Protective role of Parkin in skeletal muscle contractile and mitochondrial function
Protective role of Parkin in skeletal muscle contractile and mitochondrial function
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DOI：
10.1113/jp275604
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发表时间：
2018-07-01
影响因子：
5.5
通讯作者：
Hussain, Sabah N. A.
中科院分区：
文献类型：
--
作者：
Gouspillou, Gilles;Godin, Richard;Hussain, Sabah N. A.
Parkin是由Park 2基因编码的E3泛素连接酶。帕金参与了线粒体自噬的调节，线粒体自噬是一种质量控制过程，其中有缺陷的线粒体被隔离在自噬体中并被递送到溶酶体进行降解。虽然帕金主要研究其在帕金森病神经元变性中的作用，但其在其他组织中的作用在很大程度上仍然未知。在本研究中，我们研究了Park 2基因敲除（Park 2（-/-））小鼠的骨骼肌，以检验Parkin在正常骨骼肌线粒体质量控制中发挥生理作用的假设，该组织高度依赖于线粒体含量和功能。我们首先表明，胫骨前肌（TA）的Park 2（-/-）小鼠显示轻微但显着的比力下降。Park 2（-/-）肌肉也显示出IIB型纤维肥大的趋势，而肌纤维类型比例没有改变。与Park 2（+/+）肌相比，Park 2（-/-）骨骼肌的线粒体功能显著受损，表现为ADP刺激的线粒体呼吸速率显著降低、解偶联、含有线粒体DNA（mtDNA）编码亚基的呼吸链复合物活性降低以及对通透性转换孔开放的敏感性增加。Park 2（-/-）小鼠的肌肉也显示线粒体前融合蛋白Mfn 2的含量减少和前分裂蛋白Drp 1的增加，表明线粒体碎片化增加。最后，Park 2消融导致骨骼肌中基础自噬通量增加。总体而言，本研究的结果表明，帕金在正常骨骼肌的正常线粒体和收缩功能的维持中起着保护作用。
Parkin is an E3 ubiquitin ligase encoded by the Park2 gene. Parkin has been implicated in the regulation of mitophagy, a quality control process in which defective mitochondria are sequestered in autophagosomes and delivered to lysosomes for degradation. Although Parkin has been mainly studied for its implication in neuronal degeneration in Parkinson disease, its role in other tissues remains largely unknown. In the present study, we investigated the skeletal muscles of Park2 knockout (Park2(-/-)) mice to test the hypothesis that Parkin plays a physiological role in mitochondrial quality control in normal skeletal muscle, a tissue highly reliant on mitochondrial content and function. We first show that the tibialis anterior (TA) of Park2(-/-) mice display a slight but significant decrease in its specific force. Park2(-/-) muscles also show a trend for type IIB fibre hypertrophy without alteration in muscle fibre type proportion. Compared to Park2(+/+) muscles, the mitochondrial function of Park2(-/-) skeletal muscles was significantly impaired, as indicated by the significant decrease in ADP-stimulated mitochondrial respiratory rates, uncoupling, reduced activities of respiratory chain complexes containing mitochondrial DNA (mtDNA)-encoded subunits and increased susceptibility to opening of the permeability transition pore. Muscles of Park2(-/-) mice also displayed a decrease in the content of the mitochondrial pro-fusion protein Mfn2 and an increase in the pro-fission protein Drp1 suggesting an increase in mitochondrial fragmentation. Finally, Park2 ablation resulted in an increase in basal autophagic flux in skeletal muscles. Overall, the results of the present study demonstrate that Parkin plays a protective role in the maintenance of normal mitochondrial and contractile functions in normal skeletal muscles.