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Open AccessArticle

A Low-Therapeutic Dose of Lithium Inhibits GSK3 and Enhances Myoblast Fusion in C2C12 Cells

1
Department of Kinesiology, Brock University 1812 Sir Isaac Brock Way, St. Catharines, ON L2S 3A1, Canada
2
Centre for Bone and Muscle Health, Brock University 1812 Sir Isaac Brock Way, St. Catharines, ON L2S 3A1, Canada
3
Department of Biological Sciences, Brock University 1812 Sir Isaac Brock Way, St. Catharines, ON L2S 3A1, Canada
4
Lunenfeld-Tanenbaum Research Institute, Sinai Health System, 600 University Avenue, Toronto, ON M5G 1X5, Canada
*
Author to whom correspondence should be addressed.
Cells 2019, 8(11), 1340; https://doi.org/10.3390/cells8111340
Received: 4 October 2019 / Revised: 23 October 2019 / Accepted: 26 October 2019 / Published: 29 October 2019
Glycogen synthase kinase 3 (GSK3) slows myogenic differentiation and myoblast fusion partly by inhibiting the Wnt/β-catenin signaling pathway. Lithium, a common medication for bipolar disorder, inhibits GSK3 via Mg+ competition and increased Ser21 (GSK3α) or Ser9 (GSK3β) phosphorylation, leading to enhanced myoblast fusion and myogenic differentiation. However, previous studies demonstrating the effect of lithium on GSK3 have used concentrations up to 10 mM, which greatly exceeds concentrations measured in the serum of patients being treated for bipolar disorder (0.5–1.2 mM). Here, we determined whether a low-therapeutic (0.5 mM) dose of lithium could promote myoblast fusion and myogenic differentiation in C2C12 cells. C2C12 myotubes differentiated for three days in media containing 0.5 mM lithium chloride (LiCl) had significantly higher GSK3β (ser9) and GSK3α (ser21) phosphorylation compared with control myotubes differentiated in the same media without LiCl (+2–2.5 fold, p < 0.05), a result associated with an increase in total β-catenin. To further demonstrate that 0.5 mM LiCl inhibited GSK3 activity, we also developed a novel GSK3-specific activity assay. Using this enzyme-linked spectrophotometric assay, we showed that 0.5 mM LiCl-treated myotubes had significantly reduced GSK3 activity (−86%, p < 0.001). Correspondingly, 0.5 mM LiCl treated myotubes had a higher myoblast fusion index compared with control (p < 0.001) and significantly higher levels of markers of myogenesis (myogenin, +3-fold, p < 0.001) and myogenic differentiation (myosin heavy chain, +10-fold, p < 0.001). These results indicate that a low-therapeutic dose of LiCl is sufficient to promote myoblast fusion and myogenic differentiation in muscle cells, which has implications for the treatment of several myopathic conditions. View Full-Text
Keywords: lithium; glycogen synthase kinase 3; myoblast fusion lithium; glycogen synthase kinase 3; myoblast fusion
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Kurgan, N.; Whitley, K.C.; Maddalena, L.A.; Moradi, F.; Stoikos, J.; Hamstra, S.I.; Rubie, E.A.; Kumar, M.; Roy, B.D.; Woodgett, J.R.; Stuart, J.A.; Fajardo, V.A. A Low-Therapeutic Dose of Lithium Inhibits GSK3 and Enhances Myoblast Fusion in C2C12 Cells. Cells 2019, 8, 1340.

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