Inflammation and muscle wasting - NF-kB signaling and mir-31 regulate muscle function

肌肉的力量和功能对人类的生活质量和寿命有严重的影响。年龄和慢性疾病导致肌肉萎缩，而这种肌肉质量和力量的损失与不良疾病结果、残疾和死亡率直接相关。目前还没有药物可以治疗肌肉损失。运动等其他对策对衰老和患病的肌肉效果较差，因为它们更容易因收缩引起肌肉损伤，导致恢复不足。这种对肌肉损伤的易感性与肌营养不良蛋白的缺失直接相关，肌营养不良蛋白是一种连接肌纤维细胞骨架和细胞外基质的基本结构蛋白。肌营养不良蛋白在先天性疾病、年龄和非先天性人类疾病中的丧失与显著的炎症和氧化成分相关。针对抗氧化机制的干预能够部分恢复肌营养不良蛋白。衰老、炎症和氧化对肌营养不良蛋白水平影响的分子机制仍然知之甚少。最近，已经发现了特异性降低肌营养不良蛋白翻译的微rna （miRs）。加州大学Baar实验室最近表明，其中一种miRs （miR-31）在衰老肌肉中升高6倍以上，可以直接调节肌营养不良蛋白水平，并通过NF-kB受到炎症信号的影响。由于多种原因，NF-kB转录因子家族与肌肉萎缩直接相关，指向一个共同的机制。尽管NF-kB在肌肉萎缩中很重要，但其转录靶点仍然很大程度上未知。强有力的初步数据表明，miR-31水平通过典型NF-kB信号的特定炎症途径升高，但可以通过非典型NF-kB信号保护肌肉免受收缩性损伤而降低。这些初步数据为更深入地分析典型和非典型NF-kB信号在衰老肌肉中调节miR-31和肌营养不良蛋白水平中的作用提供了有力的理论依据。为了了解炎症、mIR-31、肌营养不良蛋白和肌肉功能之间的相互作用，我们将研究典型/非典型NF-kB信号之间的平衡如何调节mIR-31水平、肌营养不良蛋白、肌肉力量和收缩性损伤。该项目是朝着炎症、氧化应激和肌营养不良蛋白损失之间关系的直接机制证据迈出的重要一步。我们将探讨增强肌肉力传递、减少收缩引起的肌肉损伤和防止肌肉萎缩的干预措施。通过进一步了解肌营养不良蛋白丧失的分子机制以及随后设计适当的干预措施，我们的目标是改善数百万肌肉丧失患者的生活质量。

Muscle strength and functionality have a severe impact on human quality of life and longevity. Age and chronic diseases cause muscle wasting, and this loss of muscle mass and strength is directly related to negative disease outcomes, disability and mortality rates. Currently no pharmaceutical treatment for muscle loss is available. Other countermeasures such as exercise are less effective in ageing and diseased muscles, as they become more prone to contraction-induced muscle injury causing insufficient recovery. This susceptibility to muscle injury is directly correlated with loss of dystrophin, an essential structural protein that links the cytoskeleton of the muscle fiber to the extracellular matrix. The loss of dystrophin in congenital disorders, but also with age and in non-congenital human diseases is associated with a significant inflammatory and oxidative component. Interventions targeting antioxidative mechanisms were able to partially restore dystrophin. The molecular mechanisms underlying the effects of aging, inflammation and oxidation on dystrophin levels remain poorly understood. Recently, micro RNAs (miRs) that specifically decrease dystrophin translation (dystromirs) have been identified. The Baar laboratory at the University of California has recently shown that one of these miRs (miR-31) is elevated over 6-fold in aging muscle, can directly regulate dystrophin protein levels and is affected by inflammatory signaling through NF-kB. The NF-kB family of transcription factors have been directly tied to muscle wasting due to a multitude of causes, pointing towards a common mechanism. Even though it is clear that NF-kB is important in muscle wasting, its transcriptional targets remain largely unknown. Strong preliminary data indicate that miR-31 levels are increased through a specific inflammatory pathway of canonical NF-kB signaling, but can be decreased through atypical NF-kB signaling protecting muscle from contraction-induced injury.These preliminary data provide a strong rationale for more in depth analysis of the role of the canonical and atypical NF-kB signaling in the regulation of miR-31 and dystrophin levels in old muscles. To understand the interplay between inflammation, mIR-31, dystrophin, and muscle function, we will examine how the balance between canonical/atypical NF-kB signaling regulates miR-31 levels, dystrophin protein, muscle strength and contraction-induced injury. This project is a significant step towards direct mechanistic evidence of the relationship between inflammation, oxidative stress and dystrophin loss. We will investigate interventions to enhance muscle force transfer, decrease contraction-induced muscle injury, and prevent muscle wasting. By furthering our understanding of the molecular mechanisms underlying the loss of dystrophin and the subsequent design of appropriate interventions, we aim to improve the quality of life of millions of patients suffering from muscle loss.