McGee Sean L, Swinton Courtney, Morrison Shona, Gaur Vidhi, Campbell Duncan E, Jorgensen Sebastian B, Kemp Bruce E, Baar Keith, Steinberg Gregory R, Hargreaves M
Metabolic Remodelling Laboratory, Metabolic Research Unit, School of Medicine, Deakin University, Waurn Ponds, Victoria, Australia; Division of Cell Signalling and Metabolism, Baker International Diabetes Institute Heart and Diabetes Institute, Melbourne, Victoria, Australia;
Metabolic Remodelling Laboratory, Metabolic Research Unit, School of Medicine, Deakin University, Waurn Ponds, Victoria, Australia;
FASEB J. 2014 Aug;28(8):3384-95. doi: 10.1096/fj.14-249359. Epub 2014 Apr 14.
Some gene deletions or mutations have little effect on metabolism and metabolic adaptation because of redundancy and/or compensation in metabolic pathways. The mechanisms for redundancy and/or compensation in metabolic adaptation in mammalian cells are unidentified. Here, we show that in mouse muscle and myogenic cells, compensatory regulation of the histone deacetylase (HDAC5) transcriptional repressor maintains metabolic integrity. HDAC5 phosphorylation regulated the expression of diverse metabolic genes and glucose metabolism in mouse C2C12 myogenic cells. However, loss of AMP-activated protein kinase (AMPK), a HDAC5 kinase, in muscle did not affect HDAC5 phosphorylation in mouse skeletal muscle during exercise, but resulted in a compensatory increase (32.6%) in the activation of protein kinase D (PKD), an alternate HDAC5 kinase. Constitutive PKD activation in mouse C2C12 myogenic cells regulated metabolic genes and glucose metabolism. Although aspects of this response were HDAC5 phosphorylation dependent, blocking HDAC5 phosphorylation when PKD was active engaged an alternative compensatory adaptive mechanism, which involved post-transcriptional reductions in HDAC5 mRNA (-93.1%) and protein. This enhanced the expression of a specific subset of metabolic genes and mitochondrial metabolism. These data show that compensatory regulation of HDAC5 maintains metabolic integrity in mammalian cells and reinforces the importance of preserving the cellular metabolic adaptive response.
由于代谢途径中的冗余和/或补偿作用，一些基因缺失或突变对代谢及代谢适应性影响甚微。哺乳动物细胞中代谢适应性冗余和/或补偿的机制尚不清楚。在此，我们表明，在小鼠肌肉和肌源性细胞中，组蛋白去乙酰化酶（HDAC5）转录抑制因子的补偿性调节维持了代谢完整性。HDAC5磷酸化调节小鼠C2C12肌源性细胞中多种代谢基因的表达及葡萄糖代谢。然而，肌肉中HDAC5激酶——AMP激活的蛋白激酶（AMPK）缺失，在运动过程中并不影响小鼠骨骼肌中HDAC5的磷酸化，但会导致另一种HDAC5激酶——蛋白激酶D（PKD）的激活出现代偿性增加（32.6%）。小鼠C2C12肌源性细胞中组成型PKD激活调节代谢基因和葡萄糖代谢。虽然这种反应的某些方面依赖于HDAC5磷酸化，但在PKD激活时阻断HDAC5磷酸化会启动一种替代性的代偿适应机制，该机制涉及HDAC5 mRNA（-93.1%）和蛋白的转录后减少。这增强了特定代谢基因子集的表达及线粒体代谢。这些数据表明，HDAC5的补偿性调节维持了哺乳动物细胞的代谢完整性，并强化了保留细胞代谢适应性反应的重要性。
