Siu P M, Alway S E
Laboratory of Muscle Biology and Sarcopenia, Division of Exercise Physiology, West Virginia University School of Medicine, Morgantown, West Virginia 26506, USA.
Apoptosis. 2006 Jun;11(6):967-81. doi: 10.1007/s10495-006-6315-4.
Apoptosis has been implicated in mediating denervation-induced muscle wasting. In this study we determined the effect of interference of apoptosis on muscle wasting during denervation by using mice genetically deficient in pro-apoptotic Bax. After denervation, muscle wasting was evident in both wild-type and Bax(-/-) muscles but reduction of muscle weight was attenuated in Bax(-/-) mice. Apoptotic DNA fragmentation increased in wild-type denervated muscles whereas there was no statistical increase in DNA fragmentation in denervated muscles from Bax(-/-) mice. Mitochondrial AIF and Smac/DIABLO releases and Bcl-2, p53 and HSP27 increased whereas XIAP and MnSOD decreased to a similar extent in muscles from wild-type and Bax(-/-) mice following denervation. Mitochondrial cytochrome c release was elevated in denervated muscles from wild-type mice but the increase was suppressed in muscles from Bax(-/-) mice. Increases in caspase-3 and -9 activities and oxidative stress markers H(2)O(2), MDA/4-HAE and nitrotyrosine were all evident in denervated muscles from wild-type mice but these changes were absent in muscles from Bax(-/-) mice. Moreover, ARC increased exclusively in denervated Bax(-/-) muscle. Our data indicate that under conditions of denervation, pro-apoptotic signalling is suppressed and muscle wasting is attenuated when the Bax gene is lacking. These findings suggest that interventions targeting apoptosis may be valuable in ameliorating denervation-associated pathologic muscle wasting in certain neuromuscular disorders that involve partial or full denervation.
细胞凋亡与去神经支配诱导的肌肉萎缩有关。在本研究中，我们通过使用促凋亡蛋白Bax基因缺失的小鼠，确定了干扰细胞凋亡对去神经支配期间肌肉萎缩的影响。去神经支配后，野生型和Bax(-/-)小鼠的肌肉均出现明显萎缩，但Bax(-/-)小鼠的肌肉重量减轻程度减弱。野生型去神经支配的肌肉中凋亡性DNA片段增加，而Bax(-/-)小鼠去神经支配的肌肉中DNA片段没有统计学上的增加。去神经支配后，野生型和Bax(-/-)小鼠肌肉中的线粒体AIF和Smac/DIABLO释放以及Bcl-2、p53和HSP27增加，而XIAP和MnSOD下降程度相似。野生型小鼠去神经支配的肌肉中线粒体细胞色素c释放增加，但Bax(-/-)小鼠肌肉中的增加受到抑制。野生型小鼠去神经支配的肌肉中caspase-3和-9活性以及氧化应激标志物H(2)O(2)、MDA/4-HAE和硝基酪氨酸均明显增加，但Bax(-/-)小鼠肌肉中没有这些变化。此外，ARC仅在去神经支配的Bax(-/-)肌肉中增加。我们的数据表明，在去神经支配的情况下，当缺乏Bax基因时，促凋亡信号被抑制，肌肉萎缩减弱。这些发现表明，针对细胞凋亡的干预措施可能对改善某些涉及部分或完全去神经支配的神经肌肉疾病中与去神经支配相关的病理性肌肉萎缩有价值。
