MicroRNA control of muscle development and disease
Introduction
The development of cardiac and skeletal muscle is orchestrated by evolutionarily conserved networks of transcription factors that regulate the expression of genes involved in muscle growth, differentiation, and contractility. The most ancient of these myogenic transcription factors is the MADS (MCM1, Agamous, Deficiens, Serum response factor) box transcription factor myocyte enhancer factor-2 (MEF2), which directly activates the majority of muscle genes through combinatorial interactions with other transcription factors [1]. In cardiac muscle, MEF2 and another MADS-box transcription factor, serum response factor (SRF), cooperatively activate cardiac gene expression by association with GATA, T-box, and Nkx2.5 transcription factors, as well as the myocardin family of transcriptional co-activators, whereas in skeletal muscle MEF2 activates the myogenic differentiation program in conjunction with the basic-helix-loop-helix (bHLH) transcription factors, MyoD and myogenin [2, 3]. Recent studies have revealed that, in addition to activating genes involved in muscle differentiation and muscle contraction, these myogenic transcription factors activate the expression of a set of conserved microRNAs (miRNAs) that function to ‘fine-tune’ the output of these transcriptional networks, resulting in precise cellular responses to developmental, physiologic, and pathologic signals. The integration of miRNAs into the core muscle transcriptional program expands the precision and complexity of gene regulation in muscle cells because individual miRNAs are capable of regulating hundreds of mRNAs, and individual mRNAs can be targeted by many miRNAs. In this review, we discuss recent publications that have illuminated the roles of miRNAs in muscle development and disease.
Section snippets
miRNA biogenesis and function
miRNAs are small, evolutionarily conserved noncoding RNAs that are transcribed by RNA polymerase II as long pri-miRNAs encoding one or more miRNAs. Most miRNAs are transcribed as independent transcripts, but approximately a third are embedded within introns of protein-coding genes and processed following splicing of pre-messenger RNAs [4]. Pri-miRNAs are processed in the nucleus by the proteins Drosha and DGCR8, which produce an ∼70 nucleotide hairpin RNA, termed the pre-miRNA, which is
Muscles without miRNAs
An essential role for miRNAs in mouse development was shown by a loss-of-function mutation in the miRNA-generating enzyme, Dicer, which results in embryonic lethality by day 7.5 [11]. In order to circumvent the lethality associated with the deletion of Dicer and to study the roles of Dicer in specific tissues, several groups have generated conditional null alleles of Dicer. Deletion of Dicer in cardiomyocytes using a Cre recombinase ‘knocked-in’ to the endogenous Nkx2.5 locus, which directs
Muscle-specific miRNAs
Several individual miRNAs are specifically expressed in cardiac and skeletal muscle (Table 1) [16]. Of these, the most widely studied are members of miR-1/206 and miR-133a/133b families, which originate from bicistronic transcripts on three separate chromosomes (Figure 1) [17•]. miR-1-1 and miR-1-2 are identical and differ from miR-206 by four nucleotides, and miR-133a-1 and miR-133a-2 are identical and differ from miR-133b by two nucleotides. Cardiac and skeletal muscle specific transcription
MyomiRs
Proper function of the heart depends on the expression of myosin heavy chain (MHC) proteins MYH6 (α-MHC) and MYH7 (β-MHC). Cardiac injury results in a decrease in the expression of the adult myosin gene, Myh6, and an increase in the expression of the embryonic myosin gene, Myh7. Recently, it was discovered that these myosin genes also encode a family of miRNAs, called MyomiRs, which have important functions in regulating myosin content and stress-dependent cardiac remodeling [38].
α-MHC, the
miRNAs with functions in muscle
In addition to muscle-specific miRNAs, there are also examples of ubiquitously expressed miRNAs that have been shown to have functions in muscle. In zebrafish, miR-214 was shown to act as a positive regulator of the slow muscle phenotype, by targeting suppressor of fused (Su(fu)), a negative regulator of hedgehog signaling [40]. miR-138 was reported to contribute to chamber-specific gene expression patterns in the zebrafish heart by targeting aldehyde dehydrogenase-1a2 (RALDH2), a regulator of
miRNAs in muscle disease
Several important studies have indicated that miRNA expression is dysregulated in cardiac and skeletal muscle disease and in some cases individual miRNAs have been shown to cause or alleviate disease. The first series of such studies focused on the profiling of miRNAs in hypertrophic murine and human hearts and revealed a common set of miRNAs that are elevated in hypertrophic hearts [43, 44, 45, 46]. One of these miRNAs, miR-195, was shown to be sufficient to induce heart failure and death due
Therapeutic manipulation of miRNAs with antagomiRs and miR mimics
Therapeutic manipulation of miRNAs represents a potentially powerful approach to treat cardiovascular and skeletal muscle diseases. In this regard, cholesterol-modified antisense oligonucleotides, referred to as antagomiRs, show remarkable efficacy in the inhibition of miRNAs following intravenous delivery in vivo [53]. Engelhardt and co-workers showed that delivery of an antagomiR to miR-21, a miRNA upregulated in failing hearts, preserved cardiac function and reduced cardiac fibrosis
Conclusions
Although many important findings have been made within the past few years, our current knowledge about the function of miRNAs in muscle development and disease is still quite limited given the multitude of possible interactions between transcription factors, miRNAs, and their target mRNAs. Future studies will need to focus on characterizing the in vivo functions of individual vertebrate miRNAs followed by the identification of their downstream target mRNAs. Identification of the miRNA
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
We apologize to the many researchers whose work was not cited in this review owing to space limitations. We thank Jose Cabrera for graphics and Jennifer Brown for editorial assistance. Work in the laboratory of ENO is supported by grants from the NIH, the Donald W Reynolds Center for Clinical Cardiovascular Research, the Leducq Foundation, the Sandler Foundation for Asthma Research, and the Robert A Welch Foundation. AHW is supported by a training grant from the National Heart, Lung, and Blood
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