Inhibition of glycogen biosynthesis via mTORC1 suppression as an adjunct therapy for Pompe disease

Ashe, Karen M.; Taylor, Kristin M.; Chu, Qiuming; Meyers, Elizabeth; Ellis, Allen; Jingozyan, Varvara; Klinger, Katherine W.; Finn, Patrick F.; Cooper, Christopher G. F.; Chuang, Wei-Lien; Marshall, John; McPherson, John M.; Mattaliano, Robert J.; Cheng, Seng H.; Scheule, Ronald K.; Moreland, Rodney J.

doi:10.1016/j.ymgme.2010.05.001

Cited by 42 publications

(52 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…reported that rapamycin reduced lysosomal glycogen accumulation in the skeletal muscle of GAA-KO mice likely through the inhibition of total glycogen synthesis [22]. In this study, we showed that rapamycin significantly reduced glucose uptake and glycogen levels in primary skeletal muscle cells from patients with GSD IIIa, which coincides with the reduction of glucose transporter 1 and total glycogen synthase (Fig.…”

Section: Discussionsupporting

confidence: 71%

“…However, these approaches are not suitable for GSD III due to the lack of receptor-mediated uptake of the enzyme by target cells and the difficulty in the delivery of the large-sized glycogen debranching enzyme expression cassette. Previous studies demonstrated that inhibition of glycogen synthesis is an effective therapeutic approach for Pompe disease [22,30]. Sipula et al demonstrated that mTOR inhibition by rapamycin significantly reduced glucose uptake and glycogen synthesis in cultured rat skeletal muscle cells [20].…”

Section: Discussionmentioning

confidence: 99%

“…In vitro, rapamycin significantly reduced glucose uptake and glycogen synthesis in cultured rat skeletal muscle cells [20]; pretreatment of HepG2 liver cells with rapamycin resulted in a decrease in glycogen synthase (Gys) activity in an insulinindependent manner [21]. In vivo, rapamycin combined with recombinant human acid α-glucosidase (GAA) treatment improved glycogen clearance in the target tissue of adult GAA-KO mice; rapamycin alone increased phosphorylation (inactivation) of Gys and reduced glycogen accumulation in skeletal muscles of young GAA-KO mice [22]. Moreover, multiple studies have shown that rapamycin has a strong antifibrogenic effect on liver cirrhosis in rats that underwent bile duct ligation [23][24][25][26][27].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Brooks

Thurberg

et al. 2014

J Mol Med

View full text Add to dashboard Cite

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 latetreatment 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.

show abstract

Section: Discussionsupporting

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Brooks

Thurberg

et al. 2014

J Mol Med

View full text Add to dashboard Cite

show abstract

“…This increase was not due to higher levels of mRNA (Figure 1) and may therefore be related to an increase in the stability of the enzyme in these Pompe tissues. 21 However, there were no differences in the levels of glycogen synthase in the liver of Pompe mice compared to those of wild-type control animals. Gys1 mRNA levels were assessed in TA muscles of male C57Bl/6 mice injected and electroporated with individual PMOs as described in the Materials and Methods.…”

Section: A Pmo Confers Selective Knockdown Of Gys1 Mrna In Murine Musclementioning

confidence: 85%

Antisense oligonucleotide-mediated suppression of muscle glycogen synthase 1 synthesis as an approach for substrate reduction therapy of Pompe disease

Clayton¹,

Nelson²,

Weeden³

et al. 2015

Molecular Genetics and Metabolism

Self Cite

View full text Add to dashboard Cite

“…mTOR is a serine/threonine kinase which is part of different multiprotein complexes such as mTORC1 and mTORC2. Recently, it has been found that GAA-KO mice treated with rapamycin, an inhibitor of mTORC1, exhibited a significant decrease of muscular glycogen storage due to the phosphorylation-mediated inhibition of GYS1 (71). Furthermore, it has been demonstrated that the mTORC1 pathway regulates the muscular glycogen synthesis without affecting the liver glycogen synthesis.…”

Section: Substrate Reduction Therapymentioning

confidence: 99%

New insights into therapeutic options for Pompe disease

2011

View full text Add to dashboard Cite

SummaryGlycogen storage disease type II or Pompe disease (GSD II, MIM 232300) is a rare inherited metabolic myopathy caused by a deficiency of lysosomal acid a-glucosidase or acid maltase (GAA; EC 3.2.1.20), resulting in a massive lysosomal glycogen accumulation in cardiac and skeletal muscles. Affected individuals exhibit either severe hypotonia associated with hypertrophic cardiomyopathy (infantile forms) or progressive muscle weakness (late-onset forms). Even if enzyme replacement therapy has recently become a standard treatment, it suffers from several limitations. This review will present the main results of enzyme replacement therapy and the recent findings concerning alternative treatments for Pompe disease, such as gene therapy, enzyme enhancement therapy, and substrate reduction therapy. IUBMBIUBMB Life, 63(11): 979-986, 2011

show abstract

Inhibition of glycogen biosynthesis via mTORC1 suppression as an adjunct therapy for Pompe disease

Cited by 42 publications

References 29 publications

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

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

Antisense oligonucleotide-mediated suppression of muscle glycogen synthase 1 synthesis as an approach for substrate reduction therapy of Pompe disease

New insights into therapeutic options for Pompe disease

Contact Info

Product

Resources

About