title: Metalloproteinase expression is altered in cardiac and skeletal muscle in cancer cachexia.
abstract: 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 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.
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio; Molecular, Cellular and Developmental Biology Graduate Program, The Ohio State University, Columbus, Ohio;
authors.forename: Raymond D
authors.initials: RD
authors.lastname: Devine
authors.affiliation: Division of Biosciences, College of Dentistry, The Ohio State University, Columbus, Ohio;
authors.forename: Sabahattin
authors.initials: S
authors.lastname: Bicer
authors.affiliation: Division of Biosciences, College of Dentistry, The Ohio State University, Columbus, Ohio;
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Reiser
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Rheinische Friedrich-Wilhelms-University, University Medical Center, Bonn, Germany; and.
authors.forename: Markus
authors.initials: M
authors.lastname: Velten
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio; Department of Physiology and Cell Biology, The Ohio State University, Columbus, Ohio; College of Nursing, The Ohio State University, Columbus, Ohio Loren.wold@osumc.edu.
authors.forename: Loren E
authors.initials: LE
authors.lastname: Wold
mesh_terms: D000818:Animals; D002100:Cachexia / Q000209:etiology / Q000378:metabolism*; D005260:Female; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D018482:Muscle, Skeletal / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D009374:Neoplasms, Experimental / Q000150:complications; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D020782:Matrix Metalloproteinases
keywords: cancer cachexia; extracellular matrix; matrix metalloproteinase; tissue inhibitors of matrix metalloproteinase