Dkk3 dependent transcriptional regulation controls age related skeletal muscle atrophy

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

doi:10.1038/s41467-018-04038-6

Dkk3 dependent transcriptional regulation controls age related skeletal muscle atrophy

Nat Commun. 2018 May 1;9(1):1752. doi: 10.1038/s41467-018-04038-6.

Authors

Jie Yin^{1

2}, Lele Yang^{1

2}, Yangli Xie³, Yan Liu¹, Sheng Li¹, Wenjun Yang¹, Bo Xu^{1

2}, Hongbin Ji¹, Lianghua Ding⁴, Kun Wang⁴, Gang Li⁵, Lin Chen³, Ping Hu^{6

7}

Affiliations

¹ State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Sciences, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, 200031, Shanghai, China.
² CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
³ Department of Rehabilitation Medicine, Center of Bone Metabolism and Repair, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, The Third Military Medical University, 400042, Chongqing, China.
⁴ The 3rd Affiliated Hospital of Soochow University, Soochow University, 185 Jvqian Road, 21300, Changzhou, Jiangsu, China.
⁵ Department of Neurology, East Hospital, Tongji University School of Medicine, 200120, Shanghai, China.
⁶ State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Sciences, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, 200031, Shanghai, China. hup@sibcb.ac.cn.
⁷ CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China. hup@sibcb.ac.cn.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing
Adult
Aged
Aging / pathology
Animals
Cachexia / pathology
Forkhead Box Protein O3 / metabolism
Gene Expression Regulation / physiology*
Humans
Intercellular Signaling Peptides and Proteins / physiology*
Mice
Mice, Inbred C57BL
Middle Aged
Muscle Proteins / genetics
Muscle Proteins / metabolism
Muscle, Skeletal / pathology*
Muscular Atrophy / prevention & control*
Promoter Regions, Genetic
SKP Cullin F-Box Protein Ligases / genetics
SKP Cullin F-Box Protein Ligases / metabolism
Sarcopenia / pathology*
Starvation / pathology
Transcription, Genetic / physiology*
Tripartite Motif Proteins / genetics
Tripartite Motif Proteins / metabolism
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / metabolism
beta Catenin / metabolism

Substances

Adaptor Proteins, Signal Transducing
Dkk3 protein, mouse
Forkhead Box Protein O3
FoxO3 protein, mouse
Intercellular Signaling Peptides and Proteins
Muscle Proteins
Tripartite Motif Proteins
beta Catenin
Fbxo32 protein, mouse
SKP Cullin F-Box Protein Ligases
Trim63 protein, mouse
Ubiquitin-Protein Ligases