MECHANISMS OF MUSCLE AGING--ANALYSIS AND INTERVENTION

本单元的目标是确定肌肉纤维类型的命运 标记在肌肉发育和衰老的不同阶段，并 通过选择性前体细胞消融来调制纤维类型。光纤类型，如果 肌肉功能的基本决定因素和纤维成分的变化 是肌肉退行性变的主要成分 随着年龄的增长和神经肌肉疾病。生理学 纤维组成的分支已经在 许多系统和纤维特异性基因已经被识别出来。 然而，个别纤维类型的命运，无论是在发展中 胚胎和衰老或退化的肌肉中，仍然存在。我们 建议利用几项新开发的技术来解决这些问题 问题。我们将使用一种新的转基因方法，用一只鸟 基于逆转录病毒的细胞标记策略进行谱系分析 转基因小鼠肌肉中的纤维前体。我们将修改cre/lox 永久标记不同纤维类型的二元转基因系统 衰老的肌肉，这样他们的命运就可以终生跟随 动物的跨度。最后，我们将评估扰动的效果 通过选择性地消融不同类型的纤维来合成肌纤维， 利用病毒传递的重组酶激活标志基因或毒素基因 转基因小鼠肌肉。这些实验将澄清重要的 骨骼肌功能中尚未解决的问题；即身份和 参与年龄相关性萎缩的纤维的命运。

The goals of this unit are to establish the fate of muscle fiber types marked at different stages of muscle development and senescence, and to modulate fiber type by selective precursor cell ablation. Fiber type if an essential determinant of muscle function, and changes in fiber composition represent a major component in the muscle degeneration associated both with aging and with neuromuscular diseases. The physiological ramifications of fiber composition have been extensively studied in numerous systems, and fiber specific genes have been identified. Nevertheless, the fate of individual fiber types, both in the developing embryo and in senescent or degenerating muscle, remains.obscure. We propose to exploit several newly developed technologies to address these questions. We will use a novel transgenic approach using an avian retrovirus-based cell marking strategy to perform lineage analysis on fiber precursors in transgenic mouse muscle. We will modify the cre/lox binary transgenic system to permanently mark different fiber types in senescent muscle, so that their fate can be followed throughout the life span of the animal. Finally, we will assess the effect of perturbing muscle fiber composition by selective ablation of different fiber types, using virally delivered recombinase to activate marker or toxin genes in transgenic mouse muscles. These experiments will clarify important unresolved issues in skeletal muscle function; namely, the identity and fate of fibers involved in age-related atrophy.