Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada.
J Appl Physiol (1985). 2011 Sep;111(3):688-95. doi: 10.1152/japplphysiol.00279.2011. Epub 2011 Jun 23.
Receptor interacting protein 1 (RIP140) has recently been demonstrated to be a key player in the regulation of skeletal muscle mitochondrial content. We have shown that β-guanadinopropionic acid (β-GPA) feeding reduces RIP140 protein content and mRNA levels concomitant with increases in mitochondrial content (Williams DB, Sutherland LN, Bomhof MR, Basaraba SA, Thrush AB, Dyck DJ, Field CJ, Wright DC. Am J Physiol Endocrinol Metab 296: E1400-E1408, 2009). Since β-GPA feeding reduces high-energy phosphate levels and activates AMPK, alterations reminiscent of exercise, we hypothesized that exercise training would reduce RIP140 protein content. We further postulated that an acute bout of exercise, or interventions known to induce the expression of mitochondrial enzymes or genes involved in mitochondrial biogenesis, would result in decreases in nuclear RIP140 content. Two weeks of daily swim training increased markers of mitochondrial content in rat skeletal muscle independent of reductions in RIP140 protein. Similarly, high-intensity exercise training in humans failed to reduce RIP140 content despite increasing skeletal muscle mitochondrial enzymes. We found that 6 wk of daily 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) injections had no effect on RIP140 protein content in rat skeletal muscle while RIP140 content from LKB1 knockout mice was unaltered despite reductions in mitochondria. An acute bout of exercise, AICAR treatment, and epinephrine injections increased the mRNA levels of PGC-1α, COXIV, and lipin1 independent of decreases in nuclear RIP140 protein. Surprisingly these interventions increased RIP140 mRNA expression. In conclusion our results demonstrate that decreases in RIP140 protein content are not required for exercise and AMPK-dependent increases in skeletal muscle mitochondrial content, nor do acute perturbations alter the cellular localization of RIP140 in parallel with the induction of genes involved in mitochondrial biogenesis.
受体相互作用蛋白 1（RIP140）最近被证明是调节骨骼肌线粒体含量的关键因素。我们已经表明，β-胍基丙氨酸（β-GPA）喂养会降低 RIP140 蛋白含量和 mRNA 水平，同时增加线粒体含量（Williams DB，Sutherland LN，Bomhof MR，Basaraba SA，Thrush AB，Dyck DJ，Field CJ，Wright DC。Am J Physiol Endocrinol Metab 296：E1400-E1408，2009）。由于β-GPA 喂养会降低高能磷酸水平并激活 AMPK，类似于运动的改变，我们假设运动训练会降低 RIP140 蛋白含量。我们进一步假设，急性运动或已知可诱导线粒体酶或参与线粒体生物发生的基因表达的干预措施，会导致核 RIP140 含量降低。两周的日常游泳训练增加了大鼠骨骼肌中线粒体含量的标志物，而 RIP140 蛋白减少。同样，尽管人类的高强度运动训练增加了骨骼肌线粒体酶，但未能降低 RIP140 含量。我们发现，6 周的日常 5-氨基咪唑-4-甲酰胺-1-β-D-核糖呋喃苷（AICAR）注射对大鼠骨骼肌中的 RIP140 蛋白含量没有影响，而 LKB1 敲除小鼠的 RIP140 含量不变，尽管线粒体减少。急性运动、AICAR 处理和肾上腺素注射增加了 PGC-1α、COXIV 和 lipin1 的 mRNA 水平，而核 RIP140 蛋白减少。令人惊讶的是，这些干预措施增加了 RIP140 mRNA 的表达。总之，我们的结果表明，RIP140 蛋白含量的降低不是运动和 AMPK 依赖性增加骨骼肌线粒体含量所必需的，急性干扰也不会改变 RIP140 的细胞定位，同时诱导参与线粒体生物发生的基因。
