Mitochondrial DNA-deletion mutations accumulate intracellularly to detrimental levels in aged human skeletal muscle fibers
Mitochondrial DNA-deletion mutations accumulate intracellularly to detrimental levels in aged human skeletal muscle fibers
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DOI：
10.1086/507132
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发表时间：
2006-09-01
影响因子：
9.8
通讯作者：
Aiken, Judd M.
中科院分区：
文献类型：
--
作者：
Bua, Entela;Johnson, Jody;Aiken, Judd M.
随着年龄的增长，骨骼肌质量下降会造成严重的健康后果，但这种下降的分子基础仍然不清楚。虽然线粒体DNA(MtDNA)缺失突变已被证明随着年龄的增长而积累，但为了使这些异常基因组具有生理相关性，它们必须在细胞内积累到高水平，并存在于大量细胞中。我们使用组织学和聚合酶链式反应(PCR)分析方法，检测了49-93岁的受试者股外侧肌(VL)中线粒体DNA缺失突变，以确定衰老人体肌肉中线粒体的生理和基因组完整性。显示线粒体电子传输系统(ETS)异常的VL肌纤维的数量从49岁时的估计6%增加到92岁时的31%。我们分析了48例正常老年人单个ETS异常、细胞色素C氧化酶阴性/琥珀酸脱氢酶高反应(COX5(-)/SDH++)纤维的线粒体基因型，并在所有异常纤维中发现了mtDNA缺失突变。缺失突变是纤维内的克隆性突变，伴随着COX5(-)/SDH++区。对单纤维Ets异常区域的野生型和含有缺失的mtDNA基因组的定量PCR分析表明，这些缺失突变累积到有害水平(占总mtDNA的190%)。
Skeletal muscle - mass loss with age has severe health consequences, yet the molecular basis of the loss remains obscure. Although mitochondrial DNA ( mtDNA) - deletion mutations have been shown to accumulate with age, for these aberrant genomes to be physiologically relevant, they must accumulate to high levels intracellularly and be present in a significant number of cells. We examined mtDNA-deletion mutations in vastus lateralis (VL) muscle of human subjects aged 49 - 93 years, using both histologic and polymerase-chain-reaction (PCR) analyses, to determine the physiological and genomic integrity of mitochondria in aging human muscle. The number of VL muscle fibers exhibiting mitochondrial electrontransport-system (ETS) abnormalities increased from an estimated 6% at age 49 years to 31% at age 92 years. We analyzed the mitochondrial genotype of 48 single ETS-abnormal, cytochrome c oxidase-negative/succinate dehydrogenase-hyperreactive (COX5(-)/SDH++) fibers from normal aging human subjects and identified mtDNA-deletion mutations in all abnormal fibers. Deletion mutations were clonal within a fiber and concomitant to the COX5(-)/SDH++ region. Quantitative PCR analysis of wild-type and deletion-containing mtDNA genomes within ETS-abnormal regions of single fibers demonstrated that these deletion mutations accumulate to detrimental levels (190% of the total mtDNA).