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Effects of ageing on expression of the muscle-specific E3 ubiquitin ligases and Akt-dependent regulation of Foxo transcription factors in skeletal muscle

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Abstract

Controversy exists as to whether the muscle-specific E3 ubiquitin ligases MAFbx and MuRF1 are transcriptionally upregulated in the process of sarcopenia. In the present study, we investigated the effects of ageing on mRNA/protein expression of muscle-specific E3 ubiquitin ligases and Akt/Foxo signalling in gastrocnemius muscles of female mice. Old mice exhibited a typical sarcopenic phenotype, characterized by loss of muscle mass and strength, decreased amount of myofibrillar proteins, incidence of aberrant muscle fibres, and genetic signature to sarcopenia. Activation levels of Akt were lower in adult and old mice than in young mice. Consequently, Akt-mediated phosphorylation levels of Foxo1 and Foxo3 proteins were decreased. Nuclear levels of Foxo1 and Foxo3 proteins showed an overall increasing trend in old mice. MAFbx mRNA expression was decreased in old mice relative to adult mice, whereas MuRF1 mRNA expression was less affected by ageing. At the protein level, MAFbx was less affected by ageing, whereas MuRF1 was increased in old mice relative to adult mice, with ubiquitin–protein conjugates being increased with ageing. In conclusion, we provided evidence for no mRNA upregulation of muscle-specific E3 ubiquitin ligases and disconnection between their expression and Akt/Foxo signalling in sarcopenic mice. Their different responsiveness to ageing may reflect different roles in sarcopenia.

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Acknowledgments

This research was supported by MEXT (the Ministry of Education, Culture, Sports, Science and Technology) (Grant in Aid for Scientific Research (C), 25350882), Japan.

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Authors and Affiliations

  1. Department of Information Physics and Computing, Graduate School of Information Science and Technology, The University of Tokyo, Tokyo, Japan

    Akira Wagatsuma, Yuzo Takayama, Takayuki Hoshino & Kunihiko Mabuchi

  2. Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, Tokyo, Japan

    Masataka Shiozuka & Ryoichi Matsuda

  3. Biotechnology Research Institute for Drug Discovery, National Institute of Advanced Industrial Science and Technology (AIST), Ibaraki, Japan

    Yuzo Takayama

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  1. Akira Wagatsuma
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Wagatsuma, A., Shiozuka, M., Takayama, Y. et al. Effects of ageing on expression of the muscle-specific E3 ubiquitin ligases and Akt-dependent regulation of Foxo transcription factors in skeletal muscle. Mol Cell Biochem 412, 59–72 (2016). https://doi.org/10.1007/s11010-015-2608-7

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