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

Abstract

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.

High glucose induces formation of tau hyperphosphorylation via Cav-1-mTOR pathway: A potential molecular mechanism for diabetes-induced cognitive dysfunction

“…mTOR/S6K signalling could regulate glucose metabolism including inhibiting glucose uptake, improving glycogen synthesis and stimulating glycolysis [15–19], and a feedback regulation mechanism of mTOR by glucose metabolism is suggested by the findings that HGC activates mTOR signalling in rat PC12 pheochromocytoma cells (a clonal cell line closely related to sympathetic neurons) and HT22 cells (an immortalized mouse hippocampal cell line) [63, 64]. It was demonstrated that the chronic activation of mTOR by high glucose results in insulin resistance [65] and the hyperactivation of mTOR is involved in diabetic complications [66].…”

“…mTOR/S6K signalling is required for glucose metabolism and memory formation [15–20]. However, the over-activated mTOR/S6K signalling is thought to be implicated in cognitive dysfunction [21].…”

m-TOR Inhibitors in the Current Practice

“…Prospective clinical trial in SLE patients with sirolimus is ongoing [74][75][76]. Scleroderma m-TOR can plays a role in fibrotic diseases and autoimmunity, and blockade of the mTORC pathway through blocking the profibrotic effects of TGF-β can play a part in the treatment of scleroderma (or systemic sclerosis), however, this approach is currently under investigation [77].…”

Large animal models and new therapies for glycogen storage disease

“…Rapamycin, a specific inhibitor of mTOR, decreased muscle glycogen content and liver fibrosis in GSD IIIa-affected curly coated retrievers using high dose therapy at both early and late time points. Further, rapamycin inhibited glucose uptake by suppressing glycogen synthase and glucose transporter 1 expression in muscle cells cultured from GSD IIIa patients (Yi et al 2014). These data suggest that small molecule drugs, such as rapamycin, may be useful in the treatment of GSD III.…”