ROLE OF ANGIOTENSIN II IN SKELETAL MUSCLE HYPERTROPHY

促进骨骼肌生长与医疗条件极其相关，在这种情况下，肌肉萎缩会导致低生活质量和因制度化而导致的高医疗费用。这项拟议的研究将探索血管紧张素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，但在骨骼肌组织中将是一个全新的发现。利用大鼠骨骼肌肥大的协同消融模型，本实验将确定：1)AII肽及其前体在骨骼肌中是否随着负荷的增加而上调，2)通过抑制血管紧张素转换酶(ACE)抑制AII的产生来防止负荷诱导的骨骼肌肥大，以及3)骨骼肌中是否存在AII受体。有希望的试验数据表明，在这个模型中，ACE抑制可以至少减轻46%的肥厚。此外，还建议检测AII反应的细胞内信号通路，包括粘着斑激酶和血清反应因子，这两个信号通路对于负荷诱导的骨骼肌肥大也是必要的。识别促进骨骼肌生长的新的激素机制可能导致药物、基因药物或其他针对骨骼肌萎缩的对策。

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.