Kim Young-Bum, Peroni Odile D, Aschenbach William G, Minokoshi Yasuhiko, Kotani Ko, Zisman Ariel, Kahn C Ronald, Goodyear Laurie J, Kahn Barbara B
Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, 99 Brookline Avenue, Boston, MA 02215, USA.
Mol Cell Biol. 2005 Nov;25(21):9713-23. doi: 10.1128/MCB.25.21.9713-9723.2005.
Mice with muscle-specific knockout of the Glut4 glucose transporter (muscle-G4KO) are insulin resistant and mildly diabetic. Here we show that despite markedly reduced glucose transport in muscle, muscle glycogen content in the fasted state is increased. We sought to determine the mechanism(s). Basal glycogen synthase activity is increased by 34% and glycogen phosphorylase activity is decreased by 17% (P < 0.05) in muscle of muscle-G4KO mice. Contraction-induced glycogen breakdown is normal. The increased glycogen synthase activity occurs in spite of decreased signaling through the insulin receptor substrate 1 (IRS-1)-phosphoinositide (PI) 3-kinase-Akt pathway and increased glycogen synthase kinase 3beta (GSK3beta) activity in the basal state. Hexokinase II is increased, leading to an approximately twofold increase in glucose-6-phosphate levels. In addition, the levels of two scaffolding proteins that are glycogen-targeting subunits of protein phosphatase 1 (PP1), the muscle-specific regulatory subunit (RGL) and the protein targeting to glycogen (PTG), are strikingly increased by 3.2- to 4.2-fold in muscle of muscle-G4KO mice compared to wild-type mice. The catalytic activity of PP1, which dephosphorylates and activates glycogen synthase, is also increased. This dominates over the GSK3 effects, since glycogen synthase phosphorylation on the GSK3-regulated site is decreased. Thus, the markedly reduced glucose transport in muscle results in increased glycogen synthase activity due to increased hexokinase II, glucose-6-phosphate, and RGL and PTG levels and enhanced PP1 activity. This, combined with decreased glycogen phosphorylase activity, results in increased glycogen content in muscle in the fasted state when glucose transport is reduced.
肌肉特异性敲除葡萄糖转运蛋白4（Glut4）的小鼠（肌肉-G4KO小鼠）具有胰岛素抵抗且患有轻度糖尿病。在此我们表明，尽管肌肉中的葡萄糖转运显著减少，但禁食状态下肌肉糖原含量却增加了。我们试图确定其机制。在肌肉-G4KO小鼠的肌肉中，基础糖原合酶活性增加了34%，糖原磷酸化酶活性降低了17%（P<0.05）。收缩诱导的糖原分解是正常的。尽管基础状态下通过胰岛素受体底物1（IRS-1）-磷酸肌醇（PI）3-激酶-Akt途径的信号传导减少且糖原合酶激酶3β（GSK3β）活性增加，但糖原合酶活性仍增加。己糖激酶II增加，导致6-磷酸葡萄糖水平增加约两倍。此外，与野生型小鼠相比，肌肉-G4KO小鼠肌肉中作为蛋白磷酸酶1（PP1）糖原靶向亚基的两种支架蛋白，即肌肉特异性调节亚基（RGL）和糖原靶向蛋白（PTG）的水平显著增加了3.2至4.2倍。使糖原合酶去磷酸化并激活的PP1的催化活性也增加。这一作用超过了GSK3的影响，因为GSK3调节位点上的糖原合酶磷酸化减少。因此，肌肉中显著减少的葡萄糖转运导致糖原合酶活性增加，这是由于己糖激酶II、6-磷酸葡萄糖、RGL和PTG水平增加以及PP1活性增强所致。这与糖原磷酸化酶活性降低相结合，导致在葡萄糖转运减少的禁食状态下肌肉中的糖原含量增加。
