CHANGES IN GENE EXPRESSION IN SENESCENT MUSCLE

初步研究发现，在衰老的人类肌肉中，相对于年轻的成年肌肉，可能存在大量表达不足或过度的mRNAs。这项拟议的研究的目的是前瞻性地确定这些转录本中的哪些持续受到衰老的影响，并进一步表征这些差异。具体地说，将在从年轻(18-29岁)和老年(65-79岁)男性和女性获得的人类肌肉样本中检查mRNA表达和蛋白质表达之间的关系。因为2型肌纤维比1型肌纤维更容易随着年龄的增长而萎缩，所以这些mRNAs在不同类型的纤维中的相对表达将被确定。在初步研究中，许多转录本在老年肌肉中表达不足，编码参与电子传递和ATP合成的线粒体蛋白。我们将研究线粒体DNA拷贝数、线粒体转录因子A和核呼吸因子在这些mRNAs低表达中的作用。许多在初步研究中差异表达的转录本只进行了部分测序。对于那些在前瞻性研究中也有差异表达的基因，将确定完整的mRNAs序列。这些信息将被用来推断氨基酸序列，从而能够研究蛋白质的表达，并可能提供关于蛋白质功能的线索。这项拟议研究产生的知识可能有助于更好地理解老年肌肉萎缩和功能障碍的分子基础，以及更好地理解有丝分裂后细胞衰老的基本生物学。

Preliminary studies have identified numerous mRNAs that may be under- or over-expressed in senescent human muscle relative to young adult muscle. The objective of the proposed research is to prospectively determine which of these transcripts are consistently affected by aging, and to further characterize these differences. Specifically, the relation between mRNA expression and protein expression will be examined in human muscle samples obtained from younger (18-29 yr) and older (65-79 yr) men and women. Because type 2 muscle fibers tend to atrophy more with age than type 1 fibers, the relative expression of these mRNAs in different fiber types will be determined. Many of the transcripts under-expressed in older muscle in the preliminary study encode mitochondrial proteins involved in electron transport and ATP synthesis. The roles of mitochondrial DNA copy number, mitochondrial transcription factor A, and nuclear respiratory factors in the under-expression of these mRNAs will be examined. Many of the transcripts differentially expressed in the preliminary study have been only partially sequenced. For those that are also differentially expressed in the prospective study, the full mRNA sequence will be determined. This information will be used to deduce the amino acid sequence, allowing studies of protein expression, and possibly providing clues about protein function. The knowledge generated by the proposed research may lead to a better understanding of the molecular basis of muscle atrophy and dysfunction in old age, and a better understanding of the basic biology of aging of postmitotic cells.