Insulin and Insulin-Like Growth Factor 1 Signaling Preserves Sarcomere Integrity in the Adult Heart.
Insulin and Insulin-Like Growth Factor 1 Signaling Preserves Sarcomere Integrity in the Adult Heart.
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DOI：
10.1128/mcb.00163-22
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发表时间：
2022-10-20
影响因子：
5.3
通讯作者：
中科院分区：
文献类型：
--
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胰岛素和胰岛素样生长因子 1 (IGF1) 信号传导由胰岛素受体底物 1 (IRS1) 和 IRS2 转导。为了阐明胰岛素和 IGF1 信号在成年心脏中的生理作用和冗余作用，我们培育了具有可诱导心肌细胞特异性缺失胰岛素和 IGF1 受体或 IRS1 和 IRS2 的小鼠。两种模型均出现扩张型心肌病，大多数小鼠在基因删除后 8 周死亡。心力衰竭的特点是心肌细胞丢失和混乱、促凋亡信号传导增加以及自噬增加。通过激活 mTOR 信号传导抑制自噬并不能预防心力衰竭。转录分析显示，早在基因删除后 3 天，血清反应因子 (SRF) 转录活性降低，编码肌节和间隙连接蛋白的基因 mRNA 水平降低，这与基因删除后 1 周内肌节破坏和闰盘的超微结构证据一致。这些数据证实了组成型胰岛素和 IGF1 信号在抑制成人心脏自噬和细胞凋亡信号中的保守作用。本研究还发现胰岛素和 IGF1 信号在调节 SRF 介导的转录程序中发挥着意想不到的作用，该程序维持编码蛋白质的基因表达，支持成人心脏中肌节的完整性，其减少会导致心力衰竭的快速发展。
Insulin and insulin-like growth factor 1 (IGF1) signaling is transduced by insulin receptor substrate 1 (IRS1) and IRS2. To elucidate physiological and redundant roles of insulin and IGF1 signaling in adult hearts, we generated mice with inducible cardiomyocyte-specific deletion of insulin and IGF1 receptors or IRS1 and IRS2. Both models developed dilated cardiomyopathy, and most mice died by 8 weeks post-gene deletion. Heart failure was characterized by cardiomyocyte loss and disarray, increased proapoptotic signaling, and increased autophagy. Suppression of autophagy by activating mTOR signaling did not prevent heart failure. Transcriptional profiling revealed reduced serum response factor (SRF) transcriptional activity and decreased mRNA levels of genes encoding sarcomere and gap junction proteins as early as 3 days post-gene deletion, in concert with ultrastructural evidence of sarcomere disruption and intercalated discs within 1 week after gene deletion. These data confirm conserved roles for constitutive insulin and IGF1 signaling in suppressing autophagic and apoptotic signaling in the adult heart. The present study also identifies an unexpected role for insulin and IGF1 signaling in regulating an SRF-mediated transcriptional program, which maintains expression of genes encoding proteins that support sarcomere integrity in the adult heart, reduction of which results in rapid development of heart failure.
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影响因子：
29
作者：
Dong XC;Copps KD;Guo S;Li Y;Kollipara R;DePinho RA;White MF
通讯作者：
White MF
影响因子：
5
作者：
Bugger H;Riehle C;Jaishy B;Wende AR;Tuinei J;Chen D;Soto J;Pires KM;Boudina S;Theobald HA;Luptak I;Wayment B;Wang X;Litwin SE;Weimer BC;Abel ED
通讯作者：
Abel ED
影响因子：
--
作者：
Kim, Jaetaek;Wende, Adam R.;Abel, E. Dale
通讯作者：
Abel, E. Dale
DOI：
10.1152/ajpheart.00392.2013
发表时间：
2014-05-01
影响因子：
4.8
作者：
El Accaoui, Ramzi N.;Gould, Sarah T.;Weiss, Robert M.
通讯作者：
Weiss, Robert M.
影响因子：
16
作者：
Bruning, JC;Michael, MD;Kahn, CR
通讯作者：
Kahn, CR