Dkk3 dependent transcriptional regulation controls age related skeletal muscle atrophy
Open accessAbstract
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.
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Age-related muscle loss is consequent to β-catenin recruitment on FoxO3-binding sites to enhance expression of atrogin-1 and MuRF1.
“The age-related muscle loss is consequent to β-catenin recruitment on FoxO3-binding sites to enhance the expression of atrogin-1 and MuRF1 expression69.”
From Mechanisms of muscle atrophy and hypertrophy: implications in health and disease (2021) · cites this paper as [69]
DKK3 downregulation reduces age-related muscle loss but not cancer- or fasting-mediated muscle atrophy.
“DKK3 is upregulated in aging and its overexpression caused muscle atrophy, while its downregulation reduced age-related muscle loss but not cancer- or fasting-mediated muscle atrophy.”
From Mechanisms of muscle atrophy and hypertrophy: implications in health and disease (2021) · cites this paper as [69]
DKK3 is upregulated in aging.
“DKK3 is upregulated in aging and its overexpression caused muscle atrophy, while its downregulation reduced age-related muscle loss but not cancer- or fasting-mediated muscle atrophy.”
From Mechanisms of muscle atrophy and hypertrophy: implications in health and disease (2021) · cites this paper as [69]
DKK3 overexpression causes muscle atrophy.
“DKK3 is upregulated in aging and its overexpression caused muscle atrophy, while its downregulation reduced age-related muscle loss but not cancer- or fasting-mediated muscle atrophy.”
From Mechanisms of muscle atrophy and hypertrophy: implications in health and disease (2021) · cites this paper as [69]
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References 66 · Cited by 72
- Authors
- Yin, J., Yang, L., Xie, Y., Liu, Y., Li, S., Yang, W., Xu, B., Ji, H., Ding, L., Wang, K., Li, G., Chen, L., & Hu, P.
- Affiliations
- Chinese Academy of Sciences (CN)
- Army Medical University (CN)
- Soochow University (CN)
- Tongji University (CN)
- Corresponding author
- Hu, Ping
- ORCID
- Venue
- Nature Communications
- Published
- 2018-05-01
- Volume
- 9
- Issue
- 1
- Pages
- 1752-1752
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC5931527
- OpenAlex
- W2806508890
- Cited by
- 72
- References
- 66
- Citations by year
- 2026: 5 · 2025: 12 · 2024: 17 · 2023: 11 · 2022: 4 · 2021: 14 · 2020: 6 · 2019: 3
- FWCI
- 2.05
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Commonwealth Scientific and Industrial Research Organisation
- National Natural Science Foundation of China (91649104, 2017YFA0102700, 81530071, 31671536, 81200355)
- Chinese Academy of Sciences (XDA16020400)
- Science and Technology Commission of Shanghai Municipality (Y753S11802)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Physiology › Nutrition and Health in Aging
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Muscle metabolism and nutrition
- Keywords
- Dickkopf-3, sarcopenia, age-related muscle loss, skeletal muscle, FOXO3, atrogin-1, MuRF1, E3 ubiquitin ligase, transcriptional regulation, therapeutic target, diagnostic biomarkers
- MeSH terms
- Tripartite Motif Proteins, Forkhead Box Protein O3, Adult, Aged, Aging, Animals, Cachexia, Gene Expression Regulation, Humans, Mice, Inbred C57BL, Middle Aged, Muscle Proteins, Muscular Atrophy, Promoter Regions, Genetic, Starvation, Transcription, Genetic, Muscle, Skeletal, Intercellular Signaling Peptides and Proteins, Ubiquitin-Protein Ligases, SKP Cullin F-Box Protein Ligases, Adaptor Proteins, Signal Transducing, beta Catenin, Mice, Sarcopenia
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