Metalloproteinase Expression is Altered in Cardiac and Skeletal Muscle of Cancer Cachexia.
Am J Physiol Heart Circ Physiol. 2015 Jun 19:ajpheart.00106.2015. Epub 2015 Jun 19. PMID: 26092976
Raymond D Devine
Cardiac and skeletal muscle dysfunction is a recognized effect of cancer-induced 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 this study, we utilized 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, -3, -9, and -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 TIMPs. Cardiac muscle showed significant protein increase in MMP-2, -3, -9, and -14, while skeletal muscles showed increases in MMP-2,-3, and -14. Furthermore, collagen deposition was increased after c26 adenocarcinoma-induced cancer cachexia as indicated by an increased LV Picro-sirius 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 treatment of cancer-induced cachexia.