Regulation of the Insulin-Like Growth Factor (IGF) System During Catabolic Conditions

The mechanisms responsible for the muscle wasting that accompanies infection are poorly defined. Although inflammatory cytokines, such as TNF, IL-1 and IL-6, have been suggested as mediators of the enhanced muscle catabolism, it is unlikely that these cytokines act directly at the tissue level. Insulin-like growth factor (IGF)-I is a key endogenous anabolic hormone which can directly reduce proteolysis and enhance protein synthesis. Studies from our laboratory indicate that trauma, infection and endotoxin as well as exogenous administration of either TNF or IL-1 are capable of modulating various elements of the IGF system in the circulation and in muscle. Studies in the laboratory attempt to integrate mechanisms of action from the cellular level to the whole animal or person. In vivo studies are conducted to determine the role of cytokines and hormonal mediators in mediating the sepsis-induced changes in the growth hormone (GH)-IGF axis. In addition, in vitro studies are on-going that examine the potency of TNF, IL-1 and IL-6 on gene expression and secretion of IGF-I and IGF binding proteins in cultured hepatocytes and Kupffer cells. Moreover, the ability of cytokines to antagonize the anabolic actions of IGF-I on skeletal muscle protein synthesis and protein breakdown in cell culture is also being examined.

The second line of investigation in the laboratory involves elucidating the mechanism by which alcohol alters both the hepatic production of IGF-I and IGF binding protein-1, and how these changes work in concert to contribute to the muscle wasting associated with chronic alcohol consumption. These studies involve the use of rodent models of acute and chronic alcoholism, and the study of the GH-IGF axis using both in vivo and in vitro techniques. Our long-term goal in these studies is to better understand the mechanism for the alterations in muscle protein balance that remains a major cause of morbidity and mortality in patients with a history of chronic alcohol abuse.