Muscle-specific knockout of general control of amino acid synthesis 5 (GCN5) does not enhance basal or endurance exercise-induced mitochondrial adaptation.
Muscle-specific knockout of general control of amino acid synthesis 5 (GCN5) does not enhance basal or endurance exercise-induced mitochondrial adaptation.
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DOI：
10.1016/j.molmet.2017.10.004
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发表时间：
2017-12
影响因子：
8.1
通讯作者：
Philp A
中科院分区：
文献类型：
--
作者：
Dent JR;Martins VF;Svensson K;LaBarge SA;Schlenk NC;Esparza MC;Buckner EH;Meyer GA;Hamilton DL;Schenk S;Philp A
赖氨酸乙酰化是调节骨骼肌代谢功能的重要翻译后修饰。乙酰转移酶是氨基酸合成 5 (GCN5) 的一般控制酶，已被认为通过其对过氧化物酶体增殖物激活受体-γ 辅激活因子-1α (PGC-1α) 的抑制作用作为线粒体生物发生的调节剂。然而，GCN5 对骨骼肌代谢和线粒体对体内耐力运动的适应的具体贡献仍有待确定。我们的目的是确定骨骼肌中 GCN5 的缺失是否会增强线粒体密度和功能，以及对耐力运动训练的适应性反应。我们使用 Cre-LoxP 方法来生成肌肉特异性 GCN5 敲除 (mKO) 的小鼠和 floxed 野生型 (WT) 同窝小鼠。我们测量了久坐小鼠和进行 20 天自愿耐力运动训练的小鼠的全身能量消耗，以及线粒体密度、生物发生和骨骼肌功能的标记。尽管成功敲低了 mKO 小鼠骨骼肌中的 GCN5 活性，但 mKO 和 WT 小鼠的全身能量消耗以及骨骼肌线粒体丰度和最大呼吸能力相当。此外，耐力运动介导的线粒体生物发生或 PGC-1α 蛋白含量增加不存在基因型差异。这些结果表明，体内 GCN5 的缺失不会促进小鼠骨骼肌的代谢重塑。开发新型肌肉特异性 GCN5 敲除 (mKO) 小鼠模型。 GCN5 mKO 不影响身体成分或 24 小时全身代谢。 GCN5 mKO 小鼠的基础线粒体丰度或呼吸能力没有表现出变化。 GCN5 mKO 小鼠中运动诱导的骨骼肌线粒体生物合成并未增强。
Lysine acetylation is an important post-translational modification that regulates metabolic function in skeletal muscle. The acetyltransferase, general control of amino acid synthesis 5 (GCN5), has been proposed as a regulator of mitochondrial biogenesis via its inhibitory action on peroxisome proliferator activated receptor-γ coactivator-1α (PGC-1α). However, the specific contribution of GCN5 to skeletal muscle metabolism and mitochondrial adaptations to endurance exercise in vivo remain to be defined. We aimed to determine whether loss of GCN5 in skeletal muscle enhances mitochondrial density and function, and the adaptive response to endurance exercise training. We used Cre-LoxP methodology to generate mice with muscle-specific knockout of GCN5 (mKO) and floxed, wildtype (WT) littermates. We measured whole-body energy expenditure, as well as markers of mitochondrial density, biogenesis, and function in skeletal muscle from sedentary mice, and mice that performed 20 days of voluntary endurance exercise training. Despite successful knockdown of GCN5 activity in skeletal muscle of mKO mice, whole-body energy expenditure as well as skeletal muscle mitochondrial abundance and maximal respiratory capacity were comparable between mKO and WT mice. Further, there were no genotype differences in endurance exercise-mediated mitochondrial biogenesis or increases in PGC-1α protein content. These results demonstrate that loss of GCN5 in vivo does not promote metabolic remodeling in mouse skeletal muscle. Development of a novel muscle-specific GCN5 knockout (mKO) mouse model. GCN5 mKO does not affect body composition or 24 h whole-body metabolism. GCN5 mKO mice do not exhibit changes in basal mitochondrial abundance or respiratory capacity. Exercise-induced mitochondrial biogenesis in skeletal muscle is not enhanced in GCN5 mKO mice.
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DOI：
10.1073/pnas.0808207105
发表时间：
2008-11-04
影响因子：
11.1
作者：
Coste, Agnes;Louet, Jean-Francois;Auwerx, Johan
通讯作者：
Auwerx, Johan
影响因子：
56.9
作者：
Choudhary, Chunaram;Kumar, Chanchal;Mann, Matthias
通讯作者：
Mann, Matthias
DOI：
10.1016/j.bbapap.2009.11.023
发表时间：
2010-08
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Dominy JE Jr;Lee Y;Gerhart-Hines Z;Puigserver P
通讯作者：
Puigserver P
影响因子：
7.7
作者：
Jin, Qihuang;Zhuang, Lenan;Ge, Kai
通讯作者：
Ge, Kai
影响因子：
4.8
作者：
Amat, Ramon;Planavila, Anna;Villarroya, Francesc
通讯作者：
Villarroya, Francesc