View

Schmid R, Hovda L . Acute Hepatic Failure in a Dog after Xylitol Ingestion. J Med Toxicol. 2015; 12(2):201-5. PMC: 4880608. DOI: 10.1007/s13181-015-0531-7. View

10.

Vannoy C, Xiao W, Lu P, Xiao X, Lu Q . Efficacy of Gene Therapy Is Dependent on Disease Progression in Dystrophic Mice with Mutations in the FKRP Gene. Mol Ther Methods Clin Dev. 2017; 5:31-42. PMC: 5415313. DOI: 10.1016/j.omtm.2017.02.002. View

11.

Gee S, Montanaro F, Lindenbaum M, Carbonetto S . Dystroglycan-alpha, a dystrophin-associated glycoprotein, is a functional agrin receptor. Cell. 1994; 77(5):675-86. DOI: 10.1016/0092-8674(94)90052-3. View

12.

Brockington M, Blake D, Prandini P, Brown S, Torelli S, Benson M . Mutations in the fukutin-related protein gene (FKRP) cause a form of congenital muscular dystrophy with secondary laminin alpha2 deficiency and abnormal glycosylation of alpha-dystroglycan. Am J Hum Genet. 2001; 69(6):1198-209. PMC: 1235559. DOI: 10.1086/324412. View

13.

Cataldi M, Blaeser A, Lu P, Leroy V, Lu Q . ISPD Overexpression Enhances Ribitol-Induced Glycosylation of α-Dystroglycan in Dystrophic FKRP Mutant Mice. Mol Ther Methods Clin Dev. 2020; 17:271-280. PMC: 6970132. DOI: 10.1016/j.omtm.2019.12.005. View

14.

Ervasti J, Campbell K . Membrane organization of the dystrophin-glycoprotein complex. Cell. 1991; 66(6):1121-31. DOI: 10.1016/0092-8674(91)90035-w. View

15.

Keramaris E, Lu P, Tucker J, Lu Q . Expression of glycosylated α-dystroglycan in newborn skeletal and cardiac muscles of fukutin related protein (FKRP) mutant mice. Muscle Nerve. 2016; 55(4):582-590. DOI: 10.1002/mus.25378. View

16.

Sugita S, Saito F, Tang J, Satz J, Campbell K, Sudhof T . A stoichiometric complex of neurexins and dystroglycan in brain. J Cell Biol. 2001; 154(2):435-45. PMC: 2150755. DOI: 10.1083/jcb.200105003. View

17.

Talts J, Andac Z, Gohring W, Brancaccio A, Timpl R . Binding of the G domains of laminin alpha1 and alpha2 chains and perlecan to heparin, sulfatides, alpha-dystroglycan and several extracellular matrix proteins. EMBO J. 1999; 18(4):863-70. PMC: 1171179. DOI: 10.1093/emboj/18.4.863. View

18.

Chan Y, Keramaris-Vrantsis E, Lidov H, Norton J, Zinchenko N, Gruber H . Fukutin-related protein is essential for mouse muscle, brain and eye development and mutation recapitulates the wide clinical spectrums of dystroglycanopathies. Hum Mol Genet. 2010; 19(20):3995-4006. DOI: 10.1093/hmg/ddq314. View

19.

Palmieri A, Manara R, Bello L, Mento G, Lazzarini L, Borsato C . Cognitive profile and MRI findings in limb-girdle muscular dystrophy 2I. J Neurol. 2011; 258(7):1312-20. DOI: 10.1007/s00415-011-5930-3. View

20.

Beltran-Valero de Bernabe D, Voit T, Longman C, Steinbrecher A, Straub V, Yuva Y . Mutations in the FKRP gene can cause muscle-eye-brain disease and Walker-Warburg syndrome. J Med Genet. 2004; 41(5):e61. PMC: 1735772. DOI: 10.1136/jmg.2003.013870. View