Strle Klemen, Broussard Suzanne R, McCusker Robert H, Shen Wen-Hong, LeCleir Julie M, Johnson Rodney W, Freund Gregory G, Dantzer Robert, Kelley Keith W
Laboratories of Immunophysiology, Department of Animal Sciences, University of Illinois, Urbana, Illinois 61801, USA.
Endocrinology. 2006 Sep;147(9):4363-73. doi: 10.1210/en.2005-1541. Epub 2006 Jun 15.
The stress kinase c-jun N-terminal kinase (JNK) was recently shown to be involved in the pathophysiology of major inflammatory conditions, including Alzheimer's disease, stroke, obesity, and type II diabetes. However, the role of JNK in regulating inflammatory events in skeletal muscle is only beginning to be explored. IGF-I is the major hormone that promotes muscle growth and development. Here we used a novel, JNK interacting protein (JIP)-derived JNK peptide inhibitor to establish that JNK suppresses the biological activity of IGF-I in skeletal muscle progenitor cells. In these myoblasts, TNFalpha and its downstream receptor substrates, neutral-sphingomyelinase (N-SMase) and N-acetyl-d-sphingosine (C2-ceramide), induce JNK kinase activity in a time-dependent manner. Consistent with these results, TNFalpha induces JNK binding to insulin receptor substrate 1 (IRS-1) but is unable to inhibit IGF-I-induced IRS-1 tyrosine phosphorylation in myoblasts that are treated with the JNK peptide inhibitor. More importantly, JNK activation induced by TNFalpha, C2-ceramide, and N-SMase is associated with reduced expression of the critical muscle transcription factor myogenin as well as the differentiation marker myosin heavy chain (MHC). The JNK peptide inhibitor, but not the control peptide, completely reverses this inhibition of both myogenin and MHC. In the absence of IGF-I, TNFalpha, C2-ceramide, N-SMase and the JNK inhibitor are inactive, as shown by their inability to affect IRS tyrosine phosphorylation and protein expression of myogenin and MHC. These results establish that the resistance of muscle progenitor cells to IGF-I, which is caused by inflammatory stimuli, is mediated by the JNK stress kinase pathway.
应激激酶c-jun氨基末端激酶（JNK）最近被证明参与了包括阿尔茨海默病、中风、肥胖症和II型糖尿病在内的主要炎症性疾病的病理生理过程。然而，JNK在调节骨骼肌炎症事件中的作用才刚刚开始被探索。胰岛素样生长因子-I（IGF-I）是促进肌肉生长和发育的主要激素。在这里，我们使用了一种新型的、源自JNK相互作用蛋白（JIP）的JNK肽抑制剂来确定JNK在骨骼肌祖细胞中抑制IGF-I的生物学活性。在这些成肌细胞中，肿瘤坏死因子-α（TNFα）及其下游受体底物中性鞘磷脂酶（N-SMase）和N-乙酰-D-鞘氨醇（C2-神经酰胺）以时间依赖性方式诱导JNK激酶活性。与这些结果一致，TNFα诱导JNK与胰岛素受体底物1（IRS-1）结合，但在经JNK肽抑制剂处理的成肌细胞中不能抑制IGF-I诱导的IRS-1酪氨酸磷酸化。更重要的是，TNFα、C2-神经酰胺和N-SMase诱导的JNK激活与关键肌肉转录因子肌细胞生成素以及分化标志物肌球蛋白重链（MHC）的表达降低有关。JNK肽抑制剂而非对照肽完全逆转了对肌细胞生成素和MHC的这种抑制作用。在没有IGF-I的情况下，TNFα、C2-神经酰胺、N-SMase和JNK抑制剂无活性，这表现为它们无法影响IRS酪氨酸磷酸化以及肌细胞生成素和MHC的蛋白表达。这些结果表明，炎症刺激导致的肌肉祖细胞对IGF-I的抵抗是由JNK应激激酶途径介导的。
