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Dkk3 dependent transcriptional regulation controls age related skeletal muscle atrophy

Jie Yin1,2, Lele Yang1,2, Yangli Xie3

  • 1State 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.

Nature Communications
|May 3, 2018
PubMed

Insights

Dickkopf 3 (Dkk3) drives age-related muscle atrophy by activating specific genes. Reducing Dkk3 in older muscles improves muscle size and function, suggesting Dkk3 as a therapeutic target for sarcopenia.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Gerontology

Background:

  • Age-related muscle atrophy, or sarcopenia, is a primary cause of disability in the elderly.
  • The molecular drivers of sarcopenia remain incompletely understood.
  • Dickkopf 3 (Dkk3), a secreted glycoprotein, has not been previously linked to muscle aging.

Purpose of the Study:

  • To investigate the role of Dickkopf 3 (Dkk3) in the molecular mechanisms of age-related muscle atrophy (sarcopenia).
  • To explore Dkk3 as a potential diagnostic marker and therapeutic target for sarcopenia.

Main Methods:

  • Mice models with forced Dkk3 expression in young muscles and reduced Dkk3 expression in aged muscles were utilized.
  • Molecular analyses focused on nuclear import of β-catenin and its interaction with FoxO3.
  • Gene transcription of E3 ubiquitin ligases Fbxo32 and Trim63 was assessed.

Main Results:

  • Forced Dkk3 expression in young mice induced muscle atrophy.
  • Reducing Dkk3 expression in aged mice restored muscle size and function.
  • Dkk3 promoted nuclear import of β-catenin, enhancing its interaction with FoxO3.
  • This interaction led to increased transcription of Fbxo32 and Trim63, key drivers of muscle atrophy.

Conclusions:

  • Dickkopf 3 (Dkk3) plays a significant role in age-related muscle atrophy (sarcopenia).
  • Dkk3 facilitates muscle atrophy by modulating the β-catenin/FoxO3 pathway, thereby upregulating Fbxo32 and Trim63.
  • Dkk3 presents a potential diagnostic marker and therapeutic target for sarcopenia.

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