MiR-17 and miR-19 cooperatively promote skeletal muscle cell differentiation

Delin Kong,Rongtao Zhou,Mei He,Chun-Bo Teng,Lin Yang,Yang Liang,Yun-Qin Yan

doi:10.1007/s00018-019-03165-7

Abstract

Skeletal myogenesis is a highly coordinated process that involves cell proliferation, differentiation and fusion controlled by a complex gene regulatory network. The microRNA gene cluster miR-17–92 has been shown to be related to this process; however, the exact role of each cluster member remains unclear. Here, we show that miR-17 and miR-20a could effectively promote the differentiation of both C2C12 myoblasts and primary bovine satellite cells. In contrast, miR-18a might play a negative role in C2C12 cell differentiation, while miR-19 and miR-92a had little influence. Transcriptome and target analyses revealed that miR-17 could act on Ccnd2, Jak1 and Rhoc genes that are critical for cell proliferation and/or fusion. Notably, the addition of miR-19 could reverse the lethal effect of miR-17 and could thus facilitate the maturation of myotubes. Furthermore, by co-injecting the lentiviral shRNAs of miR-17 and miR-19 into mouse tibialis anterior muscles, we demonstrated the wound healing abilities of the two miRNAs. Our findings indicate that in combination with miR-19, miR-17 is a potent inducer of skeletal muscle differentiation.

Highlights

In vertebrates, skeletal myogenesis is a highly coordinated process that is fundamental to the development, growth and regeneration of skeletal muscle
The expression levels of the miR-17–92 cluster members were all decreased during the normal differentiation of C2C12 cells, except for that of miR-18a, which increased during the early stages and decreased later (Fig. 1c)
SiCcnd2 and siJak1 were successful in GM (Figs. 3e, S3d). These results indicated that the effects of miR-17 could be achieved in part by directly targeting Ccnd2 and Jak1 that are well known for maintaining cell proliferation, as well as Rhoc that is more involved in suppressing cell motility and regulating cell fusion

Summary

Introduction

Skeletal myogenesis is a highly coordinated process that is fundamental to the development, growth and regeneration of skeletal muscle. In response to exercise or damage, skeletal muscle can robustly regenerate owing to the residence of multipotent satellite cells [1]. The highly conserved miR-17–92 cluster is one of the most investigated miRNA clusters. It consists of six miRNAs as follows: miR-17, -18a, -19a, -20a, -19b-1, and -92a-1 (Fig. S1a). The miR-17–92 cluster was first found to be an oncomir in malignant B cell lymphoma [11]. MiR-19a and -19b were identified to be the key oncogenic ones by targeting PTEN (phosphate and tensin homologue), increasing the PI3K–AKT signalling pathway for the maintenance and survival of B-lymphoma; miR-17 did

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