Sialic acid has putative signaling roles in muscle disorders of aging

描述（由申请人提供）：散发性包涵体肌炎（sIBM）是最常见的与衰老相关的获得性肌肉疾病。sIBM折磨50岁以上的个体。当肌肉无力逐渐发展时，疾病是无情地进行性的，导致远端和近端肌肉的严重萎缩和严重无力。受影响的人在发病后5-10年内坐轮椅。患者肌肉活检的病理分析揭示了两种病理：（1）炎性细胞浸润和（2）肌肉退行性变化，包括边缘空泡形成、蛋白质聚集体夹杂物和肌纤维分解。尽管有这些知识，但导致肌肉退化和肌肉无力的确切致病级联反应仍知之甚少。此外，sIBM的炎症和退行性成分之间的关系仍然是一个谜。因此，sIBM没有有效的治疗方法。唾液酸生物合成失调与包涵体肌病（IBM）发病机制有关。遗传性包涵体肌病（hIBM）是一种常染色体隐性遗传性疾病，其编码的酶催化唾液酸生物合成的第一个关键步骤，在HIBM患者中发现了UDP-N-乙酰葡糖胺-2-差向异构酶/N-乙酰甘露糖胺激酶基因（GNE）的突变。hIBM的病理学与sIBM相似。此外，像sIBM一样，hIBM是一种衰老疾病;尽管在出生时有一个突变基因，但在GNE中携带hIBM突变的人在达到一定年龄之前不会出现肌肉无力，通常是20多岁。了解GNE突变和随后的唾液酸稳态破坏如何影响转录和信号传导网络，将有助于深入了解IBM中失调的途径。本提案的目的1是确定唾液酸作为信号分子的能力。这将揭示IBM肌肉中失调的途径。目的2是确定作为信号分子的唾液酸代谢物，并发现作为唾液酸传感器的蛋白质。这项工作的结果将揭示IBM疾病的新治疗靶点。目的3是确定唾液酸信号转导对亚细胞定位的依赖性。总之，这些实验将揭示糖代谢的新作用，并为IBM这一常见的毁灭性疾病提供机制性见解。

DESCRIPTION (provided by applicant): Sporadic inclusion body myositis (sIBM) is the most common acquired muscle disease associated with aging. sIBM afflicts individuals older than 50 years of age. While muscle weakness develops gradually, the disease is relentlessly progressive, leading to gross atrophy and severe weakness of both the distal and proximal muscles. Afflicted individuals are wheelchair bound within 5-10 years of onset. Pathologic analyses of patient muscle biopsies reveal two pathologies: (1) infiltration of inflammatory cells and (2) muscle degenerative changes consisting of rimmed vacuole formation, protein aggregate inclusions, and myonuclear breakdown. Despite this knowledge, the exact pathogenic cascade that leads to muscle degeneration and muscle weakness is poorly understood. Furthermore, the relationship between the inflammatory and degenerative components of sIBM remains a mystery. As a result, no effective treatment for sIBM exists. Dysregulation of sialic acid biosynthesis is implicated in inclusion body myopathy (IBM) pathogenesis. Mutations in UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase gene (GNE), which encodes the enzyme that catalyzes the first committed step of sialic acid biosynthesis, have been found in patients suffering from hereditary inclusion body myopathy (hIBM), an autosomal recesive disease. The pathology of hIBM mimics sIBM. Additionally, like sIBM, hIBM is a disease of aging; despite having a mutant gene at birth, humans harboring hIBM mutations in GNE do not develop muscle weakness until they reach a certain age, typically their mid-20s. Understanding how mutations in GNE and subsequent disruption of sialic acid homeostasis affects transcriptional and signaling networks will provide insight into pathways dysregulated in IBM. Aim 1 of this proposal is to ascertain the ability of sialic acid to act as a signaling molecule. This will reveal pathways dysregulated in IBM muscle. Aim 2 is to determine the sialic acid metabolite(s) that is acting as a signaling molecule and to discover the protein that is acting as a sialic acid sensor. The results of this work will reveal new therapeutic targets for IBM disease. The purpose of aim 3 is to determine the dependence of sialic acid signaling on subcellular localization. Taken together, these experiments will reveal novel roles for sugar metabolism and provide mechanistic insight into IBM, a common, devastating disease.