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，有一些行动正常的老年人，他们由于疾病或受伤而经历了一个或多个不能行动的时期，无法恢复行动能力。即使接受了广泛的康复治疗，这些人中的许多人也无法恢复到受伤前的功能水平。一种动物模型模拟了人类的这种情况。接受10天后肢制动的年轻和老年大鼠都表现出废用萎缩，但只有年轻大鼠的骨骼肌成功地从这种废用萎缩中再生，因为在恢复77天后，老年肌肉没有再生。假设2写道：“在所采用的微阵列上存在的对应于生长因子、生长因子受体或受体后信号的200个mRNA中，有10个在老年大鼠和年轻大鼠之间将有所不同，因为在重新加载期间，老年大鼠的骨骼肌未能从制动诱导的萎缩中恢复过来。具体目标1将确定与陈旧骨骼肌在重新加载过程中未能从制动诱导的萎缩中拯救自己有关的mRNA池。另一种观察是，短期应用IGF-I将挽救废弃萎缩后无法再生的旧肌肉。然而，这种影响只是暂时的，因为继续将IGF-I应用于陈旧肌肉会耗尽剩余的卫星细胞增殖和肌肉废物。因此，必须确定所有有缺陷的生长因子反应。特定目标2将在后肢固定后将IGF-I应用于老年肌肉，以进一步识别那些在老年肌肉中没有反应，但在年轻肌肉中有反应的基因。为了支持特定目标1和2中的数据分析，特定目标4将开发一个基于计算机的自动化微阵列数据分析系统，用于高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。识别与陈旧性肌肉再生失败相关的不适当表达的mRNAs将允许更科学地拯救陈旧性萎缩肌肉的生长因子。

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.