Lally James S V, Ford Rebecca J, Johar Jasper, Crane Justin D, Kemp Bruce E, Steinberg Gregory R
Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
St. Vincent's Institute of Medical Research and Department of Medicine, University of Melbourne, Fitzroy, Victoria, Australia.
Physiol Rep. 2015 May;3(5). doi: 10.14814/phy2.12343.
Fibronectin type III domain-containing protein 5 (FNDC5) expression is controlled by the transcriptional co-activator, peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC1α). FNDC5 expression has been shown to be increased in muscle in response to endurance exercise in some but not all studies, therefore a greater understanding of the mechanisms controlling this process are needed. The AMP-activated protein kinase (AMPK) is activated by exercise in an intensity dependent manner and is an important regulator of PGC1α activity; therefore, we explored the role of AMPK in the regulation of FNDC5 using AMPK β1β2 double muscle-null mice (AMPK DMKO), which lack skeletal muscle AMPK activity. We found that FNDC5 expression is dramatically reduced in resting muscles of AMPK DMKO mice compared to wild-type littermates. In wild-type mice, activating phosphorylation of AMPK was elevated immediately post contraction and was abolished in muscle from AMPK DMKO mice. In contrast, PGC1α was increased in both wild-type and AMPK DMKO mice 3 h post contraction but FNDC5 protein expression was not altered. Lastly, acute or chronic activation of AMPK with the pharmacological AMPK activator AICAR did not increase PGC1α or FNDC5 expression in muscle. These data indicate that skeletal muscle AMPK is required for the maintenance of basal FNDC5 expression.
含III型纤连蛋白结构域蛋白5（FNDC5）的表达受转录共激活因子过氧化物酶体增殖物激活受体γ共激活因子1α（PGC1α）调控。在一些但并非所有研究中，耐力运动后肌肉中FNDC5的表达已被证明会增加，因此需要更深入了解控制这一过程的机制。AMP激活的蛋白激酶（AMPK）在运动中以强度依赖的方式被激活，是PGC1α活性的重要调节因子；因此，我们使用缺乏骨骼肌AMPK活性的AMPKβ1β2双肌肉敲除小鼠（AMPK DMKO）来探究AMPK在FNDC5调控中的作用。我们发现，与野生型同窝小鼠相比，AMPK DMKO小鼠静息肌肉中FNDC5的表达显著降低。在野生型小鼠中，收缩后立即升高的AMPK激活磷酸化在AMPK DMKO小鼠的肌肉中消失。相反，收缩后3小时，野生型和AMPK DMKO小鼠中的PGC1α均增加，但FNDC5蛋白表达未改变。最后，用药物性AMPK激活剂AICAR对AMPK进行急性或慢性激活，并未增加肌肉中PGC1α或FNDC5的表达。这些数据表明，骨骼肌AMPK是维持基础FNDC5表达所必需的。
