Sakamoto Kei, Göransson Olga, Hardie D Grahame, Alessi Dario R
MRC Protein Phosphorylation Unit, School of Life Sciences, University of Dundee, Scotland, UK.
Am J Physiol Endocrinol Metab. 2004 Aug;287(2):E310-7. doi: 10.1152/ajpendo.00074.2004. Epub 2004 Apr 6.
Activation of AMP-activated protein kinase (AMPK) by exercise and metformin is beneficial for the treatment of type 2 diabetes. We recently found that, in cultured cells, the LKB1 tumor suppressor protein kinase activates AMPK in response to the metformin analog phenformin and the AMP mimetic drug 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR). We have also reported that LKB1 activates 11 other AMPK-related kinases. The activity of LKB1 or the AMPK-related kinases has not previously been studied in a tissue with physiological relevance to diabetes. In this study, we have investigated whether contraction, phenformin, and AICAR influence LKB1 and AMPK-related kinase activity in rat skeletal muscle. Contraction in situ, induced via sciatic nerve stimulation, significantly increased AMPKalpha2 activity and phosphorylation in multiple muscle fiber types without affecting LKB1 activity. Treatment of isolated skeletal muscle with phenformin or AICAR stimulated the phosphorylation and activation of AMPKalpha1 and AMPKalpha2 without altering LKB1 activity. Contraction, phenformin, or AICAR did not significantly increase activities or expression of the AMPK-related kinases QSK, QIK, MARK2/3, and MARK4 in skeletal muscle. The results of this study suggest that muscle contraction, phenformin, or AICAR activates AMPK by a mechanism that does not involve direct activation of LKB1. They also suggest that the effects of excercise, phenformin, and AICAR on metabolic processes in muscle may be mediated through activation of AMPK rather than activation of LKB1 or the AMPK-related kinases.
运动和二甲双胍激活AMP活化蛋白激酶（AMPK）对2型糖尿病的治疗有益。我们最近发现，在培养细胞中，LKB1肿瘤抑制蛋白激酶可响应二甲双胍类似物苯乙双胍和AMP模拟药物5-氨基咪唑-4-甲酰胺-1-β-D-呋喃核糖苷（AICAR）激活AMPK。我们还报道LKB1可激活其他11种与AMPK相关的激酶。此前尚未在与糖尿病具有生理相关性的组织中研究LKB1或与AMPK相关激酶的活性。在本研究中，我们调查了收缩、苯乙双胍和AICAR是否会影响大鼠骨骼肌中LKB1和与AMPK相关激酶的活性。通过坐骨神经刺激诱导的原位收缩显著增加了多种肌纤维类型中AMPKα2的活性和磷酸化水平，而不影响LKB1的活性。用苯乙双胍或AICAR处理分离的骨骼肌可刺激AMPKα1和AMPKα2的磷酸化和激活，而不改变LKB1的活性。收缩、苯乙双胍或AICAR并未显著增加骨骼肌中与AMPK相关激酶QSK、QIK、MARK2/3和MARK4的活性或表达。本研究结果表明，肌肉收缩、苯乙双胍或AICAR通过不涉及直接激活LKB1的机制激活AMPK。它们还表明，运动、苯乙双胍和AICAR对肌肉代谢过程的影响可能是通过激活AMPK介导的，而不是通过激活LKB1或与AMPK相关的激酶。
