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  3. Canonical Wnt signaling affects calcium homeostasis in serum-treated AC16 cells through MLN-mediated SERCA2a regulation

Canonical Wnt signaling affects calcium homeostasis in serum-treated AC16 cells through MLN-mediated SERCA2a regulation

  • J Mol Cell Biol. 2025 Dec 5:mjaf050. doi: 10.1093/jmcb/mjaf050.
Ang Li 1 2,  Yuanyuan Shen 1,  Zhenyan Li 1,  Wenyu Jiang 1,  Jie Su 1,  Xiaomin Song 3,  Lin Li 1 3
Affiliations

Affiliations

  • 1 School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Science, Hangzhou 310024, China.
  • 2 School of Basic Medical Sciences, Dalian University of Technology, Dalian 116024, China.
  • 3 Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
PMID: 41348974 DOI: 10.1093/jmcb/mjaf050
Abstract

The canonical Wnt/β-catenin pathway critically regulates cardiac calcium homeostasis, yet its interplay with microenvironmental factors remains unclear. This study reveals that fetal bovine serum (FBS) treatment alters Wnt-mediated calcium dynamics in AC16 cardiomyocytes. While Wnt activation elevates cytosol calcium in serum-free conditions, FBS supplementation reverses this response: Wnt inhibitors (SFRP2, XAV939, and LF3) induce cytosol calcium accumulation, while the activators (LiCl and Wnt3a) lose efficacy. Mechanistically, FBS ablates RyR2 expression, uncoupling calcium-induced calcium release. Consequently, calcium handling shifts to SERCA2a-dependent regulation. We identify myoregulin (MLN) as a pivotal effector of the Wnt/β-catenin signaling with Wnt inhibition upregulating MLN to suppress SERCA2a activity. MLN knockdown (90% suppression) abolishes the effects of Wnt inhibitors on SERCA2a function and calcium distribution patterns. RyR2 reconstitution in FBS-treated cells restores calcium release but not Wnt activation responses, confirming the dominant role of MLN. Crucially, a combination of RyR2 overexpression and MLN depletion fully restores Wnt-calcium responses, phenocopying serum-free conditions. Our work establishes a serum-dependent regulatory axis where Wnt/β-catenin signaling maintains calcium homeostasis by repressing MLN, thereby preserving SERCA2a function. This FBS-induced shift mirrors pathological adaptations in heart failure, positioning MLN as a therapeutic target for calcium-handling disorders.

Keywords

AC16 cells; MLN; SERCA2a; Wnt; cardiac calcium homeostasis.

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