MECHANISMS OF MUSCLE AGING--ANALYSIS AND INTERVENTION

本单元的目标是建立肌纤维类型的命运 在肌肉发育和衰老的不同阶段， 通过选择性前体细胞消融来调节纤维类型。光纤类型，如果 肌肉功能的基本决定因素，以及纤维成分的变化 代表了肌肉退化的主要组成部分， 与衰老和神经肌肉疾病有关。生理 纤维组合物的衍生物已经被广泛研究， 已经鉴定了许多系统和纤维特异性基因。 然而，无论是在发展中国家， 胚胎和在衰老或退化的肌肉，肌肉。我们 我建议利用几种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， 基于逆转录病毒的细胞标记策略， 转基因小鼠肌肉中的纤维前体。我们将修改cre/lox 二元转基因系统永久标记不同纤维类型， 衰老的肌肉，使他们的命运可以遵循整个生命 动物的跨度。最后，我们将评估扰动的影响。 通过选择性消融不同纤维类型的肌纤维组成， 使用病毒递送的重组酶来激活标记或毒素基因， 转基因小鼠肌肉。这些实验将阐明重要的 骨骼肌功能中尚未解决的问题;即， 与年龄相关性萎缩有关的纤维的命运。

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.