Abstract
A common characteristic of ageing is disrupted homeostasis between growth and atrophy of skeletal muscle resulting in loss of muscle mass and function, which is associated with sarcopenia. Sarcopenia is related to impaired balance, increased falls and decline in quality of life of older people. Ageing-related transcriptome and proteome changes in skeletal muscle have been characterised, however the molecular mechanisms underlying sarcopenia are still not fully understood. microRNAs are novel regulators of gene expression known to modulate skeletal muscle development and homeostasis. Expression of numerous microRNAs is disrupted in skeletal muscle with age however, the functional consequences of this are not yet understood. Given that a single microRNA can simultaneously affect multiple signalling pathways, microRNAs are potent modulators of pathophysiological changes occurring during ageing. Here we use microRNA and transcript expression profiling together with microRNA functional assays to show that disrupted microRNA:target interactions play an important role in maintaining muscle homeostasis. We identified miR-181a as a regulator of the sirtuin1 (Sirt1) gene expression in skeletal muscle and show that the expression of miR-181a and its target gene is disrupted in skeletal muscle from old mice. Moreover, we show that miR-181a:Sirt1 interactions regulate myotube size. Our results demonstrate that disrupted microRNA:target interactions are likely related to the pathophysiological changes occurring in skeletal muscle during ageing.Electronic supplementary materialThe online version of this article (doi:10.1007/s10522-016-9638-8) contains supplementary material, which is available to authorized users.
Highlights
Age-related loss of skeletal muscle mass and function, associated with sarcopenia, results in frailty, decline in strength and decrease in quality of life of older people
To model microRNA:target interactions in skeletal muscle during ageing, an unbiased microRNA and microglobulin and/or 18S (mRNA) expression profiling was performed on the tibilais anterior (TA) muscle of adult and old mice using microarrays (Figure S1)
The molecular mechanisms involved in sarcopenia development are not fully understood, it is clear that transcriptomic, proteomic and epigenetic changes are involved. miRNAs can simultaneously modulate many signalling pathways and are likely to be high-throughput regulators of pathophysiological changes associated with sarcopenia
Summary
Age-related loss of skeletal muscle mass and function, associated with sarcopenia, results in frailty, decline in strength and decrease in quality of life of older people. MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression at the posttranscriptional level. Mature miRNAs are generated from primary-miRNA (pri-miRNA) precursors which are cleaved by the enzyme Drosha forming the pre-miRNA transcript. The pre-miRNA is transported into the cytoplasm, where the enzyme Dicer generates a 19–24 base pair miRNA duplex (Bartel 2004). The mature miRNA strand is incorporated into the RISC complex (RNA Induced Silencing Complex). MiRNAs guide the RISC to partially complementary sequences, usually contained within the 30 UTR of target mRNA transcripts, resulting in target mRNA degradation and/or inhibition of translation. Most mammalian miRNAs have only partially complementary sequences to their target mRNAs (Bartel 2004) resulting in challenging bioinformatic prediction of the target genes
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