Regulation of Growth Factors and Cytokines in Skeletal Muscle and Muscle CellsGrowth hormone (GH) and insulin-like growth factor-I (IGF-I) are potent regulators of muscle mass. Transgenic mice that over- express these proteins exhibit dramatically enlarged skeletal muscles. In contrast, malnutrition, critical illness, sepsis, and aging are all associated with a dramatic reduction in muscle mass and function. The circulating concentration of IGF-I and the expression of IGF-I in skeletal muscle are also reduced during catabolic states. Consequently, GH has been used clinically to increase lean body mass in patients with muscle wasting. Likewise, delivery of IGF-I specifically into skeletal muscle has been proposed as a genetic therapy for muscle disorders. A better understanding of the regulation of endogenous IGF-I in skeletal muscle and muscle cells is therefore of importance.
One hypothesis is that skeletal muscle itself synthesizes inflammatory cytokines that down regulate the expression of IGF-I and that this alters the accretion of lean body mass. Recently we have demonstrated that LPS-stimulates cytokine expression in mouse skeletal muscle via Toll-like receptor-4 (TLR-4) signaling. Mice that harbor a mutation in TLR-4 have a greatly reduced expression of cytokine mRNAs in skeletal muscle in response to LPS. Our laboratory has shown that human and mouse myoblasts express a variety of LPS-responsive mRNAs including: IL-6, IL-1, IL-1Ra, IL-12, and TNF. Since myoblasts also express cytokines in response to peptidoglycan from the cell wall of the Gram-positive bacteria a number of pathogen-associated molecules may influence muscle cytokine expression.
Because LPS alters the local expression of TNF and IGF-I in mouse skeletal muscle we examined whether TNF directly inhibits IGF-I mRNA expression in C2C12 myoblasts. Addition of LPS or TNF directly to C2C12 myoblasts decreased IGF-I mRNA by 50-80%. The TNF-induced decrease in IGF-I mRNA was both dose- and time-dependent and occurred in both myoblasts and differentiated myotubes. TNF also completely prevented GH-inducible IGF-I mRNA expression and thus this system is being used to study the mechanism of GH resistance that occurs during catabolic conditions. | 
