SIRT1 Protein, by Blocking the Activities of Transcription Factors FoxO1 and FoxO3, Inhibits Muscle Atrophy and Promotes Muscle Growth
SIRT1 Protein, by Blocking the Activities of Transcription Factors FoxO1 and FoxO3, Inhibits Muscle Atrophy and Promotes Muscle Growth
复制标题
DOI：
10.1074/jbc.m113.489716
复制
发表时间：
2013-10-18
影响因子：
4.8
通讯作者：
Goldberg, Alfred L.
中科院分区：
文献类型：
--
作者：
Lee, Donghoon;Goldberg, Alfred L.
在几种细胞类型中，蛋白去乙酰化酶SIRT1调节FoxO转录因子的活性，FoxO转录因子的激活在肌肉萎缩中至关重要。然而，SIRT1对骨骼肌中FoxOs活性和肌肉大小调节的可能影响尚未被研究。在这里，我们表明，在食物剥夺后，II型骨骼肌（胫骨前肌）的SIRT1水平急剧下降，表现出明显的萎缩，这与肝脏（SIRT1上升）、心脏或比目鱼肌（SIRT1不变）不同。通过电穿孔在小鼠肌肉中维持高水平的SIRT1显著抑制由禁食和去神经支配引起的肌肉萎缩，而这些保护作用需要其去乙酰化酶活性。SIRT1过表达通过阻断fox01和fox03的激活来减少肌肉萎缩。因此，它阻止了关键atrogenes的诱导，包括肌肉特异性泛素连接酶atrogin1和MuRF1，以及多种自噬（Atg）基因，并阻止了整体蛋白水解的增加。在正常肌肉中，SIRT1通过电穿孔过表达导致纤维快速肥大，而PI3K-AKT信号通路却没有被激活。因此，SIRT1激活有利于出生后的肌肉生长，其下降似乎对禁食期间的肌肉萎缩至关重要。因此，SIRT1激活代表了一种有吸引力的可能的药理学方法来防止肌肉萎缩和恶病质。
In several cell types, the protein deacetylase SIRT1 regulates the activities of FoxO transcription factors whose activation is critical in muscle atrophy. However, the possible effects of SIRT1 on the activity of FoxOs in skeletal muscle and on the regulation of muscle size have not been investigated. Here, we show that after food deprivation, SIRT1 levels fall dramatically in type II skeletal muscles (tibialis anterior), which show marked atrophy, unlike in the liver (where SIRT1 rises) or heart or the soleus, a type I muscle (where SIRT1 is unchanged). Maintenance of high SIRT1 levels by electroporation in mouse muscle inhibits markedly the muscle wasting induced by fasting as well as by denervation, and these protective effects require its deacetylase activity. SIRT1 overexpression reduces muscle wasting by blocking the activation of FoxO1 and 3. It thus prevents the induction of key atrogenes, including the muscle-specific ubiquitin ligases, atrogin1 and MuRF1, and multiple autophagy (Atg) genes and the increase in overall proteolysis. In normal muscle, SIRT1 overexpression by electroporation causes rapid fiber hypertrophy without, surprisingly, activation of the PI3K-AKT signaling pathway. Thus, SIRT1 activation favors postnatal muscle growth, and its fall appears to be critical for atrophy during fasting. Consequently, SIRT1 activation represents an attractive possible pharmacological approach to prevent muscle wasting and cachexia.