Drp1 knockdown induces severe muscle atrophy and remodelling, mitochondrial dysfunction, autophagy impairment and denervation
Drp1 knockdown induces severe muscle atrophy and remodelling, mitochondrial dysfunction, autophagy impairment and denervation
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DOI：
10.1113/jp279802
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发表时间：
2020-07-07
影响因子：
5.5
通讯作者：
Gouspillou, Gilles
中科院分区：
文献类型：
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作者：
Dulac, Maude;Leduc-Gaudet, Jean-Philippe;Gouspillou, Gilles
关键点维持最佳的线粒体含量和功能对肌肉健康至关重要。线粒体动力学在线粒体质量控制中起关键作用;然而，线粒体裂变在骨骼肌健康中发挥的确切作用仍不清楚。在这里，我们报告了在成年小鼠骨骼肌中敲除Drp 1（一种调节线粒体分裂的蛋白质）4个月导致严重的肌肉萎缩（40-50%）。Drp 1敲低还导致ADP刺激的呼吸减少，自噬受损标记物增加，肌肉再生，去神经支配，纤维化和氧化应激增加。我们的数据表明，Drp 1对于维持正常的线粒体功能至关重要，Drp 1的缺失严重损害肌肉健康。线粒体在骨骼肌生理学中发挥核心作用，包括能量供应、能量敏感信号传导途径的调节、活性氧产生/信号传导、钙稳态和细胞凋亡的调节。因此，维持最佳线粒体含量和功能对肌肉细胞至关重要。线粒体现在被认为是高度动态的细胞器，能够通过融合和分裂过程改变其形态。可靠的实验证据表明，线粒体动力学在线粒体质量控制中起关键作用，并且在与肌肉萎缩和消耗相关的许多病症中已经报道了调节线粒体动力学的蛋白质的表达的改变。然而，线粒体分裂在骨骼肌健康中发挥的确切作用仍不清楚。为了解决这个问题，我们研究了通过肌肉注射腺相关病毒（AAV）对成年小鼠骨骼肌引入的Drp 1（一种调节线粒体裂变的蛋白质）敲低的影响。敲除Drp 1 4个月导致非常严重的肌肉萎缩（40-50%）。Drp 1敲低还导致ADP刺激的呼吸减少，肌肉再生、去神经支配、纤维化、氧化应激和自噬受损的标志物增加。我们的研究结果表明，Drp 1对于维持正常的线粒体功能至关重要，并且Drp 1抑制严重损害肌肉健康。
Key pointsThe maintenance of optimal mitochondrial content and function is critical for muscle health. Mitochondrial dynamics play key roles in mitochondrial quality control; however, the exact role that mitochondrial fission plays in skeletal muscle health remains unclear. Here we report knocking down Drp1 (a protein regulating mitochondrial fission) for 4 months in adult mouse skeletal muscle resulted in severe muscle atrophy (40-50%). Drp1 knockdown also led to a reduction in ADP-stimulated respiration, an increase in markers of impaired autophagy and increased muscle regeneration, denervation, fibrosis and oxidative stress. Our data indicate that Drp1 is crucial for the maintenance of normal mitochondrial function and that Drp1 depletion severely impairs muscle health. Mitochondria play central roles in skeletal muscle physiology, including energy supply, regulation of energy-sensitive signalling pathways, reactive oxygen species production/signalling, calcium homeostasis and the regulation of apoptosis. The maintenance of optimal mitochondrial content and function is therefore critical for muscle cells. Mitochondria are now well known as highly dynamic organelles, able to change their morphology through fusion and fission processes. Solid experimental evidence indicates that mitochondrial dynamics play key roles in mitochondrial quality control, and alteration in the expression of proteins regulating mitochondrial dynamics have been reported in many conditions associated with muscle atrophy and wasting. However, the exact role that mitochondrial fission plays in skeletal muscle health remains unclear. To address this issue, we investigated the impact of Drp1 (a protein regulating mitochondrial fission) knockdown, introduced via intramuscular injection of adeno-associated virus (AAV) on adult mouse skeletal muscle. Knocking down Drp1 for 4 months resulted in very severe muscle atrophy (40-50%). Drp1 knockdown also led to a reduction in ADP-stimulated respiration and increases in markers of muscle regeneration, denervation, fibrosis, oxidative stress and impaired autophagy. Our findings indicate that Drp1 is essential for the maintenance of normal mitochondrial function and that Drp1 suppression severely impairs muscle health.