Overexpression of NF90-NF45 Represses Myogenic MicroRNA Biogenesis, Resulting in Development of Skeletal Muscle Atrophy and Centronuclear Muscle Fibers.

Abstract

MicroRNAs (miRNAs) are involved in the progression and suppression of various diseases through translational inhibition of target mRNAs. Therefore, the alteration of miRNA biogenesis induces several diseases. The nuclear factor 90 (NF90)-NF45 complex is known as a negative regulator in miRNA biogenesis. Here, we showed that NF90-NF45 double-transgenic (dbTg) mice develop skeletal muscle atrophy and centronuclear muscle fibers in adulthood. Subsequently, we found that the levels of myogenic miRNAs, including miRNA 133a (miR-133a), which promote muscle maturation, were significantly decreased in the skeletal muscle of NF90-NF45 dbTg mice compared with those in wild-type mice. However, levels of primary transcripts of the miRNAs (pri-miRNAs) were clearly elevated in NF90-NF45 dbTg mice. This result indicated that the NF90-NF45 complex suppressed miRNA production through inhibition of pri-miRNA processing. This finding was supported by the fact that processing of pri-miRNA 133a-1 (pri-miR-133a-1) was inhibited via binding of NF90-NF45 to the pri-miRNA. Finally, the level of dynamin 2, a causative gene of centronuclear myopathy and concomitantly a target of miR-133a, was elevated in the skeletal muscle of NF90-NF45 dbTg mice. Taken together, we conclude that the NF90-NF45 complex induces centronuclear myopathy through increased dynamin 2 expression by an NF90-NF45-induced reduction of miR-133a expression in vivo.

• Authors: Hiroshi Todaka, Takuma Higuchi, Ken-ichi Yagyu, Yasunori Sugiyama, Fumika Yamaguchi, Keiko Morisawa, Masafumi Ono, Atsuki Fukushima, Masayuki Tsuda, Taketoshi Taniguchi, Shuji Sakamoto
• Journal: Molecular and cellular biology (Mol Cell Biol) Vol. 35 Issue 13 Pg. 2295-308 (Jul 2015) ISSN: 1098-5549 [Electronic] United States
• PMID: 25918244 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Chemical References

• MicroRNAs
• Mirn133 microRNA, mouse
• Nuclear Factor 45 Protein
• Nuclear Factor 90 Proteins
• Dynamin II

Topics

• Animals
• Cell Line
• Dynamin II (genetics, metabolism)
• Female
• Gene Expression Regulation
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• MicroRNAs (genetics, metabolism)
• Muscle, Skeletal (metabolism, pathology)
• Muscular Atrophy (genetics, metabolism, pathology)
• Nuclear Factor 45 Protein (genetics, metabolism)
• Nuclear Factor 90 Proteins (genetics, metabolism)
• Up-Regulation