MiR-199-3p enhances muscle regeneration and ameliorates aged muscle and muscular dystrophy

Masashi Fukuoka,Hideo Shimizu,Hirohiko Hohjoh,Masayuki Sekiguchi,Kosumo Numao,Hiromi Fujita,Yasuko Nakamura

doi:10.1038/s42003-021-01952-2

Abstract

Parabiosis experiments suggest that molecular factors related to rejuvenation and aging circulate in the blood. Here, we show that miR-199-3p, which circulates in the blood as a cell-free miRNA, is significantly decreased in the blood of aged mice compared to young mice; and miR-199-3p has the ability to enhance myogenic differentiation and muscle regeneration. Administration of miR-199 mimics, which supply miR-199-3p, to aged mice resulted in muscle fiber hypertrophy and delayed loss of muscle strength. Systemic administration of miR-199 mimics to mdx mice, a well-known animal model of Duchenne muscular dystrophy (DMD), markedly improved the muscle strength of mice. Taken together, cell-free miR-199-3p in the blood may have an anti-aging effect such as a hypertrophic effect in aged muscle fibers and could have potential as a novel RNA therapeutic for DMD as well as age-related diseases. The findings provide us with new insights into blood-circulating miRNAs as age-related molecules.

Highlights

Parabiosis experiments suggest that molecular factors related to rejuvenation and aging circulate in the blood
Thousands of miRNA genes have been found in animals and plants [see the microRNA database: http://www.mirbase.org/index.shtml]
The difference in the miRNAs between young and aged blood was confirmed by quantitative reverse transcription-polymerase chain reaction, and further reproduced using RNA sources extracted from small vesicles, so called exosomes, isolated from the plasma (Supplementary Fig. 1)

Summary

Introduction

Parabiosis experiments suggest that molecular factors related to rejuvenation and aging circulate in the blood. The findings strongly suggest that certain factors related to rejuvenation and aging are present, and circulating with blood in the vascular system; such circulating factors are not yet fully understood[13]. MiRNAs are present in the blood as cell-free nucleotides and circulate in the vascular system[26,27]. Such cell-free miRNAs (cf-miRNAs) are incorporated into small vesicles called extracellular vesicles or associated with proteins, thereby gaining protection from extracellular nucleases[25,28]. Cf-miRNAs may reflect changes in the physical condition; such miRNAs may be potential biomarkers for monitoring life maintenance systems, as well as diseases

Methods

Results

Conclusion