Exercise, Skeletal Muscle and Circulating microRNAs

Abstract

Regular exercise stimulates numerous structural, metabolic, and morphological adaptations in skeletal muscle. These adaptations are vital to maintain human health over the life span. Exercise is therefore seen as a primary intervention to reduce the risk of chronic disease. Advances in molecular biology, biochemistry, and bioinformatics, combined with exercise physiology, have identified many key signaling pathways as well as transcriptional and translational processes responsible for exercise-induced adaptations. Noncoding RNAs, and specifically microRNAs (miRNAs), constitute a new regulatory component that may play a role in these adaptations. The short single-stranded miRNA sequences bind to the 3′ untranslated region of specific messenger RNAs (mRNAs) on the basis of sequence homology. This results in the degradation of the target mRNA or the inhibition of protein translation causing repression of the corresponding protein. While tissue specificity or enrichment of certain miRNAs makes them ideal targets to manipulate and understand tissue development, function, health, and disease, other miRNAs are ubiquitously expressed; however, it is uncertain whether their mRNA/protein targets are conserved across different tissues. miRNAs are stable in plasma and serum and their altered circulating expression levels in disease conditions may provide important biomarker information. The emerging research into the role that miRNAs play in exercise-induced adaptations has predominantly focused on the miRNA species that are regulated in skeletal muscle or in circulation. This chapter provides an overview of these current research findings, highlights the strengths and weaknesses identified to date, and suggests where the exercise-miRNA field may move into the future.

Introduction

Physical exercise typically results in the activation of multiple intra- and extracellular signals that positively or negatively influence the transcription and translation of genes and proteins controlling skeletal muscle structure and function.1, 2 The transcription and translation processes are conjointly controlled by transcription factors,3, 4 histone modification,⁵ and DNA methylation.6, 7 microRNAs (miRNAs) were first identified 20 years ago and have generated an additional level of complexity in our understanding of transcriptional and translational regulation.8, 9 miRNAs are short, single-stranded RNA molecules (20–30 nucleotides) that bind to specific messenger RNAs (mRNAs) on the basis of sequence homology10, 11 and repress the corresponding protein expression.12, 13 miRNAs usually bind to specific sites of the 3′ untranslated region (UTR) of their target transcripts¹¹ thanks to a conserved nucleotide sequence called the “seed” region and located at base positions 2–8 on the 5′ end of the miRNA. miRNA/mRNA binding principally results in the degradation of the target mRNA,¹² but can sometimes directly inhibit protein translation. In rare cases, miRNAs can also stabilize mRNA targets.¹⁴ miRNAs are now demonstrated major regulators of biological processes¹⁵ and play an essential role in the cellular response to stress stimuli and the maintenance of healthy cellular function.

Specific miRNAs are found to be particularly enriched in specific tissues.¹⁶ MyomiR is the term referring to the miRNAs highly expressed in skeletal muscle and includes miR-1, miR-133a, miR-133b, miR-206, miR-208, miR-208b, miR-486, and miR-499.17, 18 These miRNAs regulate fundamental biological processes in the muscle, including muscle growth, development, metabolism, and repair.¹⁹ For example, myogenesis is a complex process mediated by several key transcription factors (known as myogenic regulatory factors, MRFs), including MyoD, myogenin, Myf5, and MRF4,20, 21 that closely control and coordinate every aspect of muscle growth. miRNAs in turn regulate the MRFs and therefore play an essential role in the control of muscle development. Similarly, miRNAs have been shown to be involved in muscle fiber-type regulation,²² muscle protein synthesis,23, 24 and muscle regeneration.²⁵ In the muscle, physical exercise triggers multiple short- and long-term adaptive physiological responses that essentially depend on these biological processes. Therefore, exercise influences the expression of the miRNAs present in skeletal muscle as well as the members of their biogenesis machinery.