Regulation of skeletal alpha actin expression during mu*

描述(申请人提供)：骨骼肌再生是一个基本的过程，它允许在由于缺乏运动而导致的一轮萎缩后恢复质量。不幸的是，在某些情况下，如衰老、高血压或糖尿病，骨骼肌不会通过增加肌肉质量来应对机械负荷的增加。长期目标是确定在健康条件下调节肌肉再生的细胞/分子机制，并确定在骨骼肌在一轮萎缩后不再再生的情况下，这些机制是否功能失调。肌肉质量的增加受到多个水平的调节，包括转录、翻译和翻译后水平。虽然，调控肌肉从一轮萎缩中恢复的关键分子机制仍不清楚，但众所周知，内源性生长因子在刺激肌肉生长方面发挥着不可或缺的作用。近年来，胰岛素样生长因子(IGF-I)被用于诱导骨骼肌肥大，挽救老年动物失去的肌块，以及治疗肌营养不良和肌萎缩侧索硬化症等神经肌肉疾病。 不幸的是，目前还不清楚IGF-I是如何对骨骼肌产生有益影响的。目前，影响肌肉再生过程中基因表达的转录机制尚未完全确定，而且IGF-I与这些机制的潜在相互作用也从未被探索过。了解IGF-I激活的机制对肌肉生物学领域具有重要意义，因为由于IGF-I的许多不良副作用，包括癌症，在人类医学中使用IGF-I将是困难的。避免副作用的一种潜在方法是了解IGF-I改变骨骼肌的细胞机制，然后通过药理学手段调节这些机制。具体目标1将描述骨骼肌再生过程中转录激活骨骼肌α-肌动蛋白基因所必需的顺式元件和转录因子。不幸的是，到目前为止，还没有研究检测任何顺式元件和/或反式因子在骨骼肌萎缩后的恢复过程中调节任何基因的转录激活。特异性目标2将确定IGF-I在骨骼肌再生过程中通过特定顺式元件和转录因子对骨骼肌α-肌动蛋白基因转录激活的作用。总体目标是确定IGF-I在肌肉再生过程中激活转录活性可能起到的作用。

DESCRIPTION (provided by applicant): Skeletal muscle regrowth is a fundamental process that allows the recovery of mass after a bout of atrophy induced by physical inactivity. Unfortunately, under some circumstances, such as aging, hypertension, or diabetes, the skeletal muscle does not respond to increases in mechanical load by increasing muscle mass. The long term objective is to determine the cellular/molecular mechanisms that regulate muscle regrowth under healthy conditions, and determine if the mechanisms are dysfunctional in conditions where skeletal muscle does not regrow after a bout of atrophy. Increases in muscle mass are regulated at multiple levels, including the transcriptional, translational, and posttranslational level. Although, key molecular mechanisms that regulate the recovery of muscle from a bout of atrophy remain undefined, it is well known that endogenous growth factors play an integral role in stimulating muscle growth. Recently, insulin-like growth factor (IGF-I) has been used to induce skeletal muscle hypertrophy, to rescue lost muscle mass in aged animals and to treat neuromuscular diseases such as muscular dystrophy and amyotrophic lateral sclerosis. Unfortunately, it is unclear how IGF-I is impacting beneficial effects on the skeletal muscle. Currently, the transcriptional mechanisms that impact gene expression during muscle regrowth are not completely defined, and further the potential interaction of IGF-I with these mechanisms has never been explored. The understanding of the mechanisms activated by IGF-I is of fundamental importance to the muscle biology field, since it will be difficult to use IGF-I in human medicine, due to the numerous undesired side effects of IGF-I, including cancer. One potential way to circumvent the side effects is to understand the cellular mechanisms by which IGF-I alters skeletal muscle, and then modulate these mechanisms through pharmacological means. Specific Aim 1 will delineate the cis elements and the transcription factors necessary for transcriptional activation of the skeletal a-actin gene during skeletal muscle regrowth. Unfortunately to date, no studies have examined any cis-elements and/or trans-factors that regulate transcriptional activation of any gene during recovery from a bout of skeletal muscle atrophy. Specific Aim 2 will determine the role IGF-I, has on the transcriptional activation of the skeletal a-actin gene through specific cis-elements and transcription factors during skeletal muscle regrowth. The overall goal is to determine the role IGF-I may have in activating transcriptional activity during muscle regrowth.