IGF-I is a major anabolic hormone for skeletal muscle in vivo. Yet the mechanisms by which GH and cytokines regulate IGF-I expression remain obscure. Lipopolysaccharide (LPS) dramatically alters the circulating concentration of both TNFα and IGF-I, and TNFα in part mediates the cachectic activity of LPS. Little is known about the local synthesis of IGF-I and TNFα in skeletal muscle per se. The purpose of the present study was to determine whether LPS alters the expression of TNFα and IGF-I in mouse skeletal muscle and whether TNFα directly inhibits IGF-I mRNA expression in C2C12 myoblasts. Intraperitoneal injection of LPS in C3H/SnJ mice increased the expression of TNFα protein in plasma (16-fold) and TNFα mRNA in skeletal muscle (8-fold). LPS also decreased the plasma concentration of IGF-I (30%) and IGF-I mRNA in skeletal muscle (50%, between 6 and 18 h after LPS administration). Addition of LPS or TNFα directly to C2C12 myoblasts decreased IGF-I mRNA by 50-80%. The TNFα-induced decrease in IGF-I mRNA was both dose and time dependent and occurred in both myoblasts and differentiated myotubes. TNFα selectively decreased IGF-I but not IGF-II mRNA levels, and the effect of TNFα was blocked by a specific TNF-binding protein. TNFα did not alter IGF-I mRNA levels in the presence of the protein synthesis inhibitor cycloheximide. TNFα did not change the half-life of IGF-I mRNA. TNFα completely prevented GH-inducible IGF-I mRNA expression, but this GH resistance was not attributable to impairment in signal transducer and activator of transcription-3 or -5 phosphorylation. TNFα increased both nitric oxide synthase-II mRNA and protein, and the nitric oxide donor sodium nitro-prusside decreased IGF-I mRNA levels in C2C12 cells. Yet inhibitor studies indicate that nitric oxide did not mediate the effect of TNFα on IGF-I mRNA expression. TNFα stimulated the phosphorylation of c-Jun and specific inhibition of the Jun N-terminal kinase pathway, but not other MAPK pathways, completely prevented the TNFα-induced drop in IGF-I mRNA. These data suggest that LPS stimulates TNFα expression in mouse skeletal muscle and autocrine-derived cytokines may contribute to the reduced expression of IGF-I in this tissue.
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