Mammalian skeletal muscle develops and regenerates through a process in which individual myoblasts fuse with one another to create a multinucleated syncytium. Growth hormone (GH) has long been recognized as a critical anabolic factor required for normal muscle development and regeneration. GH treatment improves muscle strength and reduces body fat in humans and animals. Moreover, increases in muscle mass and strength produced with exercise are accompanied by profound increases in the activity of the growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis. Conversely, the physiological changes that the human body undergoes with aging including sarcopenia resemble those observed in GH deficiency. However, the mechanisms through which GH produces its effects on skeletal muscle are still poorly understood. In skeletal muscle and other target tissues, GH can function independent of IGF-1 by activating signaling of its cognate receptor (GHR). Alternatively, GH can function indirectly through stimulating production of IGF-1. In this mode, IGF-1 binds to the IGF-1 type I receptor (IGF-1R) causing activation of downstream pathways which also induce anabolic activity in skeletal muscle. The close relationship between GH and IGF-1 has made it virtually impossible to distinguish actions of each of these growth factors in target tissues. Recently, we have devised a genetic approach in mice which enables selective disruption of individual components of the GH/IGF-1 axis. Using this strategy we demonstrated that GHR is absolutely required for normal skeletal muscle development and provide new evidence that GH increases muscle tissue mass by enhancing myoblast fusion. Moreover, in this proposal, we present new data which suggests that GH actions in skeletal muscle may generate additional hormonal signals that enable cross talk between muscle and fat to orchestrate global energy expenditure and regulate body composition. In this project, we will (1) define essential actions of GH in skeletal muscle and (2) identify the mode of GH action in skeletal muscle and determine its relationship to IGF-1.
These aims employ complementary genetic mouse models and their myoblasts to identify the mechanisms and of action of GH in skeletal muscle and distinguish effects of GH from those mediated by IGF-1.
The project will investigate how two important growth factor (insulin like growth factor 1 and growth hormone) work to control muscle growth. Distinguishing the actions of GH from those of IGF-1 in muscle cells during postnatal development should ultimately facilitate the development of more specific and effective therapies with these two molecules.
|Dewan, Ashvin K; Tomlinson, Ryan E; Mitchell, Stuart et al. (2015) Dysregulated TGF-? signaling alters bone microstructure in a mouse model of Loeys-Dietz syndrome. J Orthop Res 33:1447-54|
|Gan, Yujun; Zhang, Yue; Buckels, Ashiya et al. (2013) IGF-1R modulation of acute GH-induced STAT5 signaling: role of protein tyrosine phosphatase activity. Mol Endocrinol 27:1969-79|
|Bonewald, Lynda F; Kiel, Douglas P; Clemens, Thomas L et al. (2013) Forum on bone and skeletal muscle interactions: summary of the proceedings of an ASBMR workshop. J Bone Miner Res 28:1857-65|
|DiGirolamo, Douglas J; Clemens, Thomas L; Kousteni, Stavroula (2012) The skeleton as an endocrine organ. Nat Rev Rheumatol 8:674-83|