The Growth Hormone/IGF-1 Axis in Skeletal Muscle

描述（由申请人提供）：哺乳动物骨骼肌通过单个成肌细胞相互融合形成多核合胞体的过程发育和再生。生长激素（GH）一直被认为是正常肌肉发育和再生所需的关键合成代谢因子。生长激素治疗提高了人类和动物的肌肉力量，减少了身体脂肪。此外，运动产生的肌肉质量和力量的增加伴随着生长激素(GH)/胰岛素样生长因子1 （IGF-1）轴活性的显著增加。相反，随着年龄的增长，人体经历的生理变化，包括肌肉减少症，与生长激素缺乏症中观察到的相似。然而，生长激素对骨骼肌产生影响的机制仍然知之甚少。在骨骼肌和其他靶组织中，生长激素可以通过激活其同源受体（GHR）的信号而独立于IGF-1发挥作用。另外，生长激素可以通过刺激IGF-1的产生间接发挥作用。在这种模式下，IGF-1与IGF-1 I型受体（IGF-1R）结合，引起下游途径的激活，从而诱导骨骼肌的合成代谢活性。生长激素和IGF-1之间的密切关系使得几乎不可能区分这些生长因子在靶组织中的作用。最近，我们在小鼠身上设计了一种遗传方法，可以选择性地破坏GH/IGF-1轴的单个成分。使用这种策略，我们证明了GHR是正常骨骼肌发育所绝对需要的，并提供了GH通过增强成肌细胞融合来增加肌肉组织质量的新证据。此外，在本提案中，我们提出了新的数据，表明骨骼肌中的生长激素作用可能产生额外的激素信号，使肌肉和脂肪之间的串扰能够协调全球能量消耗和调节身体成分。在这个项目中，我们将(1)定义生长激素在骨骼肌中的基本作用，(2)确定生长激素在骨骼肌中的作用模式，并确定其与IGF-1的关系。这些目的是利用互补遗传小鼠模型及其成肌细胞来确定生长激素在骨骼肌中的作用机制，并区分生长激素与IGF-1介导的作用。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.