Frost R A, Lang C H
Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
J Anim Sci. 2008 Apr;86(14 Suppl):E84-93. doi: 10.2527/jas.2007-0483. Epub 2008 Jan 11.
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.
骨骼肌在响应包括病原体相关分子、炎性细胞因子和生长因子在内的环境和激素因素时表现出极大的可塑性。这些信号通过促使单个肌纤维生长或萎缩而作用于肌肉。我们最近证明，骨骼肌细胞表达多种 Toll 样受体（TLR），这些受体可识别细菌细胞壁成分，如脂多糖（LPS）。将心肌细胞暴露于 LPS 和其他 TLR 配体可引发炎症反应，最终导致细胞因子和一氧化氮合酶（NOS）2 自分泌产生一氧化氮。TLR 通过蛋白激酶发出信号，该蛋白激酶使一种抑制蛋白磷酸化并促进其降解，这种抑制蛋白通常将转录因子核因子κB（NFκB）保留在细胞质中。NFκB 抑制剂的磷酸化和降解使 NFκB 能够转运至细胞核并激活炎症基因。在骨骼肌中过表达 NFκB 激酶的组成型活性抑制剂会导致严重消瘦，并且我们发现 IkappaB 磷酸化或其蛋白水解降解的抑制剂可阻止 TLR 配体诱导的细胞因子和 NOS2 表达。LPS 和干扰素γ的组合可显著增强 LPS 刺激的 NOS2 表达的幅度和持续时间，并减少蛋白质翻译。脂多糖和干扰素γ还下调雷帕霉素哺乳动物靶点的信号传导，雷帕霉素是一种指导细胞大小变化的激酶。NOS 抑制剂可阻止肌肉细胞蛋白质合成的下降并恢复翻译信号传导，表明 NOS2 - 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大小。NFκB 和 NOS2 的长期激活已成为肌肉免疫反应的有害方面。炎症成分与生长因子信号传导之间的相互作用清楚地使肌肉处于生长与免疫的界面。
