Regulation of myoblast differentiation by metabolic perturbations induced by metformin

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Pavlidou, Theodora ; Rosina, Marco ; Fuoco, Claudia ; Gerini, Giulia ; Gargioli, Cesare ; Castagnoli, Luisa ; Cesareni, Gianni (2017)
  • Publisher: Public Library of Science
  • Journal: PLoS ONE, volume 12, issue 8 (issn: 1932-6203, eissn: 1932-6203)
  • Related identifiers: pmc: PMC5578649, doi: 10.1371/journal.pone.0182475
  • Subject: Myoblasts | Cell Differentiation | Research Article | Anatomy | Cyclins | Cell Cycle Inhibitors | Cell Processes | Morphogenesis | Muscles | Muscle Differentiation | Proteins | Phosphorylation | Skeletal Muscles | Cellular Types | Stem Cells | Biology and Life Sciences | Developmental Biology | Medicine | Animal Cells | Post-Translational Modification | Q | R | Cell Biology | Science | Biochemistry | Medicine and Health Sciences | Cell Cycle and Cell Division
    mesheuropmc: tissues | musculoskeletal system

The metabolic perturbation caused by calorie restriction enhances muscle repair by playing a critical role in regulating satellite cell availability and activity in the muscles of young and old mice. To clarify the underlying mechanisms we asked whether myoblast replication and differentiation are affected by metformin, a calorie restriction-mimicking drug. C2C12, a mouse myoblast cell line, readily differentiate in vitro and fuse to form myotubes. However, when incubated with metformin, C2C12 slow their replication and do not differentiate. Interestingly, lower doses of metformin promote myogenic differentiation. We observe that metformin treatment modulates the expression of cyclins and cyclin inhibitors thereby inducing a cell cycle perturbation that causes a delay in the G2/M transition. The effect of metformin treatment is reversible since after drug withdrawal, myoblasts can re-enter the cell cycle and/or differentiate, depending on culture conditions. Myoblasts cultured under metformin treatment fail to up-regulate MyoD and p21cip1, a key step in cell cycle exit and terminal differentiation. Although the details of the molecular mechanisms underlying the effect of the drug on myoblasts still need to be clarified, we propose that metformin negatively affects myogenic differentiation by inhibiting irreversible exit from the cell cycle through reduction of MyoD and p21cip1 levels.
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