Hypoxia Promotes Glycogen Accumulation through Hypoxia Inducible Factor (HIF)-Mediated Induction of Glycogen Synthase 1

Abstract

When oxygen becomes limiting, cells reduce mitochondrial respiration and increase ATP production through anaerobic fermentation of glucose. The Hypoxia Inducible Factors (HIFs) play a key role in this metabolic shift by regulating the transcription of key enzymes of glucose metabolism. Here we show that oxygen regulates the expression of the muscle glycogen synthase (GYS1). Hypoxic GYS1 induction requires HIF activity and a Hypoxia Response Element within its promoter. GYS1 gene induction correlated with a significant increase in glycogen synthase activity and glycogen accumulation in cells exposed to hypoxia. Significantly, knockdown of either HIF1α or GYS1 attenuated hypoxia-induced glycogen accumulation, while GYS1 overexpression was sufficient to mimic this effect. Altogether, these results indicate that GYS1 regulation by HIF plays a central role in the hypoxic accumulation of glycogen. Importantly, we found that hypoxia also upregulates the expression of UTP:glucose-1-phosphate urydylyltransferase (UGP2) and 1,4-α glucan branching enzyme (GBE1), two enzymes involved in the biosynthesis of glycogen. Therefore, hypoxia regulates almost all the enzymes involved in glycogen metabolism in a coordinated fashion, leading to its accumulation. Finally, we demonstrated that abrogation of glycogen synthesis, by knock-down of GYS1 expression, impairs hypoxic preconditioning, suggesting a physiological role for the glycogen accumulated during chronic hypoxia. In summary, our results uncover a novel effect of hypoxia on glucose metabolism, further supporting the central importance of metabolic reprogramming in the cellular adaptation to hypoxia.

Neurons Have an Active Glycogen Metabolism that Contributes to Tolerance to Hypoxia

“…In contrast to what has been reported on muscle and hepatic cell lines, 35 total GS levels in neurons remain unchanged in hypoxia, but the enzyme is activated (dephosphorylated). In hypoxia, neuronal glycogen turnover is strongly enhanced by the simultaneous activation of GS and GP (shown in Figure 4G).…”

“…Surprisingly, although glycogen was degraded in neurons exposed to hypoxia, the activation state of GS dramatically increased ( Figure 4A 35 total GS activity (a readout of the total amount of protein) remained unaltered ( Figure 4A, right panel). Glycogen synthase showed increased electrophoretic mobility by WB analysis ( Figure 4B, quantification of the WB can be found in Supplementary Figure S3), which is characteristic of the activated, dephosphorylated form of the enzyme.…”

Ischemic pre and postconditioning in skeletal muscle injury produced by ischemia and reperfusion in rats

“…Thus, preconditioning, as well as its association with postconditioning prevented the depletion of glycogen storage caused by ischemic process. These results are similar to those of Weiss et al 22 and Pescador et al 23 . The exact molecular mechanism to explain this phenomenon is yet to be understood.…”

“…A better comprehension of this process could explain physiologic adaptations to hypoxia, and also help to develop therapeutic strategies against diseases which hypoxia plays a major role 23 .…”

Hypoxia promotes glycogen synthesis and accumulation in human ovarian clear cell carcinoma

“…Several studies have considered the mechanism of facilitated glycogen accumulation of OCCC (12,13), but a conclusion has not yet been reached. Some studies have found that the glycogen accumulation in several kinds of tumor cells was accelerated under hypoxic conditions (14)(15)(16)(17)(18). Under such a hypoxic environment, hypoxia-inducible factor 1 (HIF1) is expressed and functions as the main factor regulating the metabolism of the cell (19).…”