Ojuka Edward O, Jones Terry E, Han Dong-Ho, Chen May, Holloszy John O
Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
FASEB J. 2003 Apr;17(6):675-81. doi: 10.1096/fj.02-0951com.
Skeletal muscle adapts to endurance exercise with an increase in mitochondria. Muscle contractions generate numerous potential signals. To determine which of these stimulates mitochondrial biogenesis, we are using L6 myotubes. Using this model we have found that raising cytosolic Ca2+ induces an increase in mitochondria. In this study, we tested the hypothesis that raising cytosolic Ca2+ in L6 myotubes induces increased expression of PGC-1, NRF-1, NRF-2, and mtTFA, factors that have been implicated in mitochondrial biogenesis and in the adaptation of muscle to exercise. Raising cytosolic Ca2+ by exposing L6 myotubes to caffeine for 5 h induced significant increases in PGC-1 and mtTFA protein expression and in NRF-1 and NRF-2 binding to DNA. These adaptations were prevented by dantrolene, which blocks Ca2+ release from the SR. Exposure of L6 myotubes to caffeine for 5 h per day for 5 days induced significant increases in mitochondrial marker enzyme proteins. Our results show that the adaptive response of L6 myotubes to an increase in cytosolic Ca2+ mimics the stimulation of mitochondrial biogenesis by exercise. They support the hypothesis that an increase in cytosolic Ca2+ is one of the signals that mediate increased mitochondrial biogenesis in muscle.
骨骼肌通过增加线粒体来适应耐力运动。肌肉收缩产生大量潜在信号。为了确定这些信号中哪一种能刺激线粒体生物合成，我们使用了L6肌管。利用这个模型，我们发现提高胞质Ca2+会导致线粒体增加。在本研究中，我们测试了这样一个假设：提高L6肌管中的胞质Ca2+会诱导PGC-1、NRF-1、NRF-2和mtTFA的表达增加，这些因子与线粒体生物合成以及肌肉对运动的适应性有关。通过将L6肌管暴露于咖啡因5小时来提高胞质Ca2+，可诱导PGC-1和mtTFA蛋白表达以及NRF-1和NRF-2与DNA的结合显著增加。丹曲林可阻止这些适应性变化，丹曲林能阻断Ca2+从肌浆网释放。每天将L6肌管暴露于咖啡因5小时，持续5天，可诱导线粒体标记酶蛋白显著增加。我们的结果表明，L6肌管对胞质Ca2+增加的适应性反应模拟了运动对线粒体生物合成的刺激。这些结果支持了这样一个假设：胞质Ca2+的增加是介导肌肉线粒体生物合成增加的信号之一。
