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RECEPTORS AND SIGNAL TRANSDUCTION

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

¹Department of Physical Education and Rehabilitation, Université Catholique de Louvain, Louvain-la-Neuve; ²Division of Cardiology, Université Catholique de Louvain, Brussels; ³Research Center for Exercise and Health, Faculty of Kinesiology and Rehabilitation Sciences, Katholieke Universiteit Leuven, Heverlee; and ⁴Hormone and Metabolic Research Unit, Christian de Duve Institute of Cellular Pathology, Université Catholique de Louvain, Brussels, Belgium

Submitted 17 April 2007 ; accepted in final form 20 July 2007

In myogenic C₂C₁₂ cells, 5 mM creatine increased the incorporation of labeled [³⁵S]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 -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 C₂C₁₂ cells.

protein synthesis; insulin-like growth factor; mitogen-activated protein kinase; extracellular signal-regulated kinase 1/2; 70-kDa ribosomal S6 protein kinase