Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, Karolinska University Hospital Huddinge, Stockholm, Sweden.
PLoS One. 2013;8(1):e53698. doi: 10.1371/journal.pone.0053698. Epub 2013 Jan 14.
Loss of thymidine kinase 2 (TK2) causes a heterogeneous myopathic form of mitochondrial DNA (mtDNA) depletion syndrome (MDS) in humans that predominantly affects skeletal muscle tissue. In mice, TK2 deficiency also affects several tissues in addition to skeletal muscle, including brain, heart, adipose tissue, kidneys and causes death about 3 weeks after birth. We analysed skeletal muscle and heart muscle tissues of Tk2 knockout mice at postnatal development phase and observed that TK2 deficient pups grew slower and their skeletal muscles appeared significantly underdeveloped, whereas heart was close to normal in size. Both tissues showed mtDNA depletion and mitochondria with altered ultrastructure, as revealed by transmission electron microscopy. Gene expression microarray analysis showed a strong down-regulation of genes involved in cell cycle and cell proliferation in both tissues, suggesting a lower pool of undifferentiated proliferating cells. Analysis of isolated primary myoblasts from Tk2 knockout mice showed slow proliferation, less ability to differentiate and signs of premature senescence, even in absence of mtDNA depletion. Our data demonstrate that TK2 deficiency disturbs myogenic progenitor cells function in postnatal skeletal muscle and we propose this as one of the causes of underdeveloped phenotype and myopathic characteristic of the TK2 deficient mice, in addition to the progressive mtDNA depletion, mitochondrial damage and respiratory chain deficiency in post-mitotic differentiated tissue.
缺乏胸苷激酶 2（TK2）会导致人类出现异质性肌病型线粒体 DNA（mtDNA）耗竭综合征（MDS），主要影响骨骼肌组织。在小鼠中，TK2 缺乏除了骨骼肌外，还会影响其他几种组织，包括大脑、心脏、脂肪组织、肾脏，并导致出生后约 3 周死亡。我们分析了 Tk2 敲除小鼠在出生后发育阶段的骨骼肌和心肌组织，发现 TK2 缺乏的幼鼠生长较慢，骨骼肌明显发育不良，而心脏大小接近正常。电镜观察均显示 TK2 缺陷小鼠的两种组织均存在 mtDNA 耗竭和超微结构改变。基因表达微阵列分析显示，两种组织中与细胞周期和细胞增殖相关的基因均强烈下调，提示未分化增殖细胞池较低。对 Tk2 敲除小鼠分离的原代肌母细胞的分析表明，即使在没有 mtDNA 耗竭的情况下，细胞增殖缓慢，分化能力降低，出现早衰迹象。我们的数据表明，TK2 缺乏会干扰出生后骨骼肌中的成肌祖细胞功能，除了进行性 mtDNA 耗竭、线粒体损伤和有丝分裂后分化组织中的呼吸链缺陷外，我们还提出这是 TK2 缺乏小鼠发育不良表型和肌病特征的原因之一。
