Witt Christian C, Witt Stephanie H, Lerche Stefanie, Labeit Dietmar, Back Walter, Labeit Siegfried
Institute of Anesthesiology and Intensive Care, Universitätsklinikum Mannheim, Mannheim, Germany.
EMBO J. 2008 Jan 23;27(2):350-60. doi: 10.1038/sj.emboj.7601952. Epub 2007 Dec 20.
The muscle-specific RING finger proteins MuRF1 and MuRF2 have been proposed to regulate protein degradation and gene expression in muscle tissues. We have tested the in vivo roles of MuRF1 and MuRF2 for muscle metabolism by using knockout (KO) mouse models. Single MuRF1 and MuRF2 KO mice are healthy and have normal muscles. Double knockout (dKO) mice obtained by the inactivation of all four MuRF1 and MuRF2 alleles developed extreme cardiac and milder skeletal muscle hypertrophy. Muscle hypertrophy in dKO mice was maintained throughout the murine life span and was associated with chronically activated muscle protein synthesis. During ageing (months 4-18), skeletal muscle mass remained stable, whereas body fat content did not increase in dKO mice as compared with wild-type controls. Other catabolic factors such as MAFbox/atrogin1 were expressed at normal levels and did not respond to or prevent muscle hypertrophy in dKO mice. Thus, combined inhibition of MuRF1/MuRF2 could provide a potent strategy to stimulate striated muscles anabolically and to protect muscles from sarcopenia during ageing.
肌肉特异性环状结构域蛋白MuRF1和MuRF2被认为可调节肌肉组织中的蛋白质降解和基因表达。我们通过使用基因敲除（KO）小鼠模型来测试MuRF1和MuRF2在肌肉代谢中的体内作用。单基因敲除MuRF1和MuRF2的小鼠健康且肌肉正常。通过使所有四个MuRF1和MuRF2等位基因失活获得的双基因敲除（dKO）小鼠出现了严重的心脏肥大和较轻的骨骼肌肥大。dKO小鼠的肌肉肥大在整个小鼠寿命期内持续存在，并且与慢性激活的肌肉蛋白质合成有关。在衰老过程中（4 - 18个月），与野生型对照相比，dKO小鼠的骨骼肌质量保持稳定，而体脂含量没有增加。其他分解代谢因子，如MAFbox/atrogin1，在dKO小鼠中以正常水平表达，并且对肌肉肥大没有反应或不能阻止肌肉肥大。因此，联合抑制MuRF1/MuRF2可能提供一种有效的策略，以促进横纹肌的合成代谢，并在衰老过程中保护肌肉免受肌肉减少症的影响。
