The endocrine control of animal growth is far more complex than generally presumed. A common model for growth regulation suggests that growth hormone (GH) released from the pituitary gland stimulates the production of insulin-like growth factor (IGF)-I in the liver, which in turn stimulates many of the resulting growth processes. This is known as somatomediation. The model is almost 40 years old and is a ubiquitous feature in Endocrinology textbooks. However, several recent studies suggest alternatively that IGF-I produced locally (e.g. in muscle & bones) is a far more important regulator of growth than is circulating IGF-I, although these studies define growth almost entirely from a bone perspective. The model ignores other regulatory factors (e.g. myostatin) and does not incorporate recent studies suggesting that growth dependency on circulating IGF-I may be a tissue-specific phenomenon. In fact, recent data suggest that myostatin, a potent negative and local regulator of muscle growth, may also inhibit hepatic IGF-I production and that muscle is more dependent upon circulating IGF-I than is bone. A better understanding of somatomediation and how it is influenced by myostatin will help explain this extremely important endocrine concept. The objective of this research project is to determine myostatin's novel endocrine role in negatively regulating somatomediation. The central hypothesis is that myostatin's ability to inhibit striated muscle growth is mediated in part by directly reducing the hepatic production of IGF-I and its bioavailability in circulation. The hypotheses will be tested by pursuing the following three specific aims: (1) determine how myostatin regulates circulating IGF-I, (2) determine how myostatin-regulated liver IGF-I production controls striated muscle growth and (3) determine myostatin's impact on pituitary GH release. Graduate and undergraduate students will perform these studies and will include those from under-represented groups. Results from the studies will be incorporated into courses taught by the principle investigator and will be presented in joint seminars with the Washington Center for Muscle Biology in addition to being broadly disseminated through traditional venues. The studies will also benefit society as a whole through many outreach activities that target K-12 students, their families and the general public.
