Ageing is thought to participate to the pathogenesis of sporadic inclusion-body myositis (s-IBM). Although the regenerative potential of s-IBM muscle is reduced in vivo, age-related abnormalities of satellite cells possibly accounting for the decline of muscle repair have not been demonstrated. Here we show that proliferation rate and clonogenicity of s-IBM myoblasts are significantly lower and doubling time is longer than normal age-matched controls, indicating that proliferative capacity of s-IBM muscles becomes exhausted earlier. Telomere shortening is detected in s-IBM cells suggesting premature senescence. Differently from controls, s-IBM myoblasts show increased active beta-catenin mainly localized within myonuclei, indicating active Wnt stimulation. After many rounds of muscle growth, only s-IBM myoblasts accumulate congophilic inclusions and immunoreactive Abeta(1-40) deposits. Therefore, s-IBM myoblasts seem to have a constitutively impaired regenerative capacity and the intrinsic property, upon sufficient aging in vitro, to accumulate Abeta. Our results might be valuable in understanding molecular mechanisms associated with muscle aging underlying the defective regeneration of s-IBM muscle and provide new clues for future therapeutic strategies.

译文

衰老被认为参与了散发性包涵体肌炎 (s-IBM) 的发病机理。尽管体内s-IBM肌肉的再生潜力降低,但尚未证明与年龄相关的卫星细胞异常可能导致肌肉修复下降。在这里,我们显示s-IBM成肌细胞的增殖率和克隆性明显低于正常年龄匹配的对照组,并且倍增时间更长,这表明s-IBM肌肉的增殖能力更早耗尽。在s-IBM细胞中检测到端粒缩短,提示过早衰老。与对照组不同,s-IBM成肌细胞显示主要位于肌核内的活性 β-catenin增加,表明Wnt刺激活跃。经过多轮肌肉生长后,只有s-IBM成肌细胞积累了嗜血包涵体和免疫反应性Abeta(1-40) 沉积物。因此,在体外充分老化后,s-IBM成肌细胞似乎具有组成性受损的再生能力和内在特性,以积累Abeta。我们的结果可能对理解与s-IBM肌肉再生缺陷相关的肌肉老化相关的分子机制有价值,并为未来的治疗策略提供新的线索。

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