ROLE OF ANGIOTENSIN II IN SKELETAL MUSCLE HYPERTROPHY

促进骨骼肌生长与医疗条件极其相关，在这些医疗条件下，肌肉萎缩会导致生活质量低下，并因制度化而导致医疗费用高昂。提出的研究将探讨血管紧张素II （AII）积极介导负荷诱导的骨骼肌肥大的可能性。这种现象发生在心肌中，但在骨骼肌组织中是一个全新的发现。利用大鼠骨骼肌肥厚的增效剂消融模型，本实验将确定：1)AII肽及其前体在骨骼肌中响应负荷增加而上调，2)通过抑制血管紧张素转换酶（ACE）抑制AII的产生以防止负荷诱导的骨骼肌肥厚，以及3)AII受体是否存在于骨骼肌中。有希望的试点数据表明，ACE抑制可以在该模型中减轻至少46%的肥厚。此外，研究人员还提出了测量包括局灶黏附激酶和血清反应因子在内的aii反应性细胞内信号通路的方法，这两种信号通路对于负荷诱导的骨骼肌肥大也是必需的。识别促进骨骼肌生长的新激素机制可能会导致药物，基因药物或其他对抗骨骼肌萎缩的对策。

Promoting skeletal muscle growth is extremely relevant to medical conditions in which muscle wasting contributes to low quality of life and high health care costs due to institutionalization. The proposed research would explore the possibility that angiotensin II (AII) positively mediates loading-induced skeletal muscle hypertrophy. This phenomenon occurs in cardiac muscle, but would be a completely novel finding in skeletal muscle tissue. Using the synergist ablation model of skeletal muscle hypertrophy in rats, the present experiment would determine if: 1) AII peptide and its precursors are up-regulated in skeletal muscle in response to increased loading, 2) inhibition of AII production by inhibiting angiotensin converting enzyme (ACE) prevents loading-induced skeletal muscle hypertrophy, and 3) AII receptors are present in skeletal muscle. Promising pilot data indicate that ACE inhibition may attenuate hypertrophy by at least 46 percent in this model. It is also proposed to measure an AII-responsive intracellular signaling pathway involving focal adhesion kinase and serum response factor, both of which are also necessary for loading-induced skeletal muscle hypertrophy. Identification of novel hormonal mechanisms promoting skeletal muscle growth may lead to drugs, gene medicine, or other countermeasures against skeletal muscle wasting.