Muscle-specific microRNAs as biomarkers of Duchenne Muscular Dystrophy progression and response to therapies

Abstract

Recent studies have revealed the contribution of fibro-adipogenic progenitors (FAPs) to the pathogenesis and progression of Duchenne Muscular Dystrophy (DMD). While FAPs direct compensatory regeneration at early stages of disease, as the disease progresses they contribute to the progressive replacement of contractile myofibers with fibrotic scars and fatty infiltration. Using the mouse model of DMD – the mdx mice - we have recently reported that FAPs mediate the ability of HDAC inhibitors (HDACi) to promote muscle regeneration and prevent fibro-adipogenic degeneration at early stages of disease. This effect is mediated by the induction of myomiRs that, in turn, target the SWI/SNF components BAF60A and B, thereby favoring the formation of BAF60C-based SWI/SNF complex, which directs the switch from the fibro-adipogenic to the myogenic lineage. Here we show direct evidence of induction of miR-206 and BAF60C, and reduction of BAF60A, in FAPs isolated from mdx muscles exposed to the HDACi Trichostatin A (TSA). We also discuss how increased expression of myomiRs in dystrophic muscles can be integrated with circulating myomiRs to provide accurate biomarkers of disease progression and response to treatment.

Keywords:

• DMD
• myomiRs
• FAPs
• BAF60
• diagnostic biomarkers

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Muscle-specific microRNAs as biomarkers of Duchenne Muscular Dystrophy progression and response to therapies

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Muscle-specific microRNAs as biomarkers of Duchenne Muscular Dystrophy progression and response to therapies

Funding

PLP is an Investigator of Sanford Children's Health Research Center. This work has been supported by the following grants to PLP: R01AR056712, R01AR052779 and P30 AR061303 from the National Institute of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), EPIGEN, FILAS and AFM-Telethon. This work has benefited from research funding from the European Community's Seventh Framework Program in the project FP7-Health – 2009 ENDOSTEM 241440 (Activation of vasculature associated stem cells and muscle stem cells for the repair and maintenance of muscle tissue). LG was supported by a fellowship from Fondazione Sovena.