Failed rescue of old skeletal muscle from atrophy

一个常见的临床问题是，在许多养老院中，有一些活动和功能正常的老年人，由于疾病或受伤而遭受一个或多个时期的不活动，无法恢复活动。即使进行了广泛的康复治疗，其中许多人也无法恢复到损伤前的功能水平。动物模型模仿人类的这种情况。经过10天后肢固定的年轻和年老大鼠都表现出废用性萎缩，但只有年轻大鼠的骨骼肌成功地从这种废用性萎缩中再生，因为在77天后，老肌肉没有再生。假设2写道：“当年老的骨骼肌在重新加载过程中无法从固定诱导的萎缩中拯救自己时，存在于所使用的微阵列上的200种mrna中，有10种与生长因子、生长因子受体或受体后信号传导相对应。具体目标1将确定一组mrna，这些mrna与年老骨骼肌在重新加载期间从固定诱导的萎缩中拯救自身失败有关。另一个观察结果是，短期的igf - 1应用将挽救旧肌肉在废弃萎缩后的再生失败。然而，这种效果只是短暂的，因为持续将igf - 1应用于老肌肉会耗尽剩余的卫星细胞增殖和肌肉废物。因此，必须识别所有有缺陷的生长因子反应。具体目标2将把igf - 1应用于后肢固定后的老肌肉，以进一步确定那些在老肌肉中没有反应，但在年轻肌肉中有反应的基因。特异性目标3将在特异性目标1和2中结束固定后开始表征年轻和年老肌肉之间差异表达的ESTs。为了支持具体目标1和2中的数据分析，具体目标4将开发一个基于计算机的自动化系统，用于分析微阵列数据，用于大容量数据存储的数据仓库系统，以及用于跨实验查询微阵列数据的工具。识别与衰老肌肉再生失败相关的不适当表达的mrna将使衰老萎缩肌肉的生长因子拯救更加科学。

A common clinical problem is that in many nursing homes there are mobile and functioning aged individuals who, upon being subjected to one or more periods of immobility due to illness or injury, are unable to return back to mobility. Even with extensive rehabilitative therapy, many of these individuals are unable to recover to preinjury functioning levels. An animal model mimics this human condition. Both young and old rats who undergo a 10-day period of hindlimb immobilization exhibit disuse atrophy, but only skeletal muscle from young rats successfully regrows from this disuse atrophy as old muscle had no regrowth after 77 days of recovery. Hypothesis 2 reads: "Ten of the 200 mRNAs corresponding to growth factors, growth factor receptors, or post-receptor signaling that are present on the employed microarray will differ between young and old rats during the failure of old skeletal muscle to rescue itself from immobilization-induced atrophy during reloading. Specific aim 1 will identify a pool of mRNAs associated with the failure of old skeletal muscle to rescue itself from immobilization-induced atrophy during reloading. Another observation is that short-term IGF-I application will rescue the failure of old muscle to regrow after disuse atrophy. However, this effect is only transient as continued IGF-I application to old muscle depletes remaining satellite cell proliferations and muscle wastes. Thus, all defective growth factor responses must be identified. Specific aim 2 will apply IGF-I to old muscle after hindlimb immobilization in order to further identify those genes that failed to respond in old muscles, but had responded in young muscles. Specific aim 3 will begin to characterize for those differentially expressed ESTs between young and old muscles after ending immobilization in Specific aims 1 and 2. To support data analysis in Specific aims 1 and 2, Specific aim 4 will develop a computer-based, automated system for analysis of microarray data, data warehousing system for high capacity data storage, and tools for querying microarray data across experiments. Identifying the inappropriately expressed mRNAs associated with failed muscle regrowth of old muscles will permit a more scientifically-based growth factor rescue of old atrophied muscle.