Wootton Martha, Steeghs Karen, Watt Diana, Munro June, Gordon Katrina, Ireland Hazel, Morrison Vivienne, Behan Wilhelmina, Parkinson E Kenneth
The Department of Pathology, University of Glasgow, Glasgow G11 6NT, UK.
Hum Gene Ther. 2003 Oct 10;14(15):1473-87. doi: 10.1089/104303403769211682.
Continuous cycles of muscle fiber necrosis and regeneration are characteristic of the muscular dystrophies, and in some cases this leads to premature replicative senescence of myoblasts in vitro. The molecular mechanism of senescence in human myoblasts is poorly understood but there is evidence to suggest that telomeric attrition may be one of the ways by which this is achieved. We report here, for the first time, the extension of normal human skeletal muscle cell replicative life span by the reconstitution of telomerase activity. The telomerase-expressing cells show no features of transformation in vitro and have stable genomes with diploid karyotypes, do not express exceptionally high levels of c-myc and have wild-type, unmethylated CDKN2A genes. In vivo, they regenerate to repair muscle injury in immunosuppressed RAG-1 mice. This work suggests that telomerase expression to repair short telomeres may aid the expansion of diploid human muscle cells and consequently attempts at gene therapy for muscle diseases.
肌肉纤维坏死和再生的持续循环是肌肉营养不良症的特征，在某些情况下，这会导致体外成肌细胞过早出现复制性衰老。人类成肌细胞衰老的分子机制尚不清楚，但有证据表明端粒磨损可能是实现这一过程的方式之一。我们在此首次报告，通过重建端粒酶活性可延长正常人骨骼肌细胞的复制寿命。表达端粒酶的细胞在体外未表现出转化特征，具有稳定的基因组和二倍体核型，不异常高水平表达c-myc，且具有野生型、未甲基化的CDKN2A基因。在体内，它们可再生以修复免疫抑制的RAG-1小鼠的肌肉损伤。这项工作表明，表达端粒酶以修复短端粒可能有助于二倍体人类肌肉细胞的扩增，从而为肌肉疾病的基因治疗提供帮助。
