Molecular mechanism by which AMP-activated protein kinase activation promotes glycogen accumulation in muscle.
Molecular mechanism by which AMP-activated protein kinase activation promotes glycogen accumulation in muscle.
复制标题
DOI：
10.2337/db10-1148
复制
发表时间：
2011-03
期刊：
影响因子：
7.7
通讯作者：
Sakamoto K
中科院分区：
文献类型：
--
作者：
Hunter RW;Treebak JT;Wojtaszewski JF;Sakamoto K
在能量应激过程中，AMPK（AMP-activated protein kinase）通过促进葡萄糖转运和糖酵解来产生ATP，同时通过抑制糖原合成酶（glycogen synthase，GS）的活性来抑制合成代谢糖原的合成，从而维持肌肉的能量平衡。有趣的是，AMPK的慢性激活导致骨骼肌和心肌中糖原积累的增加，这在某些情况下与心功能障碍有关。本研究的目的是阐明AMPK激活促进肌糖原积累的分子机制。我们最近产生了敲入小鼠，其中野生型肌肉GS被突变体（Arg582Ala）取代，该突变体不能被葡萄糖-6-磷酸（G6P）激活，但具有完全的催化活性，并且仍然可以通过去磷酸化正常激活。将来自GS敲入或过表达激酶死亡（KD）AMPK的转基因小鼠的肌肉与葡萄糖示踪剂和AMPK激活化合物5-氨基咪唑-4-甲酰胺核糖核苷（AICAR）离体孵育。GS活性和葡萄糖的摄取和利用（糖酵解和糖原合成）进行了评估。尽管AICAR引起GS的适度失活，但它刺激肌糖原合成，伴随着葡萄糖转运和细胞内[G6P]的增加。AICAR的这些作用需要AMPK的催化活性。引人注目的是，AICAR诱导的糖原合成在G6P不敏感的GS基因敲入小鼠中被完全消除，尽管AICAR刺激的AMPK活化、葡萄糖转运和总葡萄糖利用是正常的。我们提供了遗传证据，证明AMPK激活通过葡萄糖摄入增加和随后细胞[G6 P]升高来变构激活GS，从而促进肌肉糖原积累。
During energy stress, AMP-activated protein kinase (AMPK) promotes glucose transport and glycolysis for ATP production, while it is thought to inhibit anabolic glycogen synthesis by suppressing the activity of glycogen synthase (GS) to maintain the energy balance in muscle. Paradoxically, chronic activation of AMPK causes an increase in glycogen accumulation in skeletal and cardiac muscles, which in some cases is associated with cardiac dysfunction. The aim of this study was to elucidate the molecular mechanism by which AMPK activation promotes muscle glycogen accumulation. We recently generated knock-in mice in which wild-type muscle GS was replaced by a mutant (Arg582Ala) that could not be activated by glucose-6-phosphate (G6P), but possessed full catalytic activity and could still be activated normally by dephosphorylation. Muscles from GS knock-in or transgenic mice overexpressing a kinase dead (KD) AMPK were incubated with glucose tracers and the AMPK-activating compound 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) ex vivo. GS activity and glucose uptake and utilization (glycolysis and glycogen synthesis) were assessed. Even though AICAR caused a modest inactivation of GS, it stimulated muscle glycogen synthesis that was accompanied by increases in glucose transport and intracellular [G6P]. These effects of AICAR required the catalytic activity of AMPK. Strikingly, AICAR-induced glycogen synthesis was completely abolished in G6P-insensitive GS knock-in mice, although AICAR-stimulated AMPK activation, glucose transport, and total glucose utilization were normal. We provide genetic evidence that AMPK activation promotes muscle glycogen accumulation by allosteric activation of GS through an increase in glucose uptake and subsequent rise in cellular [G6P].
登录
查看更多内容
影响因子：
4.8
作者：
Chavez, Jose A.;Roach, William G.;Lienhard, Gustav E.
通讯作者：
Lienhard, Gustav E.
影响因子：
3.6
作者：
Akman, Hasan O.;Sampayo, James N.;Dimauro, Salvatore
通讯作者：
Dimauro, Salvatore
影响因子：
7.7
作者：
Jorgensen, SB;Nielsen, JN;Wojtaszewski, JFP
通讯作者：
Wojtaszewski, JFP
影响因子：
--
作者：
Folmes, Karalyn D.;Chan, Anita Y. M.;Dyck, Jason R. B.
通讯作者：
Dyck, Jason R. B.
影响因子：
3.9
作者：
Hanashiro, I;Roach, PJ
通讯作者：
Roach, PJ