Regulation of muscle growth by pathogen-associated molecules.
Regulation of muscle growth by pathogen-associated molecules.
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DOI：
10.2527/jas.2007-0483
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发表时间：
2008-04-01
影响因子：
3.3
通讯作者：
Lang, C H
中科院分区：
文献类型：
--
作者：
Frost, R A;Lang, C H
骨骼肌表现出极大的可塑性，以应对环境和激素因素，包括病原体相关分子，炎性细胞因子和生长因子。这些信号通过迫使单个肌肉纤维生长或萎缩来冲击肌肉。我们最近发现，骨骼肌细胞表达多种Toll样受体（TLR），识别细菌细胞壁成分，如脂多糖（LPS）。肌细胞暴露于LPS和其他TLR配体引发炎症反应，最终通过NO合酶（NOS）2自分泌产生细胞因子和NO。TLR通过蛋白激酶发出信号，所述蛋白激酶磷酸化并促进抑制性蛋白的降解，所述抑制性蛋白通常将转录因子核因子κ B（NF κ B）保留在细胞质中。NF κ B抑制剂的磷酸化和降解允许NF κ B易位到细胞核并激活炎性基因。在骨骼肌中NF κ B激酶的组成型活性抑制剂的过度表达导致严重的消耗，并且我们发现IkappaB的磷酸化或其蛋白水解降解的抑制剂防止TLR配体诱导的细胞因子和NOS 2的表达。LPS和干扰素γ的组合显著增强了LPS刺激的NOS 2表达的幅度和持续时间，并减少了蛋白质翻译。脂多糖和干扰素γ也下调来自哺乳动物雷帕霉素靶点的信号传导，雷帕霉素是一种指导细胞大小变化的激酶。NOS抑制剂阻断肌肉细胞蛋白质合成的下降并恢复翻译信号传导，表明NOS 2-NO途径的激活是观察到的肌肉蛋白质合成减少的原因。我们的工作为感染期间肌肉生长减少提供了分子解释。肌肉在很大程度上是自给自足的，因为它表达受体、信号通路和效应器来调节自身的大小。NF κ B和NOS 2的长期激活已经成为肌肉中免疫应答的有害方面。炎症成分和生长因子信号之间的相互作用清楚地将肌肉置于生长和免疫之间的界面。
Skeletal muscle demonstrates great plasticity in response to environmental and hormonal factors including pathogen-associated molecules, inflammatory cytokines, and growth factors. These signals impinge on muscle by forcing individual muscle fibers to either grow or atrophy. We recently demonstrated that skeletal muscle cells express multiple Toll-like receptors (TLR) that recognize bacterial cell wall components, such as lipopolysaccharide (LPS). Exposure of myocytes to LPS and other TLR ligands initiates an inflammatory response culminating in the autocrine production of cytokines and NO by NO synthase (NOS)2. The TLR signal through protein kinases that phosphorylate and promote the degradation of an inhibitory protein that normally retains the transcription factor, nuclear factor kappaB (NFkappaB), in the cytoplasm. Phosphorylation and degradation of the inhibitor of NFkappaB allows for translocation of NFkappaB to the nucleus and activation of inflammatory genes. Overexpression of a constitutively active inhibitor of NFkappaB kinase in skeletal muscle causes severe wasting, and we found that inhibitors of either the phosphorylation of IkappaB or its proteolytic degradation prevent TLR ligand-induced expression of cytokines and NOS2. The combination of LPS and interferon gamma dramatically enhances the magnitude and duration of LPS-stimulated NOS2 expression and reduces protein translation. Lipopolysaccharide and interferon gamma also downregulates signaling from the mammalian target of rapamycin, a kinase that directs changes in cell size. Inhibitors of NOS block the fall in muscle cell protein synthesis and restore translational signaling, indicating that activation of the NOS2-NO pathway is responsible for the observed decrease in muscle protein synthesis. Our work provides a molecular explanation for reduced muscle growth during infection. Muscle is largely self-sufficient because it expresses receptors, signaling pathways, and effectors to regulate its own size. Prolonged activation of NFkappaB and NOS2 have emerged as detrimental facets of the immune response in muscle. The interplay between inflammatory components and growth factor signaling clearly places muscle at the interface between growth and immunity.