School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada.
Am J Physiol Cell Physiol. 2013 Mar 1;304(5):C422-30. doi: 10.1152/ajpcell.00240.2012. Epub 2012 Dec 5.
Aging muscle exhibits a progressive decline in mass and strength, known as sarcopenia, and a decrease in the adaptive response to contractile activity. The molecular mechanisms mediating this reduced plasticity have yet to be elucidated. The purposes of this study were 1) to determine whether denervation-induced muscle disuse would increase the expression of autophagy genes and 2) to examine whether selective autophagy pathways (mitophagy) are altered in aged animals. Denervation reduced muscle mass in young and aged animals by 24 and 16%, respectively. Moreover, young animals showed a 50% decrease in mitochondrial content following denervation, an adaptation that was not matched by aged animals. Basal autophagy protein expression was higher in aged animals, whereas young animals exhibited a greater induction of autophagy proteins following denervation. Localization of LC3II, Parkin, and p62 was significantly increased in the mitochondrial fraction of young and aged animals following denervation. Moreover, the unfolded protein response marker CHOP and the mitochondrial dynamics protein Fis1 were increased by 17- and 2.5-fold, respectively, in aged animals. Lipofuscin granules within lysosomes were evident with aging and denervation. Thus reductions in the adaptive plasticity of aged muscle are associated with decreases in disuse-induced autophagy. These data indicate that the expression of autophagy proteins and their localization to mitochondria are not decreased in aged muscle; however, the induction of autophagy in response to disuse, along with downstream events such as lysosome function, is impaired. This may contribute to an accumulation of dysfunctional mitochondria in aged muscle.
衰老肌肉表现出质量和力量的逐渐下降，称为肌肉减少症，以及对收缩活动的适应反应减少。介导这种可塑性降低的分子机制尚未阐明。本研究的目的是 1）确定去神经诱导的肌肉废用是否会增加自噬基因的表达，2）检查选择性自噬途径（线粒体自噬）是否在老年动物中发生改变。去神经支配使年轻和老年动物的肌肉质量分别减少了 24%和 16%。此外，年轻动物去神经支配后线粒体含量减少了 50%，而老年动物则没有这种适应。基础自噬蛋白表达在老年动物中较高，而年轻动物去神经支配后自噬蛋白的诱导增加更大。LC3II、Parkin 和 p62 在年轻和老年动物去神经支配后的线粒体部分明显增加。此外， unfolded protein response 标志物 CHOP 和线粒体动力学蛋白 Fis1 分别增加了 17 倍和 2.5 倍。溶酶体中脂褐素颗粒随年龄和去神经支配而明显增加。因此，老年肌肉适应性可塑性的降低与废用诱导的自噬减少有关。这些数据表明，自噬蛋白的表达及其在线粒体中的定位在老年肌肉中并未降低；然而，对废用的自噬诱导以及溶酶体功能等下游事件的诱导受损。这可能导致老年肌肉中功能失调的线粒体积累。
