Effects of the systemic environment on muscle aging

描述(由申请人提供)： 成人骨骼肌在整个成年生活中都能旺盛地再生，但在老年时却无法做到这一点。再生潜力如此下降的原因尚不清楚，肌肉细胞变化与其老化环境变化的相对作用也尚未确定。最近的研究表明，年轻的全身环境恢复了再生特异性Notch通路的活性，并促进了衰老肌肉的修复，这表明在衰老的环境中，衰老卫星细胞的再生潜力基本上没有被正确地触发。我们的最新数据表明，导致老年人器官干细胞激活和组织修复受损的不仅仅是缺乏“积极的”全身因素，而是衰老的全身和肌肉壁龛实际上抑制了Notch的激活和老年人和年轻卫星细胞的再生潜力。也就是说，从衰老肌肉中分离的卫星细胞或在体外暴露于老化小鼠血清中的卫星细胞的再生能力受到抑制，缺乏Notch激活。此外，我们的初步数据表明，这种与年龄相关的抑制作用的分子机制是，卫星细胞在衰老环境中再生能力的降低源于其衰老的壁龛诱导这些细胞中过度的转化生长因子-β/pSmad信号，这反过来又是衰老循环和肌肉组织中转化生长因子-β家族配体水平升高的结果。非常重要的是，我们的初步结果表明，卫星细胞中的转化生长因子-β/pSmad信号的减弱可以恢复肌源性潜能和Notch的激活。这些研究强调，理解转化生长因子-β超家族对成体肌肉发生的调控以及设计肌肉干细胞中转化生长因子-β/pSmad信号的可调校正方法具有很高的治疗相关性。为了了解转化生长因子-β/pSmad信号在肌肉修复中的年龄相关作用并向治疗应用发展，需要确定1)循环和肌肉组织中转化生长因子-β-超家族配体的“年轻”正向和“年老”负水平是什么；2)在什么年龄相关水平上，转化生长因子-β/pSmad信号变得过度而对卫星细胞再生能力是“负”的；3)如何设计一个可调节的系统来精确地“年轻”地重新校准卫星细胞中的转化生长因子-β/pSmad信号。这些目标将在拟议的具体目标中加以阐述。

DESCRIPTION (provided by applicant): Adult skeletal muscle robustly regenerates throughout adult life but fails to do so in old age. The reason for such a decline in the regenerative potential is not well understood and the relative roles of the changes in muscle cells versus the alterations in their aged environment have not been defined. Recently is has been shown that a young systemic milieu restores the activity of the regeneration-specific Notch pathway and enhances repair of old muscle, suggesting that largely intact regenerative potential of aged satellite cells is not properly triggered in the aged environment. Our most recent data suggest that it is not simply the lack of "positive" systemic factors that causes impaired organ stem cell activation and tissue repair in the old, but that the aged systemic and muscle niches actually inhibit Notch activation and the regenerative potential of both old and young satellite cells. Namely, satellite cells isolated from old muscle or exposed to aged mouse serum in vitro are inhibited in their regenerative capacity and lack Notch activation. Moreover, our preliminary data identifies a molecular mechanism of this age-related inhibition by demonstrating that the reduced regenerative potential of satellite cells in the aged environments stems from excessive TGF-beta/pSmad signaling induced in these cells by their aged niches, which in turn is a result of the elevated levels of TGF- beta-family ligands in aged circulation and muscle tissue. Very importantly, our preliminary results suggest that both myogenic potential and Notch activation can be rejuvenated by attenuation of TGF-beta/pSmad signaling in satellite cells. These studies emphasize high therapeutic relevance of understanding the regulation of adult myogenesis by TGF-beta super-family and of designing the approaches for tunable calibration of TGF-beta/pSmad signaling in muscle stem cells. In order to decipher the age-related role of TGF-beta/pSmad signaling in muscle repair and to progress toward therapeutic applications, it is needed to determine 1) what are the "youthful" positive versus "aged" negative levels of TGF-beta-superfamily ligands in circulation and muscle tissue; 2) at what age-related levels TGF-beta/pSmad signaling becomes excessive and "negative" for satellite cell regenerative capacity and 3) how to design a tunable system for a precise "youthful" recalibration of TGF-beta/pSmad signaling in satellite cells. These goals will be approached here in the proposed Specific Aims.