Mitochondrial Biogenesis Drives a Vicious Cycle of Metabolic Insufficiency and Mitochondrial DNA Deletion Mutation Accumulation in Aged Rat Skeletal Muscle Fibers
Mitochondrial Biogenesis Drives a Vicious Cycle of Metabolic Insufficiency and Mitochondrial DNA Deletion Mutation Accumulation in Aged Rat Skeletal Muscle Fibers
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DOI：
10.1371/journal.pone.0059006
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发表时间：
2013-03-13
期刊：
影响因子：
3.7
通讯作者：
Aiken, Judd M.
中科院分区：
文献类型：
--
作者：
Herbst, Allen;Johnson, Chad J.;Aiken, Judd M.
衰老的肌肉具有功能失调的纤维，其中含有体细胞衍生的线粒体 DNA 缺失突变的细胞内扩张。在高丰度下，这些突变会破坏电子传递链线粒体编码蛋白亚基的表达，导致有氧呼吸缺陷的肌纤维片段。随着年龄的增长，这些纤维片段萎缩和断裂，导致肌肉质量和功能丧失。通过将单个肌纤维的显微解剖与微阵列分析相结合，我们观察了这些异常肌纤维内诱导的反应，并检测到许多影响代谢和代谢调节的基因的增加。转录谱和随后的蛋白质验证表明线粒体生物发生的非补偿性程序已经启动。我们假设线粒体生物发生的这种非适应性程序正在驱动 mtDNA 缺失突变的积累。我们通过用β-胍基丙酸（一种刺激线粒体生物发生的化合物）治疗老年大鼠来测试这一假设。 β-胍基丙酸处理增加了肌肉线粒体基因组拷贝数，并导致电子传递链负向肌纤维片段的丰度增加了 3.7 倍。我们得出的结论是，在电子传递系统中，异常的肌纤维片段、代谢不足和非代偿性线粒体生物发生的恶性循环驱动了mtDNA缺失突变的积累。
Aged muscles possess dysfunctional fibers that contain intracellular expansions of somatically derived mitochondrial DNA deletion mutations. At high abundance, these mutations disrupt the expression of mitochondrially-encoded protein subunits of the electron transport chain resulting in aerobic respiration deficient muscle fiber segments. These fiber segments atrophy and break contributing to the loss of muscle mass and function that occurs with age. By combining micro-dissection of individual muscle fibers with microarray analysis, we observed the response induced within these abnormal muscle fibers and detected an increase in many genes affecting metabolism and metabolic regulation. The transcriptional profile and subsequent protein validation suggested that a non-compensatory program of mitochondrial biogenesis was initiated. We hypothesized that this non-adaptive program of mitochondrial biogenesis was driving mtDNA deletion mutation accumulation. We tested this hypothesis by treating aged rats with beta-Guanidinopropionic acid, a compound that stimulates mitochondrial biogenesis. beta-Guanidinopropionic acid treatment increased muscle mitochondrial genome copy number and resulted in a 3.7 fold increase in the abundance of electron transport chain negative muscle fiber segments. We conclude that in electron transport system abnormal muscle fiber segments, a vicious cycle of metabolic insufficiency and non-compensatory mitochondrial biogenesis drive mtDNA deletion mutation accumulation.