SKELETAL-MUSCLE CELL-DERIVED INSULIN-LIKE GROWTH-FACTOR (IGF) BINDING-PROTEINS INHIBIT IGF-I-INDUCED MYOGENESIS IN RAT L6E9 CELLS

The insulin-like growth factors (IGFs) stimulate the differentiation o f skeletal muscle cells. IGF binding proteins (IGFBPs), which are expr essed by skeletal muscle cells, may enhance or inhibit IGF actions. To explore the role of skeletal muscle-derived IGFBPs in IGF-induced myo genesis, we compared the differentiation-inducing effects of IGF-I and des(1-3)IGF-I in rat L6E9 skeletal myoblasts. Des(1-3)IGF-I is a natu rally occurring IGF-I analog with markedly reduced affinity for IGFBPs but with an affinity for the IGF-I receptor that is comparable to tha t for native IGF-I. We find that rat L6E9 cells produce principally IG FBP-4 and BP-6, with a minor component of IGFBP-5. Both IGFBP-4 and BP -6 accumulate during differentiation and increase further in response to IGF-I or des(1-3)IGF-I treatment. We find that an IGF-I analog with reduced affinity for IGFBPs is significantly more potent than native IGF-I in stimulating myogenesis (as assessed by myogenin messenger RNA abundance and muscle creatine kinase activity), indicating that IGFBP s expressed by skeletal muscle cells inhibit differentiation induced b y IGF-I. In view of the relative abundance of IGFBP-4, its relatively high affinity for IGF-I and the low affinity of IGFBP-6 for IGF-I, it is likely that the inhibitory effect of rat skeletal muscle-derived IG FBPs on IGF-I-induced myogenesis is mediated principally by IGFBP-4.