The functional consequences of age-related changes in microRNA expression in skeletal muscle

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.

microRNA–SIRT‐1 interactions: key regulators of adult skeletal muscle homeostasis?

“…Changes in other microRNAs: miR-23a, miR-34a, miR-125b and miR-214, previously reported to regulate muscle atrophy, hypertrophy and/or regeneration, were also measured. The expression of SIRT-1 has been previously shown to be controlled by microRNAs (Soriano et al 2016). Our group has shown that changes in miR-181a levels in the muscle of old mice is associated with changes in SIRT-1 expression, and indeed that SIRT-1 is a direct miR-181a target gene (Soriano et al 2016).…”

“…Our group has shown that changes in miR-181a levels in the muscle of old mice is associated with changes in SIRT-1 expression, and indeed that SIRT-1 is a direct miR-181a target gene (Soriano et al 2016). Moreover, overexpression of miR-181a in C2C12 myotubes led to decreased myotube size, a phenotype probably regulated by changes in SIRT-1 expression (Soriano et al 2016). Interestingly, the levels of miR-181 are downregulated in muscle from old mice, whereas SIRT-1 expression is upregulated, suggesting a compensatory mechanism occurring in muscle during ageing.…”

“…The expression of SIRT‐1 has been previously shown to be controlled by microRNAs (Soriano et al . ). Our group has shown that changes in miR‐181a levels in the muscle of old mice is associated with changes in SIRT‐1 expression, and indeed that SIRT‐1 is a direct miR‐181a target gene (Soriano et al .…”

“…Our group has shown that changes in miR‐181a levels in the muscle of old mice is associated with changes in SIRT‐1 expression, and indeed that SIRT‐1 is a direct miR‐181a target gene (Soriano et al . ). Moreover, overexpression of miR‐181a in C2C12 myotubes led to decreased myotube size, a phenotype probably regulated by changes in SIRT‐1 expression (Soriano et al .…”

“…Moreover, overexpression of miR‐181a in C2C12 myotubes led to decreased myotube size, a phenotype probably regulated by changes in SIRT‐1 expression (Soriano et al . ). Interestingly, the levels of miR‐181 are downregulated in muscle from old mice, whereas SIRT‐1 expression is upregulated, suggesting a compensatory mechanism occurring in muscle during ageing.…”