TNF Signaling Acts Downstream of MiR-322/-503 in Regulating DM1 Myogenesis

Abstract

Myotonic dystrophy type 1 (DM1) is caused by the expanded CUG repeats and usually displays defective myogenesis. Although we previously reported that ectopic miR-322/-503 expression improved myogenesis in DM1 by targeting the toxic RNA, the underlying pathways regulating myogenesis that were aberrantly altered in DM1 and rescued by miR-322/-503 were still unknown. Here, we constructed DM1 and miR-322/-503 overexpressing DM1 myoblast models, which were subjected to in vitro myoblast differentiation along with their corresponding controls. Agreeing with previous findings, DM1 myoblast showed remarkable myogenesis defects, while miR-322/-503 overexpression successfully rescued the defects. By RNA sequencing, we noticed that Tumor necrosis factor (TNF) signaling was the only pathway that was significantly and oppositely altered in these two experimental sets, with it upregulated in DM1 and inhibited by miR-322/-503 overexpression. Consistently, hyperactivity of TNF signaling was detected in two DM1 mouse models. Blocking TNF signaling significantly rescued the myogenesis defects in DM1. On the contrary, TNF-α treatment abolished the rescue effect of miR-322/-503 on DM1 myogenesis. Taking together, these results implied that TNF signaling mediated the myogenesis defects in DM1 and might act downstream of miR-322/-503 in regulating the myogenesis in DM1. Moreover, the inhibition of TNF signaling benefiting myogenesis in DM1 provided us with a novel therapeutic strategy for DM1.

CREB‐binding protein and HIF‐1α/β‐catenin to upregulate miR‐322 and alleviate myocardial ischemia‐reperfusion injury

“…Additionally, miR‐322 has been implicated in cardiomyocyte function as it is involved in the formation and specification of cardiomyocytes during development 32,33 . Moreover, miR‐322/miR‐503 has been shown to play an essential role in cell differentiation, proliferation, cardiomyocyte specification, as well as hypoxia process and ischemia‐reperfusion injury 11,34–40 . The findings of the present study further support the idea that miR‐322 acts as a beneficial factor to protect against MIRI.…”

“…32,33 Moreover, miR-322/miR-503 has been shown to play an essential role in cell differentiation, proliferation, cardiomyocyte specification, as well as hypoxia process and ischemia-reperfusion injury. 11,[34][35][36][37][38][39][40] The findings of the present study further support the idea that miR-322 acts as a beneficial factor to protect against MIRI. We found that the reduced level of miR-322 during MIRI was a result of decreased levels of HIF-1α/β-catenin, which directly interacted with the promoter region of miR-322 to promote its expression.…”