Inhibition by glycogen accumulation

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In skeletal muscle, some studies found that high glycogen content repressed AMPK activation (Derave et al., 2000; Wojtaszewski et al., 2002), suggesting that AMPK system may monitor availability of this energy store by virtue of the glycogen-binding domain on its b subunit (McBride et al., 2009). The degree of AMPK activation was immense during the glycogen-depleted state in both rat and human muscles (Viollet et al., 2003; Wojtaszewski et al., 2002). However, this inverse correlation was not evident under all circumstances. In a human training study, AMPK activity was not found to be directly correlated with muscle glycogen content (McConell et al., 2008). Furthermore, in patients with McArdle’s disease (glycogen storage disease V), the activation of AMPK in response to moderate exercise was exaggerated despite high skeletal muscle glycogen levels (Nielsen et al., 2002). Other paradoxes exist as AMPK can inactivate glycogen synthase (GS) by phosphorylation on Ser7 (site 2) (Jorgensen et al., 2004). Although AMPK is activated by exercise, glycogen synthase was contradictly found dephosphorylated as well as activated after exercise. McBride and coworkers proposed a single hypothesis to explain the physiological role of glycogen binding to AMPK complex based on its structure (McBride et al., 2009). Glycogen preparations with high branching content was found to cause allosteric inhibition of AMPK, due to its binding to the glycogen-binding domain (McBride et al., 2009). It was demonstrated that oligosaccharides with single a1-6 branch points, but not a1-4, are potent allosteric inhibitors of AMPK that also inhibit phosphorylation and activation by upstream kinases. AMPK bound to fully synthesized glycogen particle is probably in an active state due to inaccessibility of internal branch points. This will lead to phosphorylation and inhibition of GS, providing feedback inhibition of further extension of glycogen particles. However, when glycogen is depleted, AMPK becomes inhibited after binding to exposed a1-6 branch points. This allows dephosphorylation of GS on site 2, promoting rapid resynthesis of glycogen. This model implies that different pools of AMPK (glycogen-bound versus glycogen-free) can phosphorylate some targets while not others (Jorgensen et al., 2004).