Keipert Susanne, Klaus Susanne, Heldmaier Gerhard, Jastroch Martin
German Institute of Human Nutrition, Group of Energy Metabolism, 14558 Nuthetal, Germany.
Biochim Biophys Acta. 2010 Feb;1797(2):324-30. doi: 10.1016/j.bbabio.2009.11.008. Epub 2009 Dec 1.
Mitochondrial uncoupling in skeletal muscle has raised a major interest as a therapeutic target for treatment of obesity, insulin sensitivity, and age-related disease. These physiological effects could be demonstrated in several mouse models ectopically expressing uncoupling protein 1 (UCP1). Here, we investigated whether UCP1 expressed under the control of the human skeletal actin (HSA) promoter in mouse skeletal muscle can be regulated, and whether it affects mitochondrial superoxide production. We show that the skeletal muscle UCP1 can be fully inhibited by a purine nucleotide (GDP) and reactivated by fatty acids (palmitate). During mitochondrial resting state (State 4), mitochondrial superoxide production is about 76% lower in transgenic mice. We suggest that this reduction is due to uncoupling activity as the administration of GDP restores superoxide production to wildtype levels. Our study confirms native behaviour of UCP1 in skeletal muscle and demonstrates beneficial effects on prevention of mitochondrial reactive oxygen species production which may reduce age-related deleterious processes.
骨骼肌中的线粒体解偶联作为治疗肥胖、胰岛素敏感性及年龄相关疾病的一个治疗靶点，已引起了广泛关注。这些生理效应在几种异位表达解偶联蛋白1（UCP1）的小鼠模型中得到了证实。在此，我们研究了在小鼠骨骼肌中由人骨骼肌肌动蛋白（HSA）启动子控制表达的UCP1是否能够被调节，以及它是否影响线粒体超氧化物的产生。我们发现，嘌呤核苷酸（GDP）可完全抑制骨骼肌UCP1，而脂肪酸（棕榈酸）可使其重新激活。在线粒体静息状态（状态4）下，转基因小鼠的线粒体超氧化物产生量降低约76%。我们认为这种降低是由于解偶联活性所致，因为给予GDP可使超氧化物产生量恢复到野生型水平。我们的研究证实了UCP1在骨骼肌中的天然特性，并证明了其对预防线粒体活性氧产生的有益作用，这可能会减少与年龄相关的有害过程。
