Hmgb3 Is Regulated by MicroRNA-206 during Muscle Regeneration

Abstract

BackgroundMicroRNAs (miRNAs) have been recently involved in most of human diseases as targets for potential strategies to rescue the pathological phenotype. Since the skeletal muscle is a spread-wide highly differentiated and organized tissue, rescue of severely compromised muscle still remains distant from nowadays. For this reason, we aimed to identify a subset of miRNAs major involved in muscle remodelling and regeneration by analysing the miRNA-profile of single fibres isolated from dystrophic muscle, which was here considered as a model of chronic damage.Methodology/Principal FindingsThe miRNA-signature associated to regenerating (newly formed) and remodelling (resting) fibres was investigated in animal models of muscular dystrophies and acute damage, in order to distinguish which miRNAs are primary related to muscle regeneration. In this study we identify fourteen miRNAs associated to dystrophic fibres responsible for muscle regeneration and remodelling, and confirm over-expression of the previously identified regeneration-associated myomiR-206. In particular, a functional binding site for myomiR-206 was identified and validated in the 3′untranslated region (3′UTR) of an X-linked member of a family of sequence independent chromatin-binding proteins (Hmgb3) that is preferentially expressed in hematopoietic stem cells. During regeneration of single muscle fibres, Hmgb3 messenger RNA (mRNA) and protein expression was gradually reduced, concurrent with the up-regulation of miR-206.Conclusion/SignificanceOur results elucidate a negative feedback circuit in which myomiR-206 represses Hmgb3 expression to modulate the regeneration of single muscle fibres after acute and chronic muscle damage. These findings suggest that myomiR-206 may be a potential therapeutic target in muscle diseases.

MicroRNAs in skeletal muscle biology and exercise adaptation

“…Following cardiotoxin injury, miR-206 is highly upregulated, suggesting a role in muscle regeneration, which is consistent with the impaired regeneration, reported in the miR-206 knockout mouse [34]. The increase in miR-206 expression is required to downregulate various genes including Pax7 , Notch3 , IGFBP5 [34] and Hmgb3 [117], all of which would be inhibitory to the differentiation process. In addition, the increase in miR-1 expression during regeneration further contributes to the downregulation of Pax7 expression [102].…”

ADAR1 deaminase contributes to scheduled skeletal myogenesis progression via stage-specific functions

“…In this capacity, DNM1 might cooperate with the myotube fusion facilitator ARHGAP26, 34 previously shown to interact strongly with DNM1. 48 Intriguingly, expression of an miRNA miR-199b, for which Dnm1 is a host gene, are highly correlated with dystrophic muscle fibers of the mdx mice, 49 further strengthening DNM1's myogenic function.…”

Non-coding RNAs in muscle differentiation and musculoskeletal disease

“…For instance, the RTK oncogene MET is targeted by microvesicles (45). These miRNAs are also increased in a wide variety of muscle disorders, such as myositis, Miyoshi myopathy, and limb-girdle muscular dystrophy (16,17,46), suggesting that inflammatory miRNAs can be a common signature of muscle diseases where chronic inflammation is present. Targeting of such miRNAs could be effectively combined with other therapeutic strategies, such as the exon skipping approach in DMD (45).…”