NUTRIM School of Nutrition and Translational Research in Metabolism, Department of Respiratory Medicine, Maastricht University Medical Center+, Maastricht, The Netherlands.
NUTRIM School of Nutrition and Translational Research in Metabolism, Department of Respiratory Medicine, Maastricht University Medical Center+, Maastricht, The Netherlands.
Biochim Biophys Acta Mol Basis Dis. 2017 Dec;1863(12):3075-3086. doi: 10.1016/j.bbadis.2017.09.018. Epub 2017 Sep 22.
Aberrant skeletal muscle mitochondrial oxidative metabolism is a debilitating feature of chronic diseases such as chronic obstructive pulmonary disease, type 2 diabetes and chronic heart failure. Evidence in non-muscle cells suggests that glycogen synthase kinase-3β (GSK-3β) represses mitochondrial biogenesis and inhibits PPAR-γ co-activator 1 (PGC-1), a master regulator of cellular oxidative metabolism. The role of GSK-3β in the regulation of skeletal muscle oxidative metabolism is unknown.
We hypothesized that inactivation of GSK-3β stimulates muscle oxidative metabolism by activating PGC-1 signaling and explored if GSK-3β inactivation could protect against physical inactivity-induced alterations in skeletal muscle oxidative metabolism.
GSK-3β was modulated genetically and pharmacologically in C2C12 myotubes in vitro and in skeletal muscle in vivo. Wild-type and muscle-specific GSK-3β knock-out (KO) mice were subjected to hind limb suspension for 14days. Key constituents of oxidative metabolism and PGC-1 signaling were investigated.
In vitro, knock-down of GSK-3β increased mitochondrial DNA copy number, protein and mRNA abundance of oxidative phosphorylation (OXPHOS) complexes and activity of oxidative metabolic enzymes but also enhanced protein and mRNA abundance of key PGC-1 signaling constituents. Similarly, pharmacological inhibition of GSK-3β increased transcript and protein abundance of key constituents and regulators of mitochondrial energy metabolism. Furthermore, GSK-3β KO animals were protected against unloading-induced decrements in expression levels of these constituents.
Inactivation of GSK-3β up-regulates skeletal muscle mitochondrial metabolism and increases expression levels of PGC-1 signaling constituents. In vivo, GSK-3β KO protects against inactivity-induced reductions in muscle metabolic gene expression.
骨骼肌线粒体氧化代谢异常是慢性阻塞性肺疾病、2 型糖尿病和慢性心力衰竭等慢性疾病的一个衰弱特征。在非肌肉细胞中的证据表明，糖原合酶激酶-3β（GSK-3β）抑制线粒体生物发生并抑制过氧化物酶体增殖物激活受体-γ 共激活因子 1（PGC-1），后者是细胞氧化代谢的主要调节因子。GSK-3β 在调节骨骼肌氧化代谢中的作用尚不清楚。
我们假设通过激活 PGC-1 信号转导，GSK-3β 的失活会刺激肌肉氧化代谢，并探讨 GSK-3β 的失活是否可以防止体力活动减少引起的骨骼肌氧化代谢改变。
在体外的 C2C12 肌管中和体内的骨骼肌中，通过基因和药理学方法调节 GSK-3β。将野生型和肌肉特异性 GSK-3β 敲除（KO）小鼠进行 14 天的后肢悬吊。研究了氧化代谢和 PGC-1 信号的关键组成部分。
在体外，GSK-3β 的敲低增加了线粒体 DNA 拷贝数、氧化磷酸化（OXPHOS）复合物的蛋白质和 mRNA 丰度以及氧化代谢酶的活性，但也增强了关键 PGC-1 信号组成部分的蛋白质和 mRNA 丰度。同样，GSK-3β 的药理学抑制增加了关键组成部分和线粒体能量代谢调节因子的转录和蛋白质丰度。此外，GSK-3β KO 动物免受卸载引起的这些组成部分表达水平降低的影响。
GSK-3β 的失活上调了骨骼肌线粒体代谢，并增加了 PGC-1 信号组成部分的表达水平。在体内，GSK-3β KO 可防止不活动引起的肌肉代谢基因表达减少。
