Zinc promotes proliferation and activation of myogenic cells via the PI3K/Akt and ERK signaling cascade

• Published in: Experimental cell research 2015-05, Vol.333 (2), p.228-237
• Main Authors: Ohashi, Kazuya, Nagata, Yosuke, Wada, Eiji, Zammit, Peter S., Shiozuka, Masataka, Matsuda, Ryoichi
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; ALBUMINS; Animals; Biosynthesis; C2C12; CATTLE; CELL CYCLE; Cell growth; Cell Line; Cell Proliferation; DEOXYURIDINE; DOSES; FIBROBLASTS; GROWTH FACTORS; INHIBITION; INJURIES; INSULIN; Insulin - physiology; MAP Kinase Signaling System; Mice; Musculoskeletal system; MYOBLASTS; MYOSIN; PHOSPHATES; Phosphatidylinositol 3-Kinases - metabolism; PHOSPHORYLATION; Protein Processing, Post-Translational; Proto-Oncogene Proteins c-akt - metabolism; RECEPTORS; Reserve cells; Satellite Cells, Skeletal Muscle - physiology; SATELLITES; Signal transduction; SIGNALS; Skeletal muscle; STEM CELLS; STIMULI; ZINC; Zinc - physiology
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2015.03.003

Skeletal muscle stem cells named muscle satellite cells are normally quiescent but are activated in response to various stimuli, such as injury and overload. Activated satellite cells enter the cell cycle and proliferate to produce a large number of myogenic progenitor cells, and these cells then differentiate and fuse to form myofibers. Zinc is one of the essential elements in the human body, and has multiple roles, including cell growth and DNA synthesis. However, the role of zinc in myogenic cells is not well understood, and is the focus of this study. We first examined the effects of zinc on differentiation of murine C2C12 myoblasts and found that zinc promoted proliferation, with an increased number of cells incorporating EdU, but inhibited differentiation with reduced myogenin expression and myotube formation. Furthermore, we used the C2C12 reserve cell model of myogenic quiescence to investigate the role of zinc on activation of myogenic cells. The number of reserve cells incorporating BrdU was increased by zinc in a dose dependent manner, with the number dramatically further increased using a combination of zinc and insulin. Akt and extracellular signal-regulated kinase (ERK) are downstream of insulin signaling, and both were phosphorylated after zinc treatment. The zinc/insulin combination-induced activation involved the phosphoinositide 3-kinase (PI3K)/Akt and ERK cascade. We conclude that zinc promotes activation and proliferation of myogenic cells, and this activation requires phosphorylation of PI3K/Akt and ERK as part of the signaling cascade. •Zinc has roles for promoting proliferation and inhibition differentiation of C2C12.•Zinc promotes activation of reserve cells.•Insulin and zinc synergize activation of reserve cells.•PI3K/Akt and ERK cascade affect zinc/insulin-mediated activation of reserve cells.