BACKGROUND Both mitophagy, a selective mechanism for clearance of mitochondria, and mitochondrial biogenesis are key processes determining mitochondrial content and oxidative capacity of the musculature. Abnormalities in these processes could therefore contribute to deterioration of peripheral muscle oxidative capacity as observed in e.g. chronic obstructive pulmonary disease. Although it has been suggested that inflammatory mediators can modulate both mitophagy and mitochondrial biogenesis, it is unknown whether acute pulmonary inflammation affects these processes in oxidative and glycolytic skeletal muscle in vivo. Therefore, we hypothesised that molecular signalling patterns of mitochondrial breakdown and biogenesis temporally shift towards increased breakdown and decreased biogenesis in the skeletal muscle of mice exposed to one single bolus of IT-LPS, as a model for acute lung injury and pulmonary inflammation. METHODS We investigated multiple important constituents and molecular regulators of mitochondrial breakdown, biogenesis, dynamics, and mitochondrial content in skeletal muscle over time in a murine (FVB/N background) model of acute pulmonary- and systemic inflammation induced by a single bolus of intra-tracheally (IT)-instilled lipopolysaccharide (LPS). Moreover, we compared the expression of these constituents between gastrocnemius and soleus muscle. RESULTS Both in soleus and gastrocnemius muscle, IT-LPS instillation resulted in molecular patterns indicative of activation of mitophagy. This coincided with modulation of mRNA transcript abundance of genes involved in mitochondrial fusion and fission as well as an initial decrease and subsequent recovery of transcript levels of key proteins involved in the molecular regulation of mitochondrial biogenesis. Moreover, no solid differences in markers for mitochondrial content were found. CONCLUSIONS These data suggest that one bolus of IT-LPS results in a temporal modulation of mitochondrial clearance and biogenesis in both oxidative and glycolytic skeletal muscle, which is insufficient to result in a reduction of mitochondrial content.

中文翻译：

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肺部炎症诱导的鼠骨骼肌线粒体和线粒体生物发生关键调节因子的改变。

背景技术线粒体（一种清除线粒体的选择性机制）和线粒体的生物发生都是决定线粒体含量和肌肉组织氧化能力的关键过程。因此，如在慢性阻塞性肺疾病中所观察到的，这些过程中的异常可能导致周围肌肉氧化能力的下降。尽管已经提出炎症介质可以调节线粒体和线粒体的生物发生，但是尚不清楚急性肺炎症是否会影响体内氧化和糖酵解骨骼肌的这些过程。因此，我们假设线粒体分解和生物发生的分子信号传导模式在时间上向暴露于单个大剂量IT-LPS的小鼠骨骼肌中分解增加和生物发生减少的方向转变，作为急性肺损伤和肺部炎症的模型。方法我们研究了在小鼠（FVB / N背景）模型中，一次大剂量单剂量内注射引起的急性肺和全身炎症的骨骼肌线粒体分解，生物发生，动力学和线粒体含量的多个重要成分和分子调节剂。气管（IT）注入的脂多糖（LPS）。此外，我们比较了腓肠肌和比目鱼肌之间这些成分的表达。结果在比目鱼肌和腓肠肌中，IT-LPS滴注导致指示线粒体激活的分子模式。这与线粒体融合和裂变相关基因的mRNA转录本丰度的调节以及线粒体生物发生的分子调控中涉及的关键蛋白的转录水平的最初降低和随后的恢复相吻合。而且，在线粒体含量的标记物上没有发现固体差异。结论这些数据表明，一次大剂量的IT-LPS会导致氧化性和糖酵解性骨骼肌线粒体清除和生物发生的时间调节，这不足以导致线粒体含量的减少。这与线粒体融合和裂变相关基因的mRNA转录本丰度的调节以及线粒体生物发生的分子调控中涉及的关键蛋白的转录水平的最初降低和随后的恢复相吻合。而且，在线粒体含量的标记物上没有发现固体差异。结论这些数据表明，一次大剂量的IT-LPS会导致氧化性和糖酵解性骨骼肌线粒体清除和生物发生的时间调节，这不足以导致线粒体含量的减少。这与线粒体融合和裂变相关基因的mRNA转录本丰度的调节以及线粒体生物发生的分子调控中涉及的关键蛋白的转录水平的最初降低和随后的恢复相吻合。而且，在线粒体含量的标记物上没有发现固体差异。结论这些数据表明，一次大剂量的IT-LPS会导致氧化性和糖酵解性骨骼肌线粒体清除和生物发生的时间调节，这不足以导致线粒体含量的减少。