Metalloproteinase expression is altered in cardiac and skeletal muscle in cancer cachexia
Metalloproteinase expression is altered in cardiac and skeletal muscle in cancer cachexia
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DOI：
10.1152/ajpheart.00106.2015
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发表时间：
2015-08-15
影响因子：
4.8
通讯作者：
Wold, Loren E.
中科院分区：
文献类型：
--
作者：
Devine, Raymond D.;Bicer, Sabahattin;Wold, Loren E.
心脏和骨骼肌功能障碍是癌症诱导的恶病质的公认效应，心脏功能的改变导致心力衰竭并对患者发病率产生负面影响。恶病质是一种复杂且多方面的疾病状态，具有导致心脏和骨骼肌功能障碍的几个潜在因素。基质金属蛋白酶（MMP）是能够降解细胞外基质（ECM）组分的酶家族。ECM的变化导致基底膜处细胞之间的连接和细胞间相互作用的破坏。在本研究中，我们使用C26腺癌诱导的癌症恶病质小鼠模型，以确定MMP基因和蛋白表达在心脏和骨骼肌中的变化。我们分析了MMP-2、MMP-3、MMP-9和MMP-14，因为它们已被证明有助于心脏和骨骼肌ECM变化，从而有助于心力衰竭和肌营养不良模型的病理学。在我们的模型中，心肌和骨骼肌中几种基质金属蛋白酶和金属蛋白酶组织抑制剂的RNA和蛋白质水平显着增加。心肌显示MMP-2、MMP-3、MMP-9和MMP-14的蛋白质显著增加，而骨骼肌显示MMP-2、MMP-3和MMP-14增加。此外，C26腺癌诱导的癌性恶病质后胶原沉积增加，如左心室天狼星红染色阳性面积增加所示。血清羟脯氨酸的增加表明胶原蛋白周转增加，涉及骨骼肌重塑。我们的研究结果表明，癌症恶病质相关的基质重塑导致心脏纤维化和可能的骨骼肌重塑。有了这些发现，基质金属蛋白酶代表了一个可能的治疗癌症引起的恶病质的治疗靶点。
Cardiac and skeletal muscle dysfunction is a recognized effect of cancerinduced cachexia, with alterations in heart function leading to heart failure and negatively impacting patient morbidity. Cachexia is a complex and multifaceted disease state with several potential contributors to cardiac and skeletal muscle dysfunction. Matrix metalloproteinases (MMPs) are a family of enzymes capable of degrading components of the extracellular matrix (ECM). Changes to the ECM cause disruption both in the connections between cells at the basement membrane and in cell-to-cell interactions. In the present study, we used a murine model of C26 adenocarcinoma-induced cancer cachexia to determine changes in MMP gene and protein expression in cardiac and skeletal muscle. We analyzed MMP-2, MMP-3, MMP-9, and MMP-14 as they have been shown to contribute to both cardiac and skeletal muscle ECM changes and, thereby, to pathology in models of heart failure and muscular dystrophy. In our model, cardiac and skeletal muscles showed a significant increase in RNA and protein levels of several MMPs and tissue inhibitors of metalloproteinases. Cardiac muscle showed significant protein increases in MMP-2, MMP-3, MMP-9, and MMP-14, whereas skeletal muscles showed increases in MMP-2, MMP-3, and MMP-14. Furthermore, collagen deposition was increased after C26 adenocarcinoma-induced cancer cachexia as indicated by an increased left ventricular picrosirius red-positive-stained area. Increases in serum hydroxyproline suggest increased collagen turnover, implicating skeletal muscle remodeling. Our findings demonstrate that cancer cachexia-associated matrix remodeling results in cardiac fibrosis and possible skeletal muscle remodeling. With these findings, MMPs represent a possible therapeutic target for the treatment of cancer-induced cachexia.