Effects of the systemic environment on muscle aging

描述（由申请人提供）： 成年骨骼肌在整个成年期都能健壮地再生，但在老年时却不能。再生潜力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尚未确定。最近已经表明，年轻的全身环境恢复再生特异性Notch途径的活性并增强老年肌肉的修复，这表明老年卫星细胞的基本完整的再生潜力在老年环境中没有被适当地触发。我们最近的数据表明，它不是简单地缺乏“积极”的系统因素，导致受损的器官干细胞激活和组织修复在老年人，但老年系统和肌肉龛实际上抑制Notch激活和再生潜力的老和年轻的卫星细胞。也就是说，从老年肌肉分离或在体外暴露于老年小鼠血清的卫星细胞的再生能力受到抑制，并且缺乏Notch活化。此外，我们的初步数据确定了这种年龄相关的抑制的分子机制，通过证明卫星细胞在老化环境中的再生潜力降低源于这些细胞中由其老化小生境诱导的过度TGF-β/pSmad信号传导，这反过来又是老化循环和肌肉组织中TGF-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，肌生成潜力和Notch激活可以通过卫星细胞中TGF-β/pSmad信号转导的衰减来恢复。这些研究强调了理解TGF-β超家族对成人肌发生的调节以及设计用于肌肉干细胞中TGF-β/pSmad信号传导的可调校准的方法的高度治疗相关性。为了解释TGF-β/pSmad信号传导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）在循环和肌肉组织中TGF-β超家族配体的“年轻”阳性与“老年”阴性水平是什么; 2）在什么样的年龄相关水平，TGF-β/pSmad信号传导变得过度并且对于卫星细胞再生能力是“负面的”，以及如何设计一个可调系统，用于卫星细胞中TGF-β/pSmad信号的精确“年轻”重新校准。这些目标将在拟议的具体目标中加以实现。

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.