Rohrbach Susanne, Gruenler Stefanie, Teschner Mirja, Holtz Juergen
Institute of Pathophysiology, Martin Luther Univ. Halle-Wittenberg, Ernst-Grube-Str. 40, 06112 Halle, Germany.
Am J Physiol Regul Integr Comp Physiol. 2006 Oct;291(4):R927-35. doi: 10.1152/ajpregu.00890.2005. Epub 2006 May 4.
Cellular redox balance is maintained by various antioxidative systems. Among those is the thioredoxin system, consisting of thioredoxin, thioredoxin reductase, and NADPH. In the present study, we examined the effects of caloric restriction (2 mo) on the expression of the cytosolic and mitochondrial thioredoxin system in skeletal muscle and heart of senescent and young rats. Mitochondrial thioredoxin reductase (TrxR2) is significantly reduced in aging skeletal and cardiac muscle and renormalized after caloric restriction, while the cytosolic isoform remains unchanged. Thioredoxins (mitochondrial Trx2, cytosolic Trx1) are not influenced by caloric restriction. In skeletal and cardiac muscle of young rats, caloric restriction has no effect on the expression of thioredoxins or thioredoxin reductases. Enforced reduction of TrxR2 (small interfering RNA) in myoblasts under exposure to ceramide or TNF-alpha causes a dramatic enhancement of nucleosomal DNA cleavage, caspase 9 activation, and mitochondrial reactive oxygen species release, together with reduced cell viability, while this TrxR2 reduction is without effect in unstimulated myoblasts under basal conditions. Oxidative stress in vitro (H2O2 in C2C12 myoblasts and myotubes) results in different changes: TrxR2, Trx2, and Trx1 are induced without alterations in the cytosolic thioredoxin reductase isoforms. Thus aging is associated with a TrxR2 reduction in skeletal muscle and heart, which enhances susceptibility to apoptotic stimuli but is renormalized after short-term caloric restriction. Exogenous oxidative stress does not result in these age-related changes of TrxR2.
细胞氧化还原平衡由多种抗氧化系统维持。其中包括硫氧还蛋白系统，该系统由硫氧还蛋白、硫氧还蛋白还原酶和NADPH组成。在本研究中，我们检测了热量限制（2个月）对衰老和年轻大鼠骨骼肌及心脏中胞质和线粒体硫氧还蛋白系统表达的影响。线粒体硫氧还蛋白还原酶（TrxR2）在衰老的骨骼肌和心肌中显著降低，热量限制后恢复正常，而胞质异构体则保持不变。硫氧还蛋白（线粒体Trx2、胞质Trx1）不受热量限制的影响。在年轻大鼠的骨骼肌和心肌中，热量限制对硫氧还蛋白或硫氧还蛋白还原酶的表达没有影响。在暴露于神经酰胺或肿瘤坏死因子-α的成肌细胞中，通过小干扰RNA强制降低TrxR2会导致核小体DNA切割显著增强、半胱天冬酶9激活、线粒体活性氧释放，同时细胞活力降低，而在基础条件下未受刺激的成肌细胞中，这种TrxR2的降低没有影响。体外氧化应激（C2C12成肌细胞和肌管中的H2O2）会导致不同的变化：TrxR2、Trx2和Trx1被诱导，而胞质硫氧还蛋白还原酶异构体没有改变。因此，衰老与骨骼肌和心脏中TrxR2的降低有关，这会增加对凋亡刺激的易感性，但短期热量限制后会恢复正常。外源性氧化应激不会导致TrxR2出现这些与年龄相关的变化。
