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Correction of glycogen storage disease type III with rapamycin in a canine model.

Publication ,  Journal Article
Yi, H; Brooks, ED; Thurberg, BL; Fyfe, JC; Kishnani, PS; Sun, B
Published in: J Mol Med (Berl)
June 2014

UNLABELLED: Recently, we reported that progression of liver fibrosis and skeletal myopathy caused by extensive accumulation of cytoplasmic glycogen at advanced age is the major feature of a canine model of glycogen storage disease (GSD) IIIa. Here, we aim to investigate whether rapamycin, a specific inhibitor of mTOR, is an effective therapy for GSD III. Our data show that rapamycin significantly reduced glycogen content in primary muscle cells from human patients with GSD IIIa by suppressing the expression of glycogen synthase and glucose transporter 1. To test the treatment efficacy in vivo, rapamycin was daily administered to GSD IIIa dogs starting from age 2 (early-treatment group) or 8 months (late-treatment group), and liver and skeletal muscle biopsies were performed at age 12 and 16 months. In both treatment groups, muscle glycogen accumulation was not affected at age 12 months but significantly inhibited at 16 months. Liver glycogen content was reduced in the early-treatment group but not in the late-treatment group at age 12 months. Both treatments effectively reduced liver fibrosis at age 16 months, consistent with markedly inhibited transition of hepatic stellate cells into myofibroblasts, the central event in the process of liver fibrosis. Our results suggest a potential useful therapy for GSD III. KEY MESSAGES: Rapamycin inhibited glycogen accumulation in GSD IIIa patient muscle cells. Rapamycin reduced muscle glycogen content in GSD IIIa dogs at advanced age. Rapamycin effectively prevented progression of liver fibrosis in GSD IIIa dogs. Our results suggest rapamycin as potential useful therapy for patients with GSD III.

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Published In

J Mol Med (Berl)

DOI

EISSN

1432-1440

Publication Date

June 2014

Volume

92

Issue

6

Start / End Page

641 / 650

Location

Germany

Related Subject Headings

  • Sirolimus
  • Liver Cirrhosis
  • Immunology
  • Glycogen Storage Disease Type III
  • Glycogen
  • Dogs
  • Animals
  • 3404 Medicinal and biomolecular chemistry
  • 0304 Medicinal and Biomolecular Chemistry
 

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Yi, H., Brooks, E. D., Thurberg, B. L., Fyfe, J. C., Kishnani, P. S., & Sun, B. (2014). Correction of glycogen storage disease type III with rapamycin in a canine model. J Mol Med (Berl), 92(6), 641–650. https://doi.org/10.1007/s00109-014-1127-4
Yi, Haiqing, Elizabeth D. Brooks, Beth L. Thurberg, John C. Fyfe, Priya S. Kishnani, and Baodong Sun. “Correction of glycogen storage disease type III with rapamycin in a canine model.J Mol Med (Berl) 92, no. 6 (June 2014): 641–50. https://doi.org/10.1007/s00109-014-1127-4.
Yi H, Brooks ED, Thurberg BL, Fyfe JC, Kishnani PS, Sun B. Correction of glycogen storage disease type III with rapamycin in a canine model. J Mol Med (Berl). 2014 Jun;92(6):641–50.
Yi, Haiqing, et al. “Correction of glycogen storage disease type III with rapamycin in a canine model.J Mol Med (Berl), vol. 92, no. 6, June 2014, pp. 641–50. Pubmed, doi:10.1007/s00109-014-1127-4.
Yi H, Brooks ED, Thurberg BL, Fyfe JC, Kishnani PS, Sun B. Correction of glycogen storage disease type III with rapamycin in a canine model. J Mol Med (Berl). 2014 Jun;92(6):641–650.
Journal cover image

Published In

J Mol Med (Berl)

DOI

EISSN

1432-1440

Publication Date

June 2014

Volume

92

Issue

6

Start / End Page

641 / 650

Location

Germany

Related Subject Headings

  • Sirolimus
  • Liver Cirrhosis
  • Immunology
  • Glycogen Storage Disease Type III
  • Glycogen
  • Dogs
  • Animals
  • 3404 Medicinal and biomolecular chemistry
  • 0304 Medicinal and Biomolecular Chemistry