IGF-II IS MORE ACTIVE THAN IGF-I IN STIMULATING L6A1 MYOGENESIS - GREATER MITOGENIC ACTIONS OF IGF-I DELAY DIFFERENTIATION

Mitogens are generally thought to inhibit myogenesis, and many cell bi ologists have found it hard to interpret observations that the insulin -like growth factors (IGFs) stimulate both proliferation and different iation of muscle cells in culture. Our previous studies suggested that the Type I IGF receptor mediates these actions. However, IGF-II and i nsulin treatment caused myoblasts to differentiate much more extensive ly, suggesting that more complex mechanisms may be involved. Here we p resent evidence that the greater mitogenic activity of IGF-I (compared to ICF-II and insulin) delays L6A1 myoblast differentiation. Under co nditions in which the mitogenic actions of IGF-I are suppressed, the s timulation of myogenesis by ICF-I approached that by IGF-II: (1) in L6 A1 cultures plated at a higher cell density; (2) in L6A1 cultures in w hich cell proliferation was inhibited by cytosine arabinoside or aphid icolin; and (3) in cultures of primary human muscle cells, which exhib it a smaller mitogenic response to IGF-I. Further evidence that the Ty pe I receptor plays a major role in relaying the signal for differenti ation was obtained by using IGF-I and ICF-II analogs. Analogs which ha ve reduced affinity for the Type I receptor showed a dramatic decrease in activity, while ananalog with increased affinity for the Type II r eceptor was no more active than native IGF-I. Our results indicate tha t both mitogenic and myogenic actions of IGF-I are mediated by the Typ e I receptor. We conclude that IGF-I delays the onset of myogenesis as a result of its mitogenic actions, and only subsequently stimulates m yogenesis. These observations reconcile the apparent conflict between our results with the IGFs and other investigators' reports of effects of other mitogens. (C) 1994 Wiley-Liss, Inc.