Husi Holger, MacDonald Alisdair, Skipworth Richard J E, Miller Janice, Cronshaw Andrew, Fearon Kenneth C H, Ross James A
Department of Diabetes and Cardiovascular Science, University of the Highlands and Islands, Centre for Health Science, IV2 3JH Inverness, UK.
Department of Clinical Sciences, University of Edinburgh, EH16 4SB Edinburgh, UK.
Biomed Rep. 2018 Jun;8(6):557-564. doi: 10.3892/br.2018.1091. Epub 2018 Apr 25.
Myosteatosis, the infiltration of fat in skeletal muscle, is associated with lower skeletal muscle density (SMD) as detected by computed tomography (CT). It increases with aging and obesity and is thought to play a role in the aetiology of insulin resistance and type II diabetes. The clinical significance of myosteatosis in cancer cachexia, however, remains to be determined. Along with demonstrable subcutaneous and visceral lipolysis, myosteatosis may also be a key component of the syndrome. We aimed to investigate the use of human urine as a non-invasive way to screen for molecular biomarkers of myosteatosis/reduced SMD using SELDI-TOF mass spectrometry. Pre-operative CT scans of patients undergoing surgery for upper gastrointestinal or hepatopancreaticobiliary cancer were analysed at the level of the third lumbar vertebrae. Myosteatosis was inferred as the presence of reduced SMD, which was defined as Hounsfield units for skeletal muscle <39.5 (two standard deviations below a normal healthy cohort). Urine was analysed by mass spectrometry using CM10 and IMAC30 SELDI-chips. Peaks observed in the CM10 and IMAC30 chip types, showed marked expressional differences between control and myosteatosis, were further investigated by mascot SELDI matrix matching. A total of 55 patients was recruited; 31 patients were found to be myosteatotic on CT scan. Application of the IMAC30-derived model to the entire cohort showed a sensitivity of 97%, specificity of 71% and an overall correctness of 85%. Application of the CM10 chipset-based model to the entire cohort, showed a 77% sensitivity, 67% specificity and 73% overall correctness. Analysis of the peaks of interest resulted in the identification of significant fragments of cathepsin C, argin, arylsulfatase A and glial fibrillary acidic protein. We identified several potential urinary molecular biomarkers associated with reduced SMD in cancer. Such markers are potentially useful in deriving a clinical screening test for myosteatosis.
肌脂肪变性，即脂肪在骨骼肌中的浸润，与计算机断层扫描（CT）检测到的较低骨骼肌密度（SMD）相关。它随着衰老和肥胖而增加，并被认为在胰岛素抵抗和II型糖尿病的病因中起作用。然而，肌脂肪变性在癌症恶病质中的临床意义仍有待确定。除了可证实的皮下和内脏脂肪分解外，肌脂肪变性也可能是该综合征的关键组成部分。我们旨在研究使用人尿液作为一种非侵入性方法，通过表面增强激光解吸电离飞行时间质谱（SELDI-TOF MS）筛选肌脂肪变性/降低的SMD的分子生物标志物。对接受上消化道或肝胆胰肿瘤手术的患者术前CT扫描在第三腰椎水平进行分析。肌脂肪变性被推断为存在降低的SMD，其定义为骨骼肌的亨氏单位<39.5（比正常健康队列低两个标准差）。使用CM10和IMAC30 SELDI芯片通过质谱分析尿液。在CM10和IMAC30芯片类型中观察到的峰，在对照和肌脂肪变性之间显示出明显的表达差异，通过Mascot SELDI基质匹配进一步研究。共招募了55名患者；31名患者在CT扫描中被发现有肌脂肪变性。将基于IMAC30的模型应用于整个队列显示敏感性为97%，特异性为71%，总体正确率为85%。将基于CM10芯片组的模型应用于整个队列，显示敏感性为77%，特异性为67%，总体正确率为73%。对感兴趣的峰进行分析导致鉴定出组织蛋白酶C、精氨酸、芳基硫酸酯酶A和胶质纤维酸性蛋白的重要片段。我们鉴定了几种与癌症中降低的SMD相关的潜在尿液分子生物标志物。这些标志物可能有助于推导肌脂肪变性的临床筛查试验。
