Genome-wide profiling of the microRNA-mRNA regulatory network in skeletal muscle with aging

Abstract

Skeletal muscle degenerates progressively, losing mass (sarcopenia) over time, which leads to reduced physical ability and often results in secondary diseases such as diabetes and obesity. The 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 and mRNAs from mouse gastrocnemius muscles at two different ages (6 and 24 months). Thirty-four microRNAs (15 up-regulated and 19 down-regulated) were differentially expressed with age, including the microRNAs miR-206 and -434, which were differentially expressed in aged muscle in previous studies. Interestingly, eight microRNAs in a microRNA cluster at the 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 may contribute to muscle aging through the positive regulation of transcription, metabolic processes, and kinase activity. Many of the age-related microRNAs have been implicated in human muscular diseases. We suggest that genome-wide microRNA profiling will expand our knowledge of microRNA function in the muscle aging process.

Age‐related changes in miR‐143‐3p:Igfbp5 interactions affect muscle regeneration

“…Changes in miRNA expression in muscle with age have been described in rodents and humans (Drummond et al ., 2008; Kim et al ., 2014); however, the functional relevance of this is not yet understood.…”

“…Satellite cell‐specific Dicer knockout in a mouse model resulted in mild myofibre atrophy (Cheung et al ., 2012). Although differential expression of miRs in muscle has been described during aging (Drummond et al ., 2008; Kim et al ., 2014), the relevance of these changes is not yet understood.…”

“…miR‐143‐5p is highly expressed in skeletal muscle tissue, and its expression is downregulated during aging (Kim et al ., 2014). A set of miR‐143 predicted targets is associated with insulin‐like growth factor (IGF) signalling (Blumensatt et al ., 2014).…”

miR-431 promotes differentiation and regeneration of old skeletal muscle by targeting Smad4

“…1A), 47 miRNAs were significantly up-regulated, and 71 miRNAs were down-regulated in old myoblasts (Tables 1, 2). We recently reported that 57% of miRNAs down-regulated in old muscle tissues were located in the Dlk-Dio3 region of chromosome 12 (Kim et al 2014). Interestingly, 63 of the 71 miRNAs (89%) down-regulated in old myoblasts were also located in the Dlk-Dio3 genomic region, suggesting that miRNAs expressed from this locus may be relevant to the process of muscle aging.…”

“…The finding that skeletal muscle-specific knockout of Dicer, a key enzyme for maturation of precursor miRNAs (pre-miRNA), causes a decrease in muscle mass and abnormal muscle formation in mice, causing perinatal death, suggests that miRNAs have a key role in normal muscle development (O'Rourke et al 2007). In addition, we recently found that the miRNA-mRNA regulatory network in skeletal muscle changes with age, suggesting that miRNAs may be involved in the process of muscle aging (Kim et al 2014).…”