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.
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