期刊
HUMAN MOLECULAR GENETICS
卷 25, 期 18, 页码 3960-3974出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddw237
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资金
- Medical Research Council (MRC) [1371292]
- Agency for Science, Technology and Research (A*STAR, Singapore)
- Estonian Research Council [PUT618]
- Swedish Research Council
- National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust
- University College London
- Great Ormond Street Hospital Children's Charity
- Oxford's RCUK Open Access Block Grant
- Medical Research Council [1371292] Funding Source: researchfish
MyomiRs are muscle-specific microRNAs (miRNAs) that regulatemyoblast proliferation and differentiation. Extracellular myomiRs (ex-myomiRs) are highly enriched in the serum of Duchenne Muscular Dystrophy (DMD) patients and dystrophic mouse models and consequently have potential as disease biomarkers. The biological significance of miRNAs present in the extracellular space is not currently well understood. Here we demonstrate that ex-myomiR levels are elevated in perinatal muscle development, during the regenerative phase that follows exercise-induced myoinjury, and concomitant with myoblast differentiation in culture. Whereas ex-myomiRs are progressively and specifically released by differentiating human primary myoblasts and C2C12 cultures, chemical induction of apoptosis in C2C12 cells results in indiscriminate miRNA release. The selective release of myomiRs as a consequence of cellular differentiation argues against the idea that they are solely waste products of muscle breakdown, and suggests they may serve a biological function in specific physiological contexts. Ex-myomiRs in culture supernatant and serum are predominantly non-vesicular, and their release is independent of ceramide-mediated vesicle secretion. Furthermore, ex-myomiRs levels are reduced in aged dystrophicmice, likely as a consequence of chronicmuscle wasting. In conclusion, we show that myomiR release accompanies periods ofmyogenic differentiation in cell culture and in vivo. SerummyomiR abundance is therefore a function of the regenerative/degenerative status of the muscle, overallmuscle mass, and tissue expression levels. These findings have implications for the use of ex-myomiRs as biomarkers for DMD disease progression and monitoring response to therapy.
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