Creatine enhances differentiation of myogenic C2C12 cells by activating both p38 and Akt/PKB pathways

Deldicque, Louise;Theisen, Daniel;Bertrand, Luc;Hespel, Peter;Francaux, Marc;et.al.
(2007) American journal of physiology : Cell physiology — Vol. 293, n° 4, p. C1263-C1271 (2007)

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Abstract
In myogenic C(2)C(12) cells, 5 mM creatine increased the incorporation of labeled [(35)S]methionine into sarcoplasmic (+20%, P < 0.05) and myofibrillar proteins (+50%, P < 0.01). Creatine also promoted the fusion of myoblasts assessed by an increased number of nuclei incorporated within myotubes (+40%, P < 0.001). Expression of myosin heavy chain type II (+1,300%, P < 0.001), troponin T (+65%, P < 0.01), and titin (+40%, P < 0.05) was enhanced by creatine. Mannitol, taurine, and beta-alanine did not mimic the effect of creatine, ruling out an osmolarity-dependent mechanism. The addition of rapamycin, the inhibitor of mammalian target of rapamycin/70-kDa ribosomal S6 protein kinase (mTOR/p70(s6k)) pathway, and SB 202190, the inhibitor of p38, completely blocked differentiation in control cells, and creatine did not reverse this inhibition, suggesting that the mTOR/p70(s6k) and p38 pathways could be potentially involved in the effect induced by creatine on differentiation. Creatine upregulated phosphorylation of protein kinase B (Akt/PKB; +60%, P < 0.001), glycogen synthase kinase-3 (+70%, P < 0.001), and p70(s6k) (+50%, P < 0.001). Creatine also affected the phosphorylation state of p38 (-50% at 24 h and +70% at 96 h, P < 0.05) as well as the nuclear content of its downstream targets myocyte enhancer factor-2 (-55% at 48 h and +170% at 96 h, P < 0.05) and MyoD (+60%, P < 0.01). In conclusion, this study points out the involvement of the p38 and the Akt/PKB-p70(s6k) pathways in the enhanced differentiation induced by creatine in C(2)C(12) cells.
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Deldicque, L., Theisen, D., Bertrand, L., Hespel, P., Hue, L., & Francaux, M. (2007). Creatine enhances differentiation of myogenic C2C12 cells by activating both p38 and Akt/PKB pathways. American journal of physiology : Cell physiology, 293(4), C1263-C1271. https://doi.org/10.1152/ajpcell.00162.2007 (Original work published 2007)