Genome-Wide Profiling of miRNA-mRNA regulatory network in Skeletal Muscle with Aging [miRNA]

Skeletal muscle degenerates progressively, loses mass (sarcopenia) along in years, and leads to reduced physical ability, often causing secondary diseases such as diabetes and obesity. It is known that regulation of gene expression by microRNAs is a key event in muscle development and disease. To understand genome-wide changes in microRNAs and mRNAs during muscle aging, we sequenced microRNAs as well as mRNAs from mouse gastrocnemius muscles at two different ages (6 versus 24-month-old). Thirty-four microRNAs (15 up-regulated and 19 down-regulated) were differentially expressed with age among which were microRNAs such as miR-206 or -434 which were differentially expressed in aged muscle in previous studies. Interestingly, seven microRNAs in a microRNA cluster at imprinted Dlk1-Dio3 locus on chromosome 12 were coordinately down-regulated. In addition, sixteen novel microRNAs were identified. Integrative analysis of microRNA and mRNA expression revealed that microRNAs contribute to muscle aging possibly through the positive regulation of transcription, metabolic process, and kinase activity. Many of the age-related microRNAs were implicated in human muscular diseases. We suggest that genome-wide microRNA profiling helps to expand our knowledge of microRNA function in the muscle aging process. miRNA profiles of gastrocnemius muscle tissues (n=10) were generated by deep sequencing using Illumina Hiseq-2000骨骼肌会发生进行性退行性病变，随年龄增长出现肌量丢失（即肌肉减少症，sarcopenia），进而导致躯体运动能力下降，常继发糖尿病、肥胖等疾病。已知微小RNA（microRNAs）对基因表达的调控是肌肉发育与疾病进程中的关键事件。为解析肌肉衰老过程中微小RNA与信使RNA（mRNA）的全基因组表达变化，我们对两个不同年龄阶段（6月龄与24月龄）小鼠腓肠肌中的微小RNA及信使RNA进行了测序。共有34个微小RNA在不同年龄小鼠间呈差异表达，其中15个上调、19个下调，包括既往研究中已报道的在衰老肌肉中差异表达的miR-206与miR-434等。值得注意的是，位于12号染色体印记Dlk1-Dio3位点的一个微小RNA簇内的7个微小RNA呈现协同下调表达。此外，本研究还鉴定出16个全新的微小RNA。对微小RNA与信使RNA表达谱的整合分析显示，微小RNA可能通过正向调控转录过程、代谢进程及激酶活性参与肌肉衰老进程。诸多与年龄相关的微小RNA均与人类肌肉疾病存在关联。本研究提示，全基因组微小RNA表达谱分析有助于拓展我们对肌肉衰老进程中微小RNA功能的认知。本研究采用Illumina Hiseq-2000平台开展深度测序，构建了10份小鼠腓肠肌组织的微小RNA表达谱（n=10）。