Non-coding RNAs in muscle differentiation and musculoskeletal disease

Abstract

RNA is likely to be the most rediscovered macromolecule in biology. Periodically, new non-canonical functions have been ascribed to RNA, such as the ability to act as a catalytic molecule or to work independently from its coding capacity. Recent annotations show that more than half of the transcriptome encodes for RNA molecules lacking coding activity. Here we illustrate how these transcripts affect skeletal muscle differentiation and related disorders. We discuss the most recent scientific discoveries that have led to the identification of the molecular circuitries that are controlled by RNA during the differentiation process and that, when deregulated, lead to pathogenic events. These findings will provide insights that can aid in the development of new therapeutic interventions for muscle diseases.

Figure 1. miRNA-mediated regulatory networks in myogenesis and skeletal muscle diseases.

Schematic representation of the differentiation stages leading from progenitor muscle cells to terminally differentiated fibers. The most relevant regulatory circuits between miRNAs and protein factors are shown. miRNA species that are up- or downregulated in dystrophic cells are represented in red and green, respectively. Polα, polymerase α.

Figure 2. Models of lncRNA function in myogenesis.

Nuclear lncRNAs may act as: (i) eRNAs, which regulate transcription through enhancer-like functions (such as core enhancer RNA and ^DRRRNA (MUNC) [refs. 70, 71, 87] in myogenesis); (ii) decoy lncRNAs, which act by sequestering chromatin or transcriptional regulators (such as MyHeart [ref. 82], which inhibits the chromatin remodeling factor BRG1); (iii) guide lncRNAs, which act by recruiting epigenetic regulators onto specific chromosomal loci (such as Bvht [ref. 104], Fendrr [ref. 105], DBE-T [80], Dum [ref. 108], Meg3 [ref. 95]); (iv) architect lncRNAs, which act by modifying the three-dimensional conformation of chromatin (such as Kcnq1ot1 lncRNA [ref. 101]). Activating (green) or repressing (red) histone modifications together with the sites of DNA methylation (black) are indicated. Additionally, cytoplasmic lncRNAs may act as (v) sponges, which compete for miRNAs (ceRNAs) or RNA binding proteins. Examples include Linc-MD1 (110), H19 (112), and Malat (116, 118) ceRNAs and LncMyoD (117); (vi) antisense lncRNAs, which base pair with mRNA to provide a binding site for specific regulators. Examples include the 1/2-sbsRNAs that induce Staufen1-mediated (STAU-mediated) mRNA decay (119). Finally, previously defined lncRNAs can encode for short peptides (vii), such as 2310015BRik (linc00948) RNA, which encodes for myoregulin (123).