ROLE FOR CYCLIC ADENOSINE-MONOPHOSPHATE IN MODULATING INSULIN-LIKE-GROWTH-FACTOR BINDING-PROTEIN SECRETION BY MUSCLE-CELLS

The modulation of insulin-like growth factor-binding protein (IGFBP) s ecretion is an important variable affecting muscle cell metabolism, pr oliferation, and differentiation. We have previously shown that secret ion of IGFBP-4 and IGFBP-5 by L6 and BC3H-1 muscle cells was stimulate d by treatment with either insulin, IGF-I, or IGF-II. Herein, these ce lls were used to further identify mechanisms involved in controlling I GFBP secretion. Agents that elevate intracellular cl?MP concentrations (dcAMP, forskolin, isoproterenol, and prostaglandin [PGE(1)]) increas e secretion of IGFBP-4 and IGFBP-5 from L6 cells. Similar increases in IGFBP secretion were found by treatment with either insulin, IGF-I, o r dcAMP. The effects of dcAMP and either insulin or IGF-I were additiv e, but the effects of insulin and IGF-I were not additive. These resul ts suggest that insulin/IGF-I and dcAMP are acting via distinct mechan isms to stimulate IGFBP secretion. Indomethacin, which blocks endogeno us prostaglandin synthesis, and progesterone, which decreases intracel lular cAMP levels, decreased IGFBP-4 and IGFBP-5 secretion. IGFBP-5 se cretion by BC3H-1 cells was increased by either insulin or IGF-I. Agen ts which elevate intracellular cAMP concentrations did not increase IG FBP-5 secretion. Additionally, these agents were not synergistic with either insulin or IGF-I. However, indomethacin and progesterone depres sed IGFBP-5 secretion by BC3H-1 cells. In summary, there appear to be at least two intracellular signaling mechanisms controlling IGFBP-4 an d IGFBP-5 secretion by L6 and BC3H-1 muscle cells. IGFBP secretion by L6 cells is stimulated by both insulin/IGF-I and cAMP-dependent pathwa ys, whereas IGFBP-5 secretion by BC3H-1 cells is stimulated only by th e insulin/IGF pathway. IGFBP secretion by both cell lines can be decre ased by agents which depress cAMP levels. Our results suggest that two divergent but synergistic pathways modulate IGFBP production and thes e mechanisms can potentially modulate IGF activity during muscle cell proliferation and differentiation. (C) 1998 Wiley-Liss, Inc.