Dkk3 dependent transcriptional regulation controls age related skeletal muscle atrophy

Jie Yin,Lele Yang,Gang Li,Yan Liu,Wenjun Yang,Sheng Li,Hongbin Ji,Lin Chen,Lianghua Ding,Kun Wang,Ping Hu,Yangli Xie,Bo Xu

doi:10.1038/s41467-018-04038-6

Abstract

Age-related muscle atrophy (sarcopenia) is the leading cause for disability in aged population, but the underlying molecular mechanisms are poorly understood. Here we identify a novel role for the secreted glycoprotein Dickkopf 3 (Dkk3) in sarcopenia. Forced expression of Dkk3 in muscles in young mice leads to muscle atrophy. Conversely, reducing its expression in old muscles restores both muscle size and function. Dkk3 induces nuclear import of β-catenin and enhances its interaction with FoxO3, which in turn activates the transcription of E3 ubiquitin ligase Fbxo32 and Trim63, driving muscle atrophy. These findings suggest that Dkk3 may be used as diagnostic marker and as therapeutic target for age-related muscle atrophy, and reveal a distinct transcriptional control of Fbxo32 and Trim63.

Highlights

Age-related muscle atrophy is the leading cause for disability in aged population, but the underlying molecular mechanisms are poorly understood
These results reveal that reduction of Dkk[3] level in old mice can improve both muscle fiber size and functions, suggesting Dkk[3] to be a potential target to treat sarcopenia
In sharp contrast to the observations in wild-type myotubes, Dkk[3] lost the ability to induce the recruitment of β-catenin to Fbxo[32] and Trim[63] promoters when FoxO3 was depleted (Fig. 6e), suggesting that FoxO3 is required for the recruitment of β-catenin to the promoters of Fbxo[32] and Trim[63]. These results suggest that Fbxo[32] and Trim[63] transcription is activated by the combination of FoxO3 and βcatenin in a Dickkopf 3 (Dkk3)-dependent manner in aging related muscle atrophy

Summary

Introduction

Age-related muscle atrophy (sarcopenia) is the leading cause for disability in aged population, but the underlying molecular mechanisms are poorly understood. Dkk[3] induces nuclear import of β-catenin and enhances its interaction with FoxO3, which in turn activates the transcription of E3 ubiquitin ligase Fbxo[32] and Trim[63], driving muscle atrophy. We identified Dkk[3] as the key secreted factor generated by muscles to induce sarcopenia and characterized the mechanism of Dkk3dependent transcription activation of Fbxo[32] and Trim[63]. These findings shed lights on understanding the causing of sarcopenia

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Results

Conclusion