Metalloproteinase expression is altered in cardiac and skeletal muscle in cancer cachexia

Abstract

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.

Signaling pathways underlying skeletal muscle wasting in experimental pulmonary arterial hypertension

“…Zymography analysis of gastrocnemius evidenced a significant increase of proteolytic activity with contribution of MMPs. The activation of MMP-2 and MMP-9 in skeletal muscle was previously reported in atrophic conditions(37), and associated with the disruption of the connections between cells at the basement membrane and of cell-to-cell interactions(38). Data supports an increased expression and activity of MMP-2 in PAH-related muscle wasting, though without the participation of MMP-9, in opposition to what happened in bladder cancer-related muscle wasting(15).…”

Minocycline attenuates cardiac dysfunction in tumor-burdened mice

“…In previous studies it has been shown that there is increased collagen deposition in the hearts of c26 tumor-bearing mice through Picrosirius red staining [14]. The study did not examine the RNA expression of collagen, which we examined in this study.…”

“…The gel was transferred onto a PVDF membrane using a wet transfer system (Bio-Rad, Hercules, CA) that was run at room temperature for 90 minutes at 100 V. The membranes were blocked for 1 hour at room temperature with a TBS-T solution containing 5% Bovine Serum Albumin (BSA). The primary antibody was suspended at the same concentration as previously [14] used and incubated overnight at 4°C. The membrane was washed in TBST in triplicate for five minutes, then secondary antibody was applied at a concentration of 1:5000 in TBST containing 2.5% BSA for an hour at room temperature.…”

“…This insufficient response leads to MMP-mediated collagen deposition in the heart presenting as fibrosis which can compromise heart structure and negatively impact function. While MMP levels were increased in the c26 cachectic mouse model [14], the degree in which they participate in remodeling remain unknown. In order to determine how increased MMP activity could lead to altered function, we utilized a known inhibitor of MMPs, minocycline.…”

Adipose tissue: between the extremes

“…MMP-2, MMP-3, and MMP-14, which degrade components of the ECM and are associated with pathology in models of heart failure and muscular dystrophy, have been shown to be induced in cardiac and skeletal muscle in the Colon26 mouse model of cancer cachexia (Devine et al, 2015). Cardiac fibrosis is also noted.…”