DAHFMO-Unit of Histology and Medical Embryology, Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, Italy.
School of Physical Education and Sport, University of São Paulo, São Paulo, Brazil.
Aging Cell. 2019 Jun;18(3):e12954. doi: 10.1111/acel.12954. Epub 2019 Apr 5.
The decline in skeletal muscle mass and strength occurring in aging, referred as sarcopenia, is the result of many factors including an imbalance between protein synthesis and degradation, changes in metabolic/hormonal status, and in circulating levels of inflammatory mediators. Thus, factors that increase muscle mass and promote anabolic pathways might be of therapeutic benefit to counteract sarcopenia. Among these, the insulin-like growth factor-1 (IGF-1) has been implicated in many anabolic pathways in skeletal muscle. IGF-1 exists in different isoforms that might exert different role in skeletal muscle. Here we study the effects of two full propeptides IGF-1Ea and IGF-1Eb in skeletal muscle, with the aim to define whether and through which mechanisms their overexpression impacts muscle aging. We report that only IGF-1Ea expression promotes a pronounced hypertrophic phenotype in young mice, which is maintained in aged mice. Nevertheless, examination of aged transgenic mice revealed that the local expression of either IGF-1Ea or IGF-1Eb transgenes was protective against age-related loss of muscle mass and force. At molecular level, both isoforms activate the autophagy/lysosome system, normally altered during aging, and increase PGC1-α expression, modulating mitochondrial function, ROS detoxification, and the basal inflammatory state occurring at old age. Moreover, morphological integrity of neuromuscular junctions was maintained and preserved in both MLC/IGF-1Ea and MLC/IGF-1Eb mice during aging. These data suggest that IGF-1 is a promising therapeutic agent in staving off advancing muscle weakness.
随着年龄的增长，骨骼肌质量和力量的下降，即所谓的肌肉减少症，是多种因素共同作用的结果，包括蛋白质合成与降解之间的失衡、代谢/激素状态的变化以及循环中炎症介质水平的变化。因此，增加肌肉质量并促进合成代谢途径的因素可能对对抗肌肉减少症具有治疗益处。其中，胰岛素样生长因子-1（IGF-1）已被牵涉到骨骼肌中的许多合成代谢途径中。IGF-1 存在不同的亚型，可能在骨骼肌中发挥不同的作用。在这里，我们研究了两种全长前肽 IGF-1Ea 和 IGF-1Eb 在骨骼肌中的作用，目的是确定它们的过表达是否以及通过何种机制影响肌肉衰老。我们报告说，只有 IGF-1Ea 的表达能在年轻小鼠中促进明显的肥大表型，而在老年小鼠中则能维持。然而，对老年转基因小鼠的检查表明，IGF-1Ea 或 IGF-1Eb 转基因的局部表达均可防止与年龄相关的肌肉质量和力量损失。在分子水平上，两种亚型都能激活自噬/溶酶体系统，该系统在衰老过程中通常会发生改变，并增加 PGC1-α 的表达，调节线粒体功能、ROS 解毒和老年时发生的基础炎症状态。此外，在衰老过程中，MLC/IGF-1Ea 和 MLC/IGF-1Eb 小鼠的神经肌肉接头的形态完整性得以维持和保留。这些数据表明，IGF-1 是一种有前途的治疗药物，可以延缓肌肉无力的进展。
