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Pharmacological inhibition of HSP90 activity negatively modulates myogenic differentiation and cell survival in C2C12 cells

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Abstract

Heat-shock protein90 (HSP90) plays an essential role in maintaining stability and activity of its clients. HSP90 is involved in cell differentiation and survival in a variety of cell types. To elucidate the possible role of HSP90 in myogenic differentiation and cell survival, we examined the time course of changes in the expression of myogenic regulatory factors, intracellular signaling molecules, and anti-/pro-apoptotic factors when C2C12 cells were cultured in differentiation condition in the presence of a HSP90-specific inhibitor, geldanamycin. Furthermore, we examined the effects of geldanamycin on muscle regeneration in vivo. Our results showed that geldanamycin inhibited myogenic differentiation with decreased expression of MyoD, myogenin and reduced phosphorylation levels of Akt1. Geldanamycin had little effect on the phosphorylation levels of p38MAPK and ERK1/2 but reduced the phosphorylation levels of JNK. Along with myogenic differentiation, geldanamycin increased apoptotic nuclei with decreased expression of Bcl-2. The skeletal muscles forced to regenerate in the presence of geldanamycin were of poor repair with small regenerating myofibers and increased connective tissues. Together, our findings suggest that HSP90 may modulate myogenic differentiation and may be involved in cell survival.

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Acknowledgments

This research was supported by the MEXT (The Ministry of Education, Culture, Sports, Science and Technology) (Grant-in Aid for Scientific Research (C), 22500658) Japan. This research was also supported in part by The Ichiro Kanehara Foundation, Comprehensive Research on Disability Health and Welfare (H22-ShinkeiKin-Ippan-016) and Nervous and Mental Disorders (20B-13) from MHLW (The Ministry of Health, Labour and Welfare) Japan.

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Authors and Affiliations

  1. Graduate School of Arts and Sciences, The University of Tokyo, Tokyo, Japan

    Akira Wagatsuma, Masataka Shiozuka, Kawachi Takayuki, Honda Yusuke & Ryoichi Matsuda

  2. Graduate School of Information Science and Technology, The University of Tokyo, Tokyo, Japan

    Akira Wagatsuma & Kunihiko Mabuchi

  3. Department of Fisheries Distribution and Management, National Fisheries University, Yamaguchi, Japan

    Naoki Kotake

  4. Department of Food and Health Sciences, Jissen Women’s University, Tokyo, Japan

    Shigeru Yamada

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  1. Akira Wagatsuma
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  2. Masataka Shiozuka
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Correspondence to Akira Wagatsuma.

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Wagatsuma, A., Shiozuka, M., Kotake, N. et al. Pharmacological inhibition of HSP90 activity negatively modulates myogenic differentiation and cell survival in C2C12 cells. Mol Cell Biochem 358, 265–280 (2011). https://doi.org/10.1007/s11010-011-0977-0

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