TNF and Interferon-Gamma Target Myosin Heavy Chain in Cancer Cachexia

Abstract

The often-fatal muscle wasting that accompanies many types of cancer is not simply a loss of muscle proteins generally, but seems to occur through a selective loss of particular muscle proteins, according to new research.The study, led by Ohio State University cancer researchers, showed that muscle wasting, also known as cachexia, results in the specific degradation of a protein known as myosin heavy chain (MyHC), which makes up 40 percent of the protein inside muscle cells that are responsible for muscle contraction."The finding gives us new insight into how the mechanism of muscle wasting, something that is still poorly understood," says Denis C. Guttridge, assistant professor of molecular virology, immunology and medical genetics, and a researcher with The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute."This study tells us that cachexia does not simply result from a general reduction of muscle proteins, but instead results from the loss of selective proteins affected during wasting. This in turns means there may be key proteins, such as myosin, that if rescued might allow us to preserve the muscle mass and prevent the process. It opens the door to possible future treatments."To the researchers' surprise, the study also suggested that the loss of muscle proteins can occur through at least two different molecular mechanisms. The findings were published in a recent issue of the Journal of Clinical Investigation.Cachexia occurs in several life-threatening diseases, including certain cancers, AIDS, congestive heart failure and the blood infection known as sepsis. Wasting can occur in late-stage cancers of the lung, pancreas and upper digestive system. It is thought to be responsible for about 30 percent of cancer deaths, Guttridge says. Unlike starvation, which depletes fat stores but leaves muscle tissue alone, wasting results in the loss of both fat and skeletal muscle.Currently, muscle wasting is thought to be caused by a general loss of muscle protein. The loss is thought to be triggered by certain signaling molecules produced by immune-system cells, and by cancer cells. These wasting-related signaling molecules belong to a class of molecules known as cytokines and include tumor necrosis factor (TNF) and interferon (IFN)-gamma.The study by Guttridge and his colleagues sought to identify the proteins inside muscle cells that are targeted by TNF and IFN-gamma. The investigators examined four core proteins involved in muscle contraction -- actin, myosin, troponin and tropomyosin - and specifically asked whether muscle wasting causes the loss of some or all four of those proteins.The researchers studied the question three different ways: by applying TNF and IFN-gamma to muscle cells growing in laboratory culture, by injecting mice with TNF and IFN-gamma-producing immune cells and by using mice carrying a human tumor. Muscle tissue was removed from the mice and analyzed for changes in the levels of the four proteins. In all three cases, only the MyHC protein was affected.However, says Guttridge, "We were surprised to find that different mechanisms could lead to the loss of the myosin protein, perhaps depending on which signal induced the wasting."Generally, Guttridge says, muscle proteins are lost through a process that first tags the proteins for destruction by enzymes that later cut them up. That's how the MyHC molecules were destroyed in the cultured muscle cells. In muscle removed from mice, however, MyHC levels fell because the TNF and IFN-gamma blocked the cell's ability to make the protein.Overall, Guttridge says, "Our data strongly suggest that signaling molecules like TNF and IFN-gamma do not cause muscle wasting by triggering a general loss of muscle proteins, but rather that they selectively target certain proteins, one of which is myosin heavy chain protein."Other OSU researchers involved in this study were Swarnali Acharyya, Katherine J. Ladner, Jeffrey Damrauer and Steven Swoap.Funding from the National Cancer Institute and the V Foundation supported this research.The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute encompasses six interdisciplinary research programs and more than 200 investigators. The OSU CCC - James is a founding member of the National Comprehensive Cancer Network; its investigators conduct research on the prevention, detection, diagnosis and treatment of cancer, generating over $95 million annually in external funding; OSU's James Cancer Hospital is consistently ranked by U.S. News & World Report as one of America's best cancer hospitals.