AIM Tieg1 is involved in multiple signalling pathways, human diseases, and is highly expressed in muscle where its functions are poorly understood. METHODS We have utilized Tieg1 knockout (KO) mice to identify novel and important roles for this transcription factor in regulating muscle ultrastructure, metabolism and mitochondrial functions in the soleus and extensor digitorum longus (EDL) muscles. RNA sequencing, immunoblotting, transmission electron microscopy, MRI, NMR, histochemical and mitochondrial function assays were performed. RESULTS Loss of Tieg1 expression resulted in altered sarcomere organization and a significant decrease in mitochondrial number. Histochemical analyses demonstrated an absence of succinate dehydrogenase staining and a decrease in cytochrome c oxidase (COX) enzyme activity in KO soleus with similar, but diminished, effects in the EDL. Decreased complex I, COX and citrate synthase (CS) activities were detected in the soleus muscle of KO mice indicating altered mitochondrial function. Complex I activity was also diminished in KO EDL. Significant decreases in CS and respiratory chain complex activities were identified in KO soleus. 1 H-NMR spectra revealed no significant metabolic difference between wild-type and KO muscles. However, 31 P spectra revealed a significant decrease in phosphocreatine and ATPγ. Altered expression of 279 genes, many of which play roles in mitochondrial and muscle function, were identified in KO soleus muscle. Ultimately, all of these changes resulted in an exercise intolerance phenotype in Tieg1 KO mice. CONCLUSION Our findings have implicated novel roles for Tieg1 in muscle including regulation of gene expression, metabolic activity and organization of tissue ultrastructure. This muscle phenotype resembles diseases associated with exercise intolerance and myopathies of unknown consequence.

中文翻译：

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Tieg1在肌肉代谢和线粒体氧化能力中的新作用。

AIM Tieg1参与多种信号途径，人类疾病，并在人们对其功能知之甚少的肌肉中高度表达。方法我们已经利用Tieg1基因敲除（KO）小鼠来确定该转录因子在比目鱼肌和趾长肌（EDL）肌肉中调节肌肉超微结构，代谢和线粒体功能的新作用和重要作用。进行了RNA测序，免疫印迹，透射电子显微镜，MRI，NMR，组织化学和线粒体功能测定。结果Tieg1表达的丧失导致肌节组织的改变和线粒体数目的显着减少。组织化学分析表明，KO比目鱼肌中没有琥珀酸脱氢酶染色，细胞色素c氧化酶（COX）酶活性降低，但相似，但降低了，EDL中的效果。在KO小鼠的比目鱼肌中检测到复合物I，COX和柠檬酸合酶（CS）活性降低，表明线粒体功能发生了改变。KO EDL中复合物I的活性也降低了。在比目鱼肌中，CS和呼吸链复合物活性明显降低。1 H-NMR光谱显示野生型和KO肌肉之间没有明显的代谢差异。但是，31 P光谱显示磷酸肌酸和ATPγ明显降低。在比目鱼肌中发现了279个基因的改变表达，其中许多在线粒体和肌肉功能中起作用。最终，所有这些变化导致了Tieg1 KO小鼠的运动耐受性表型。结论我们的发现暗示了Tieg1在肌肉中的新作用，包括基因表达的调控，代谢活动和组织超微结构的组织。这种肌肉表型类似于与运动不耐症和未知后果的肌病相关的疾病。