Loss of class IAPI3K signaling in muscle leads to impaired muscle growth, insulin response, and hyperlipidemia
Loss of class IAPI3K signaling in muscle leads to impaired muscle growth, insulin response, and hyperlipidemia
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DOI：
10.1016/j.cmet.2006.04.003
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发表时间：
2006-05-01
期刊：
影响因子：
29
通讯作者：
Cantley, Lewis C.
中科院分区：
文献类型：
--
作者：
Luo, Ji;Sobkiw, Cassandra L.;Cantley, Lewis C.
进化保守的磷脂酰肌醇3-激酶(PI3K)信号通路既介导了胰岛素的代谢作用，又介导了胰岛素样生长因子-1(IGF-1)的促生长作用。我们已经产生了在骨骼肌中同时缺乏P85α/P55α/P50α和P85β调节亚基的I-A类PI3K的小鼠。这些动物肌肉中的PI3K信号严重受损，导致肌肉重量和纤维尺寸显著减少。这些小鼠还表现出肌肉胰岛素抵抗和全身葡萄糖耐受性。尽管这些小鼠能够维持正常的空腹和进食血糖水平，但它们的体脂含量和血清游离脂肪酸和甘油三酯水平都有所提高。这些结果表明，在体内，P85是I-A类PI3K信号在肌肉生长和代谢调节中的关键中介。我们的发现还表明，肌肉PI3K信号受损可能导致与人类2型糖尿病相关的高脂血症症状。
The evolutionarily conserved phosphoinositide 3-kinase (PI3K) signaling pathway mediates both the metabolic effects of insulin and the growth-promoting effects of insulin-like growth factor-1 (IGF-1). We have generated mice deficient in both the p85 alpha/p55 alpha/p50 alpha and the p85 beta regulatory subunits of class I-A PI3K in skeletal muscles. PI3K signaling in the muscle of these animals is severely impaired, leading to a significant reduction in muscle weight and fiber size. These mice also exhibit muscle insulin resistance and whole-body glucose intolerance. Despite their ability to maintain normal fasting and fed blood glucose levels, these mice show increased body fat content and elevated serum free fatty acid and triglyceride levels. These results demonstrate that in vivo p85 is a critical mediator of class I-A PI3K signaling in the regulation of muscle growth and metabolism. Our finding also indicates that compromised muscle PI3K signaling could contribute to symptoms of hyperlipidemia associated with human type 2 diabetes.