Disruption of ATP-sensitive potassium channel function in skeletal muscles promotes production and secretion of musclin.
Disruption of ATP-sensitive potassium channel function in skeletal muscles promotes production and secretion of musclin.
复制标题
骨骼肌中 ATP 敏感性钾通道功能的破坏可促进肌肉蛋白的产生和分泌。
DOI：
10.1016/j.bbrc.2016.01.166
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发表时间：
2016
影响因子：
3.1
通讯作者：
Zingman,LeonidV
中科院分区：
文献类型：
--
作者：
Sierra,Ana;Subbotina,Ekaterina;Zhu,Zhiyong;Gao,Zhan;Koganti,SivaRamaKrishna;Coetzee,WilliamA;Goldhamer,DavidJ;Hodgson-Zingman,DeniceM;Zingman,LeonidV
肌膜 ATP 敏感钾 (KATP) 通道通过根据细胞代谢状态调节膜兴奋性和相关细胞功能的能力来控制骨骼肌能量的使用。骨骼肌 KATP 通道受损的小鼠表现出脂肪细胞尺寸减小和循环中脂肪酸释放增加。迄今为止，骨骼肌 KATP 通道功能和脂肪动员之间这种联系的分子机制尚未确定。在这里，我们证明转基因（TG）小鼠中骨骼肌特异性破坏 KATP 通道功能可促进肌肉蛋白的产生和分泌。 Musclin 是一种与心房钠尿肽 (ANP) 高度同源的肌因子，通过竞争消除来增强 ANP 信号传导。 TG 小鼠中肌肉蛋白产量的增加是由分子级联驱动的，导致转录因子叉头盒 O1 (FOXO1) 的乙酰化和核排除增强，FOXO1 是肌肉蛋白编码基因转录的抑制剂。 TG 中肌肉蛋白的产生/分泌与脂肪酸动员的增加以及循环 ANP（脂解激活剂）增加的明显趋势相伴。这些数据表明，KATP 通道依赖性肌肉蛋白的产生是一种潜在的机制联系，将“局部”骨骼肌能量消耗与从脂肪中调动身体资源联系起来。了解这些机制是设计干预措施来管理代谢紊乱（包括与体内脂肪过多和相关并发症相关的代谢紊乱）的重要一步。
Sarcolemmal ATP-sensitive potassium (KATP) channels control skeletal muscle energy use through their ability to adjust membrane excitability and related cell functions in accordance with cellular metabolic status. Mice with disrupted skeletal muscle KATPchannels exhibit reduced adipocyte size and increased fatty acid release into the circulation. As yet, the molecular mechanisms underlying this link between skeletal muscle KATPchannel function and adipose mobilization have not been established. Here, we demonstrate that skeletal muscle-specific disruption of KATPchannel function in transgenic (TG) mice promotes production and secretion of musclin. Musclin is a myokine with high homology to atrial natriuretic peptide (ANP) that enhances ANP signaling by competing for elimination. Augmented musclin production in TG mice is driven by a molecular cascade resulting in enhanced acetylation and nuclear exclusion of the transcription factor forkhead box O1 (FOXO1) – an inhibitor of transcription of the musclin encoding gene. Musclin production/secretion in TG is paired with increased mobilization of fatty acids and a clear trend toward increased circulating ANP, an activator of lipolysis. These data establish KATPchannel-dependent musclin production as a potential mechanistic link coupling “local” skeletal muscle energy consumption with mobilization of bodily resources from fat. Understanding such mechanisms is an important step toward designing interventions to manage metabolic disorders including those related to excess body fat and associated co-morbidities.