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

肌肉的力量和功能严重影响人类的生活质量和寿命。年龄和慢性病导致肌肉萎缩，这种肌肉质量和力量的丧失直接与疾病结局、残疾和死亡率负相关。目前还没有治疗肌肉萎缩的药物。其他对策，如锻炼，对老化和患病的肌肉不太有效，因为它们更容易因收缩而导致肌肉损伤，导致恢复不足。这种对肌肉损伤的敏感性与肌营养不良蛋白的丧失直接相关，肌营养不良蛋白是一种将肌肉纤维的细胞骨架与细胞外基质联系起来的基本结构蛋白。营养不良蛋白在先天性疾病中的丢失，以及与年龄和非先天性人类疾病中的丢失，都与显著的炎症和氧化成分有关。针对抗氧化机制的干预能够部分恢复营养不良蛋白。衰老、炎症和氧化对肌营养不良蛋白水平的影响的分子机制仍然知之甚少。最近，特异减少dystrophin翻译(Dystromir)的microRNAs(MiRs)已被发现。加州大学的Baar实验室最近发现，其中一种miR(miR-31)在衰老的肌肉中升高了6倍以上，可以直接调节dystrophin蛋白水平，并通过核因子-kB受到炎症信号的影响。由于多种原因，核因子-kB转录因子家族被直接与肌肉萎缩联系在一起，这指向了一个共同的机制。尽管很明显，核因子-kB在肌肉萎缩中是重要的，但它的转录靶标在很大程度上仍然不清楚。强有力的初步数据表明miR-31的水平通过典型的核因子-kB信号的特定炎症途径而升高，但可以通过非典型的核因子-kB信号来降低，以保护肌肉免受收缩诱导的损伤。这些初步数据为更深入地分析规范和非典型的核因子-kB信号在老年肌肉中miR-31和dystrophin水平的调节中的作用提供了强有力的理论基础。为了了解炎症、mir-31、dystrophin和肌肉功能之间的相互作用，我们将研究规范/非典型NF-kB信号之间的平衡如何调节miR-31水平、dystrophin蛋白、肌肉力量和收缩诱导的损伤。这个项目是朝着炎症、氧化应激和肌营养不良蛋白丢失之间的关系的直接机制证据迈出的重要一步。我们将研究加强肌肉力量转移、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dystrophin丢失的分子机制，并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.