Department of Pharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata, Osaka 573-0101, Japan.
Neurochem Int. 2011 Nov;59(6):812-20. doi: 10.1016/j.neuint.2011.08.015. Epub 2011 Aug 27.
Inner ear disorders are known to be elicited by mitochondrial dysfunction, which decreases the ATP level in the inner ear. 5'-AMP-activated protein kinase (AMPK) is a serine/threonine kinase activated by metabolic stress and by an increase in the AMP/ATP ratio. To elucidate the involvement of AMPK-derived signals in noise-induced hearing loss, we investigated whether in vivo acoustic overstimulation would activate AMPK in the cochlea of mice. Std-ddY mice were exposed to 8kHz octave band noise at a 90-, 110- or 120-dB sound pressure level (SPL) for 2h. Exposure to the noise at 110 or 120dB SPL produced outer hair cell death in the organ of Corti and permanent hearing loss. Exposure to the noise at 120-dB SPL elevated the level of the phospho-AMPK α-subunit (p-AMPKα), without affecting the protein level of this subunit, immediately and at 12-h post-exposure in the lateral wall structures including the spiral ligament and stria vascularis. In the hair cells and spiral ganglion cells, no marked change in the level of p-AMPKα was observed at any time post-exposure. The level of phospho-c-Jun N-terminal kinase (p-JNK) was increased in the lateral wall structures at 2- to 4-h post-exposure at 120dB SPL. Noise exposure significantly, but temporarily, decreased the ATP level in the spiral ligament, in an SPL-dependent manner at 110dB and above. Likewise, elevation of p-AMPKα and p-JNK levels was also observed in the lateral wall structures post-exposure to noise at an SPL of 110dB and above. Taken together, our data suggest that AMPK and JNK were activated by ATP depletion in the cochlear spiral ligament prior to permanent hearing loss induced by in vivo acoustic overstimulation.
内耳疾病已知由线粒体功能障碍引起，线粒体功能障碍降低内耳中的 ATP 水平。5'-AMP 激活的蛋白激酶（AMPK）是一种丝氨酸/苏氨酸激酶，可被代谢应激和 AMP/ATP 比值的增加激活。为了阐明 AMPK 衍生信号在内耳声损伤中的作用，我们研究了体内声过度刺激是否会激活小鼠耳蜗中的 AMPK。将 Std-ddY 小鼠暴露于 8kHz 倍频程噪声中，声压级（SPL）分别为 90、110 或 120dB 持续 2 小时。110 或 120dB SPL 的噪声暴露会导致 Corti 器中的外毛细胞死亡和永久性听力损失。暴露于 120dB SPL 的噪声会立即和暴露后 12 小时增加外侧壁结构（包括螺旋韧带和血管纹）中磷酸化 AMPKα 亚基（p-AMPKα）的水平，而不影响该亚基的蛋白水平。在毛细胞和螺旋神经节细胞中，在暴露后的任何时间都没有观察到 p-AMPKα水平的明显变化。在 120dB SPL 下，外侧壁结构中的磷酸化 c-Jun N 末端激酶（p-JNK）水平在暴露后 2 至 4 小时增加。噪声暴露以 SPL 依赖的方式显著但暂时降低了螺旋韧带中的 ATP 水平，110dB 及以上。同样，在 110dB 及以上 SPL 的噪声暴露后，外侧壁结构中也观察到 p-AMPKα 和 p-JNK 水平的升高。总之，我们的数据表明，在体内声过度刺激引起永久性听力损失之前，AMPK 和 JNK 在内耳螺旋韧带的 ATP 耗竭的情况下被激活。
