Skeletal Muscle MicroRNAs: Their Diagnostic and Therapeutic Potential in Human Muscle Diseases

Abstract

MicroRNAs (miRNAs) are small 21-24 nucleotide RNAs that are capable of regulating multiple signaling pathways across multiple tissues. MicroRNAs are dynamically regulated and change in expression levels during periods of early development, tissue regeneration, cancer, and various other disease states. Recently, microRNAs have been isolated from whole serum and muscle biopsies to identify unique diagnostic signatures for specific neuromuscular disease states. Functional studies of microRNAs in cell lines and animal models of neuromuscular diseases have elucidated their importance in contributing to neuromuscular disease progression and pathologies. The ability of microRNAs to alter the expression of an entire signaling pathway opens up their unique ability to be used as potential therapeutic entry points for the treatment of disease. Here, we will review the recent findings of key microRNAs and their dysregulation in various neuromuscular diseases. Additionally, we will highlight the current strategies being used to regulate the expression of key microRNAs as they have become important players in the clinical treatment of some of the neuromuscular diseases.

Keywords: MicroRNA; biomarker; dystrophy; muscle disease; skeletal muscle; therapy.

Fig. 1

MicroRNAs can be isolated from serum and diseased muscles as diagnostic and quantitative biomarkers. Schematic showing the potential for the use of microRNAs both as diagnostic biomarkers (A) and quantitative biomarkers (B) in neuromuscular disease. A. Serum or a muscle biopsy can be taken from a patient with a known or undiagnosed neuromuscular disease. The sample is then analyzed for expression level and compared with known expression levels of specific microRNAs known to be dysregulated in particular neuromuscular diseases. B. An exon-skipping morpholino is used as a therapeutic intervention strategy to bypass the DNA deletion of exon 50 (red letter X) of protein-encoding gene (e.g. dystrophin). The exon-skipping morpholino skips over exon 51 to restore the correct reading frame of the mRNA transcript. The resulting mRNA transcript is spliced together to restore function and/or reading frame of the mature mRNA when it will be translated into a mature protein by the ribosomal machinery. The microRNA levels are used as a non-evasive biomarker, and the microRNA biosignature is monitored for restoration to that of normal healthy muscle control expression levels.

Fig. 2

Strategies to manipulate expression levels of microRNAs for the treatment of neuromuscular diseases. Therapies using Adeno-Associated Viral vectors (AAV) delivery to increase or decrease the expression levels of a specific microRNA that could be used to treat either primary or secondary consequences of the neuromuscular disease mutations and/or its disease-associated pathological symptoms. Synthetic approaches involving microRNA inhibitors (LNAs, MOs, or other AON molecules; blue seed loop) or microRNA sponges (or other “decoy molecules”) contain microRNA binding sites (red rectangles) and might be used to inhibit microRNA function via direct antisense inhibition thereby reducing the levels of endogenous microRNAs (red seed loop) in the serum or tissue. MicroRNA sponges or decoy molecules can be used to remove the amount of circulating or (“unbound”) microRNAs in a given tissue or from serum. Other synthetic molecules, such as microRNA mimics (red seed loop; MIMIC), might be used to mimic the function of endogenous microRNAs thereby suppressing the microRNA's intended mRNA target gene.