Serum miR‐206 and other muscle‐specific microRNAs as non‐invasive biomarkers for Duchenne muscular dystrophy

Abstract

Creatine kinase has been utilized as a diagnostic marker for Duchenne muscular dystrophy (DMD), but it correlates less well with the DMD pathological progression. In this study, we hypothesized that muscle-specific microRNAs (miR-1, -133, and -206) in serum may be useful for monitoring the DMD pathological progression, and explored the possibility of these miRNAs as potential non-invasive biomarkers for the disease. By using real-time quantitative reverse transcription-polymerase chain reaction in a randomized and controlled trial, we detected that miR-1, -133, and -206 were significantly overexpressed in the serum of 39 children with DMD (up to 3.20 AE 1.20, 2 ÀDDCt ): almost 2-to 4-fold enriched in comparison to samples from the healthy controls (less than 1.15 AE 0.34, 2 ÀDDCt ). To determine whether these miRNAs were related to the clinical features of children with DMD, we analyzed the associations compared to creatine kinase. There were very good inverse correlations between the levels of these miRNAs, especially miR-206, and functional performances: high levels corresponded to low muscle strength, muscle function, and quality of life. Moreover, by receiver operating characteristic curves analyses, we revealed that these miRNAs, especially miR-206, were able to discriminate DMD from controls. Thus, miR-206 and other muscle-specific miRNAs in serum are useful for monitoring the DMD pathological progression, and hence as potential non-invasive biomarkers for the disease.

Mega roles of microRNAs in regulation of skeletal muscle health and disease

“…By targeting IGF-1 and p85α proteins, miR-29 inhibited muscle protein synthesis and myogenesis since IGF-1 and p85α are well established signaling molecules for protein translation and a decrease in these proteins was observed during muscle atrophy including sarcopenia (Owino et al, 2001; Barbour et al, 2005; Park et al, 2009; Smith et al, 2012). Overexpression of miR-29 in skeletal muscle also resulted in an increase in cell cycle arrest proteins, Cyclin-Dependent kinase inhibitor 2A, (p16Ink4A) and Retinoblastoma protein (pRB) in agreement with the increased expression of these proteins in aged muscle (Hu et al, 2014a,b). Thus, miR-29 regulates the levels of various proteins directly or indirectly eventually resulting in muscle atrophy during aging.…”

“…Several studies have determined the expression of myomiRs, miR-1, -133, and -206 levels in serum of DMD patients and found that these myomiRs were upregulated. Consistently, miR-206 correlates with DMD pathology and thus could be a useful biomarker for DMD along with creatine kinase (Cacchiarelli et al, 2011; Mizuno et al, 2011; Vignier et al, 2013; Zaharieva et al, 2013; Hu et al, 2014a,b; Roberts et al, 2014). Furthermore, miR-145 and miR-133a were shown to be potential biomarkers in a mouse model of DMD (Endo et al, 2013).…”

“…Similarly, microarray analysis of miRNAs in muscles from young (4 months) and old (28 months) rats was shown to alter (Hu et al, 2014a,b). Several miRNAs were up or down regulated.…”

The implications on clinical diagnostics of using microRNA-based biomarkers in exercise

“…Likewise, children with DMD present higher blood levels of these miRNAs, which correlate with low muscle strength and function, and with the severity of muscle damage [77]. Especially miR-206 represents a good candidate for detection and progression of DMD [77]. MiR-206 plays a role in skeletal muscle regeneration: following muscle injury, miR-206 is upregulated in satellite cells and may promote muscle regeneration [78].…”

“…Serum levels of miR-1, -133a and -206 are increased in murine and canine models of Duchenne muscular dystrophy (DMD) [3]. Likewise, children with DMD present higher blood levels of these miRNAs, which correlate with low muscle strength and function, and with the severity of muscle damage [77]. Especially miR-206 represents a good candidate for detection and progression of DMD [77].…”