Department of Regenerative Medicine, Research Institute, National Center for Geriatrics and Gerontology, Aichi, Japan.
Division for Therapies against Intractable Diseases, Institute for Comprehensive Medical Science, Fujita Health University, Aichi, Japan.
Stem Cells. 2015 Aug;33(8):2456-68. doi: 10.1002/stem.2045. Epub 2015 May 26.
Sarcopenia, age-related muscle weakness, increases the frequency of falls and fractures in elderly people, which can trigger severe muscle injury. Rapid and successful recovery from muscle injury is essential not to cause further frailty and loss of independence. In fact, we showed insufficient muscle regeneration in aged mice. Although the number of satellite cells, muscle stem cells, decreases with age, the remaining satellite cells maintain the myogenic capacity equivalent to young mice. Transplantation of young green fluorescent protein (GFP)-Tg mice-derived satellite cells into young and aged mice revealed that age-related deterioration of the muscle environment contributes to the decline in regenerative capacity of satellite cells. Thus, extrinsic changes rather than intrinsic changes in satellite cells appear to be a major determinant of inefficient muscle regeneration with age. Comprehensive protein expression analysis identified a decrease in insulin-like growth factor-II (IGF-II) level in regenerating muscle of aged mice. We found that pro- and big-IGF-II but not mature IGF-II specifically express during muscle regeneration and the expressions are not only delayed but also decreased in absolute quantity with age. Supplementation of pro-IGF-II in aged mice ameliorated the inefficient regenerative response by promoting proliferation of satellite cells, angiogenesis, and suppressing adipogenic differentiation of platelet derived growth factor receptor (PDGFR)α(+) mesenchymal progenitors. We further revealed that pro-IGF-II but not mature IGF-II specifically inhibits the pathological adipogenesis of PDGFRα(+) cells. Together, these results uncovered a distinctive pro-IGF-II-mediated self-reinforcement mechanism of muscle regeneration and suggest that supplementation of pro-IGF-II could be one of the most effective therapeutic approaches for muscle injury in elderly people.
肌肉减少症，即与年龄相关的肌肉无力，会增加老年人跌倒和骨折的频率，从而引发严重的肌肉损伤。快速有效地从肌肉损伤中恢复对于避免进一步虚弱和丧失独立性至关重要。事实上，我们发现老年小鼠的肌肉再生不足。尽管随着年龄的增长，卫星细胞（肌肉干细胞）的数量减少，但剩余的卫星细胞仍保持着与年轻小鼠相当的成肌能力。将年轻的绿色荧光蛋白（GFP）-Tg 小鼠来源的卫星细胞移植到年轻和老年小鼠中，结果表明，与年龄相关的肌肉微环境恶化导致卫星细胞再生能力下降。因此，卫星细胞的外在变化而不是内在变化似乎是导致衰老肌肉再生效率低下的主要决定因素。全面的蛋白质表达分析确定，老年小鼠再生肌肉中的胰岛素样生长因子-II（IGF-II）水平降低。我们发现，前体和大 IGF-II 而非成熟 IGF-II 在肌肉再生过程中特异性表达，其表达不仅延迟，而且随着年龄的增长绝对数量减少。在老年小鼠中补充前体 IGF-II 可通过促进卫星细胞增殖、血管生成和抑制血小板衍生生长因子受体（PDGFR）α+间充质祖细胞的脂肪生成分化来改善低效的再生反应。我们进一步发现，前体 IGF-II 而非成熟 IGF-II 特异性抑制 PDGFRα+细胞的病理性脂肪生成。总之，这些结果揭示了肌肉再生中独特的前体 IGF-II 介导的自我强化机制，并表明补充前体 IGF-II 可能是治疗老年人肌肉损伤的最有效方法之一。
