Identification of MicroRNAs Linked to Regulators of Muscle Protein Synthesis and Regeneration in Young and Old Skeletal Muscle

Abstract

BackgroundOver the course of ageing there is a natural and progressive loss of skeletal muscle mass. The onset and progression of age-related muscle wasting is associated with an attenuated activation of Akt-mTOR signalling and muscle protein synthesis in response to anabolic stimuli such as resistance exercise. MicroRNAs (miRNAs) are novel and important post-transcriptional regulators of numerous cellular processes. The role of miRNAs in the regulation of muscle protein synthesis following resistance exercise is poorly understood. This study investigated the changes in skeletal muscle miRNA expression following an acute bout of resistance exercise in young and old subjects with a focus on the miRNA species predicted to target Akt-mTOR signalling.ResultsTen young (24.2±0.9 years) and 10 old (66.6±1.1 years) males completed an acute resistance exercise bout known to maximise muscle protein synthesis, with muscle biopsies collected before and 2 hours after exercise. We screened the expression of 754 miRNAs in the muscle biopsies and found 26 miRNAs to be regulated with age, exercise or a combination of both factors. Nine of these miRNAs are highly predicted to regulate targets within the Akt-mTOR signalling pathway and 5 miRNAs have validated binding sites within the 3′ UTRs of several members of the Akt-mTOR signalling pathway. The miR-99/100 family of miRNAs notably emerged as potentially important regulators of skeletal muscle mass in young and old subjects.ConclusionThis study has identified several miRNAs that were regulated with age or with a single bout of resistance exercise. Some of these miRNAs were predicted to influence Akt-mTOR signalling, and therefore potentially skeletal muscle mass. These miRNAs should be considered as candidate targets for in vivo modulation.

Concurrent exercise incorporating high-intensity interval or continuous training modulates mTORC1 signaling and microRNA expression in human skeletal muscle

“…miRNAs have been associated with the regulation of skeletal muscle mass (49), and their expression levels are altered following both single bouts of exercise (31,72,91) and short-term exercise training (26,72). However, no studies have investigated whether miRNA expression is altered following concurrent compared with single-mode RE.…”

“…Given their purported role in posttranscriptional regulation, miRNAs have emerged as a potential regulator of exercise-induced adaptations in skeletal muscle (90). The expression of various miRNA species in human skeletal muscle is altered following both single bouts of exercise (31,72,91) and after short-term exercise training (26,72). miRNAs have been implicated in the regulation of the IGF-1/Akt, Fox-O1, and myogenesis pathways, all known to play a role in RE-induced adaptations in skeletal muscle (49), although the direct impact of miRNAs on these pathways in response to RE is yet to be experimentally validated.…”

The long and short of non-coding RNAs during post-natal growth and differentiation of skeletal muscles: Focus on lncRNA and miRNAs

“…Greater insight into interactions between the many forms of RNAs and proteins that regulate muscle growth and maintain homeostasis, is of central importance to livestock industries related to improvement of meat quality and production using molecular approaches (Hou et al, 2012;Li et al, 2012) and to clinical muscle disorders. For example, many ncRNAs have been identified in cases of aberrant muscle growth and muscle atrophy, including genetic diseases as Duchenne muscular dystrophy (Neguembor et al, 2014;Twayana et al, 2013), inflammatory conditions like cachexia (Soares et al, 2014) and age-related muscle wasting (Drummond et al, 2011); therapeutic modulation of many ncRNAs by exercise has recently been demonstrated (Zacharewicz et al, 2014). The ncRNAs are likely to represent viable therapeutic targets, or useful readouts of treatment efficacy or disease progression.…”

Regulation of Gene Expression by Exercise-Related Micrornas

“…Many beneficial effects of physical exercise have been reported: a) improvement of plasma lipid composition (decreased triglyceride; total cholesterol and LDL-cholesterol; and increased HDL-cholesterol levels), b) amelioration of glucose homeostasis (elevated insulinindependent glucose uptake; glucose transporter-4 (GLUT-4) expression; and insulin sensitivity); c) increased skeletal muscle oxidative capacity (improved biogenesis and mitochondrial metabolism), and d) reduction in inflammation markers [74,[79][80][81][82][83]. Physical exercise modulates expression of several miRs involved in protein synthesis, such as miR26a, miR-29a, miR-378, miR-451, and miR-696 [84][85][86]. However, the mechanisms involved are not fully known yet.…”