MicroRNAs and the Adaptive Response to Exercise Training
MicroRNAs (miRNAs) are a class of short, noncoding RNA molecules that bind to mRNA molecules and play a central role in regulating gene expression through posttranscriptional gene silencing (reviewed in Bushati and Cohen 2007). Most miRNAs are encoded in introns of protein-coding genes and are transcribed by RNA polymerase II as long primary-miRNAs (pri-miRNA) that encode a single miRNA or a cluster of miRNA species. Processing of pri-miRNA species in the nucleus produces stem-loop structures of ∼70 nucleotides, termed precursor-miRNA (pre-miRNA). These pre-miRNAs are transported to the cytoplasm where they are further processed, giving rise to the mature ∼19 to 22 bp of miRNA. The mature miRNA is incorporated into a ribonucleoprotein complex known as the RNA-induced silencing complex (RISC). Generally, miRNAs inhibit protein synthesis by binding (base-pairing) in the 3’ untranslated regions of target mRNAs, either repressing translation or bringing about deadenylation and subsequent degradation of mRNA targets. Individual miRNAs can target hundreds of genes, while individual mRNAs can be targeted by multiple miRNAs, making this one of the most complex gene-regulatory processes.
Studies have uncovered a cluster of muscle-specific miRNAs that regulate muscle differentiation and modulate diverse aspects of muscle function (reviewed in van Rooij, Liu, and Olson 2008). The most highly studied are miR-1, miR-133 and miR-206, which are induced during differentiation of myoblasts into myotubes (Callis et al. 2008) and play an important role in muscle mass maintenance. Other miRNA species (miR-23, miR-103, miR-107, and so on) are proposed to play an important role in regulating expression of genes encoding metabolic pathway enzymes in skeletal muscle and other tissues (Wilfred, Wang, and Nelson 2007). Interestingly, studies have shown the potential importance of miRNA regulation in skeletal-muscle adaptations to exercise (reviewed in Roth 2011). For example, miR-1 and miR-133a are downregulated in mouse skeletal muscle during functional overload–induced hypertrophy of the plantaris muscle (McCarthy and Esser 2007). In response to endurance exercise, miR-23, a putative negative regulator of the transcriptional coactivator peroxisome proliferator a coactivator 1 (PGC-1a), was downregulated in mouse skeletal muscle (Safdar et al. 2009). Importantly, downregulation of miR-23 was associated with increased expression of PGC-1a mRNA and protein, along with several downstream targets of PGC-1a signaling.
You are no doubt aware that the ability to increase muscle size in response to resistance and strength training is greater for some people than others. Have you ever wondered why strength training causes large gains in muscle mass in some people (i.e., high responders), whereas others gain very little muscle mass in response to the same training stimulus (i.e., low responders)? This is true even after accounting for differences in age, training status, exercise adherence, and diet. A study by Davidsen and colleagues (2011) helps to shed some light on this issue. In their study, vastus lateralis biopsies were taken from the top and bottom 49 responders, in terms of muscle mass gain, of 56 men who completed a 12-week strength-training program. The expression level of 21 abundant miRNAs was measured to determine whether variation in these miRNAs was able to explain the variation in resistance training–induced gains in muscle mass. They indentified 4 miRNAs that showed uniquely different responses between high responders and low responders. MiR-378, miR-29a, and miR-26a were downregulated in low responders and were unchanged in high responders, while miR-451 was upregulated only in low responders. Therefore, the regulation of protein synthesis by miRNAs may play an important role in explaining the variability in strength training adaptations. However, further research is required to uncover how these miRNAs themselves are regulated and whether they can be targeted for therapeutic interventions.