GADD45A is a mediator of mitochondrial loss, atrophy, and weakness in skeletal muscle.
GADD45A is a mediator of mitochondrial loss, atrophy, and weakness in skeletal muscle.
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GADD45A是骨骼肌中线粒体缺失、萎缩以及肌无力的介导因子。
DOI：
10.1172/jci.insight.171772
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发表时间：
2023-11-22
期刊：
影响因子：
8
通讯作者：
Adams, Christopher M.
中科院分区：
文献类型：
--
作者：
Marcotte, George R.;Miller, Matthew J.;Kunz, Hawley E.;Ryan, Zachary C.;Strub, Matthew D.;Vanderboom, Patrick M.;Heppelmann, Carrie J.;Chau, Sarah;Von Ruff, Zachary D.;Kilroe, Sean P.;Mckeen, Andrew T.;Dierdorff, Jason M.;Stern, Jennifer I.;Nath, Karl A.;Grueter, Chad E.;Lira, Vitor A.;Judge, Andrew R.;Rasmussen, Blake B.;Nair, K. Sreekumaran;Lanza, Ian R.;Ebert, Scott M.;Adams, Christopher M.
衰老以及多种疾病和损伤会损害骨骼肌的质量和功能，但其分子机制尚未完全明确。为了更好地理解这些机制，我们培育并研究了在骨骼肌中特异性表达生长停滞和DNA损伤诱导蛋白α（GADD45A）的转基因小鼠。GADD45A是一种信号蛋白，在衰老以及多种疾病和损伤过程中，其在骨骼肌中的表达会升高。我们发现，GADD45A引发了一些骨骼肌萎缩的典型细胞变化，包括骨骼肌线粒体数量减少、氧化能力下降、糖酵解型肌纤维选择性萎缩，以及尽管线粒体缺失但氧化型肌球蛋白重链却反常表达。这些细胞变化至少部分是由丝裂原活化蛋白激酶激酶激酶4（MAP kinase kinase kinase 4）介导的，这是一种可被GADD45A直接激活的蛋白激酶。通过引发这些变化，GADD45A使富含糖酵解型纤维的肌肉质量下降，并损害了肌肉力量、比力和耐力运动能力。此外，正如小鼠模型数据所预测的那样，我们发现人类骨骼肌中GADD45A的表达与肌肉无力有关。总体而言，这些研究结果表明，GADD45A是小鼠骨骼肌线粒体缺失、萎缩和无力的介导因子，也是治疗人类肌肉无力的一个潜在靶点。
Aging and many illnesses and injuries impair skeletal muscle mass and function, but the molecular mechanisms are not well understood. To better understand the mechanisms, we generated and studied transgenic mice with skeletal muscle–specific expression of growth arrest and DNA damage inducible α (GADD45A), a signaling protein whose expression in skeletal muscle rises during aging and a wide range of illnesses and injuries. We found that GADD45A induced several cellular changes that are characteristic of skeletal muscle atrophy, including a reduction in skeletal muscle mitochondria and oxidative capacity, selective atrophy of glycolytic muscle fibers, and paradoxical expression of oxidative myosin heavy chains despite mitochondrial loss. These cellular changes were at least partly mediated by MAP kinase kinase kinase 4, a protein kinase that is directly activated by GADD45A. By inducing these changes, GADD45A decreased the mass of muscles that are enriched in glycolytic fibers, and it impaired strength, specific force, and endurance exercise capacity. Furthermore, as predicted by data from mouse models, we found that GADD45A expression in skeletal muscle was associated with muscle weakness in humans. Collectively, these findings identify GADD45A as a mediator of mitochondrial loss, atrophy, and weakness in mouse skeletal muscle and a potential target for muscle weakness in humans.
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影响因子：
29
作者：
Lanza IR;Zabielski P;Klaus KA;Morse DM;Heppelmann CJ;Bergen HR 3rd;Dasari S;Walrand S;Short KR;Johnson ML;Robinson MM;Schimke JM;Jakaitis DR;Asmann YW;Sun Z;Nair KS
通讯作者：
Nair KS
影响因子：
5.6
作者：
Miller, Matthew J.;Marcotte, George R.;Basisty, Nathan;Wehrfritz, Cameron;Ryan, Zachary C.;Strub, Matthew D.;McKeen, Andrew T.;Stern, Jennifer I.;Nath, Karl A.;Rasmussen, Blake B.;Judge, Andrew R.;Schilling, Birgit;Ebert, Scott M.;Adams, Christopher M.
通讯作者：
Adams, Christopher M.
影响因子：
16.6
作者：
Milan, Giulia;Romanello, Vanina;Pescatore, Francesca;Armani, Andrea;Paik, Ji-Hye;Frasson, Laura;Seydel, Anke;Zhao, Jinghui;Abraham, Reimar;Goldberg, Alfred L.;Blaauw, Bert;DePinho, Ronald A.;Sandri, Marco
通讯作者：
Sandri, Marco
影响因子：
8
作者：
Ehmsen JT;Kawaguchi R;Kaval D;Johnson AE;Nachun D;Coppola G;Höke A
通讯作者：
Höke A
DOI：
10.1152/ajpendo.00010.2014
发表时间：
2014-08-01
影响因子：
5.1
作者：
Fox, Daniel K.;Ebert, Scott M.;Adams, Christopher M.
通讯作者：
Adams, Christopher M.