Endocrine Abstracts

Glycogen storage disease type 1b is a metabolic disorder resulting in an inability to shuttle glucose-6-phosphate across the sarcoplasmic/endoplasmic reticulum (SR/ER) lumen. Mutation of the SoLute Carrier 37a4 (slc37a4) or glucose-6-phosphate transporter (G6PT) gene responsible for the distribution of G-6-P across this membrane leads to, hypoglycemia, hepatic glycogen accumulation, hyperlipidemia, resulting in life-limiting outcomes including growth retardation and neutropenia. Slc37a4 is highly expressed in metabolic tissues such as liver, kidneys and neutrophils. Moreover, expression is also found in muscle, a tissue that does not express the G-6-Pase system. Thus, the role of G6PT action in muscle is incompletely understood and how it contributes to metabolic implications of G6PT deficiency. G6PT −/− mice are not viable, so we have begun to assess G6PT +/− mice as model of G6PT deficiency to begin assessing its roles within muscle.

G6PT +/− mice have ~ a 50% reduction in protein levels. G6P in the SR is metabolised by H6PDH, generating NADPH for 11β-HSD1 and the generation of glucocorticoids. This 50% reduction did not affect 11β-HSD1 activity, and so is not rate-limiting for this pathway reaction. Using primary cultures of quadriceps muscle as a model we have identified a defect in intracellular calcium homeostasis. Using both colourmetric calcium detection assays and Fura-4 free-calcium binding assays we demonstrate greater accumulation of free calcium in G6PT +/−muscle compared to WT. We also show that this defect in calcium is associated with increased expression of the SERCA2/ATPase pump responsible for flux of calcium into the SR lumen from the cytosol. These data suggest that the G6PT can influence calcium handling in muscle cells and that G6PT +/− muscle has dysregulated calcium homeostasis. How G6PT influences muscle calcium is unknown. These studies highlight a novel aspect of calcium regulation in muscle that may have implications for patients with GSD1b.