Effects of the systemic environment on muscle aging

全身环境对肌肉衰老的影响

• 批准号: 8079540
• 负责人: Irina M Conboy
• 金额: $ 28.57万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-15 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8079540
• 关键词: Activins; Adult; Age; Aging; Animals; Attenuated; Blood Circulation; Calibration; Cell Culture Techniques; Cell Proliferation; Cells; Data; Disease; Dominant Negative Receptor; Environment; Family; Follistatin; Generations; Goals; In Vitro; Injury; Intramuscular; Life; Ligands; Methods; Molecular; Mus; Muscle; Muscle Cells; Muscle satellite cell; Natural regeneration; Notch Signaling Pathway; Organ; Parabiosis; Pathway interactions; Pattern; Process; Proliferating; Protein Family; Proteins; Regulation; Relative (related person); Research; Research Personnel; Role; Serum; Signal Transduction; Skeletal Muscle; Smad Proteins; Smad protein; Stem cells; System; Testing; Tetracyclines; Therapeutic; Tissues; Transforming Growth Factor beta; Work; Wound Healing; activin A; age related; aged; attenuation; cell injury; design; in vivo; inhibitor/antagonist; juvenile animal; muscle aging; myogenesis; notch protein; regenerative; repaired; response; satellite cell; stem; tissue regeneration; trait; young adult

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.

描述（由申请人提供）： 成人骨骼肌在整个成年期都能强劲再生，但在老年时却无法再生。再生潜力如此下降的原因尚不清楚，并且肌肉细胞的变化与衰老环境的变化之间的相对作用尚未确定。最近的研究表明，年轻的系统环境可以恢复再生特异性Notch通路的活性，并增强老化肌肉的修复，这表明老化卫星细胞的基本完整的再生潜力在老化环境中没有被正确触发。我们最新的数据表明，导致老年人器官干细胞活化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生态位实际上抑制了Notch激活和两者的再生潜力。老的和年轻的卫星细胞。也就是说，从衰老肌肉中分离出来的卫星细胞或在体外暴露于衰老小鼠血清中的卫星细胞的再生能力受到抑制并且缺乏Notch激活。此外，我们的初步数据确定了这种与年龄相关的抑制的分子机制，证明衰老环境中卫星细胞再生潜力的降低源于这些细胞中衰老生态位诱导的过度 TGF-β/pSmad 信号传导，而这些信号转而反过来是衰老循环和肌肉组织中 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，通过减弱卫星细胞中的 TGF-β/pSmad 信号传导，可以恢复生肌潜力和 Notch 激活。这些研究强调了理解 TGF-β 超家族对成体肌生成的调节以及设计肌肉干细胞中 TGF-β/pSmad 信号传导可调校准方法的高度治疗相关性。为了破译 TGF-β/pSmad 信号在肌肉修复中与年龄相关的作用并推动治疗应用，需要确定 1) TGF-β 的“年轻”阳性水平与“老年”阴性水平是多少-循环和肌肉组织中的超家族配体； 2) 在什么与年龄相关的水平上，TGF-β/pSmad 信号变得过度并且对卫星细胞的再生能力产生“负面”影响；3) 如何设计一个可调谐系统，以精确地“年轻化”重新校准卫星中的 TGF-β/pSmad 信号细胞。这些目标将在拟议的具体目标中实现。