STIMULATION OF MYOGENIC DIFFERENTIATION BY A NEUREGULIN, GLIAL GROWTH-FACTOR 2 - ARE NEUREGULINS THE LONG-SOUGHT MUSCLE TROPHIC FACTORS SECRETED BY NERVES

It has long been known that nerves stimulate growth and maintenance of skeletal muscles in ways not dependent on physical contacts, but nume rous attempts to identify and characterize the myotrophic agent(s) sec reted by nerves have been unsuccessful. We here suggest that products of the neuregulin gene may be these agents. The neuregulins are a fami ly of proteins made by alternative splicing of a single transcript to give as many as 15 protein products. One member of this family, glial growth factor 2 (rhGGF2) is a very potent stimulator of myogenesis in L6A1 myoblasts, giving a maximal stimulation of cell fusion and creati ne kinase elevation at a concentration of 1 ng/ml (18 pM). The stimula tion of myogenesis is not rapid, but it is prolonged, continuing over a period of at least 6 days. The effects of rhGGF2 are additive with t hose of insulin-like growth factor I (IGF-I) or its analog R3-IGF-I, s uggesting that the actions of these two myotrophic agents differ in at least one rate-limiting step. We have observed one possible differenc e; unlike the IGFs, rhGGF2 does not induce elevation of the steady sta te level of myogenin mRNA.