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Atrophy of S6K1−/− skeletal muscle cells reveals distinct mTOR effectors for cell cycle and size control

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Abstract

The mammalian target of rapamycin (mTOR) and Akt proteins regulate various steps of muscle development and growth, but the physiological relevance and the downstream effectors are under investigation1,2,3,4,5,6. Here we show that S6 kinase 1 (S6K1), a protein kinase activated by nutrients and insulin-like growth factors (IGFs), is essential for the control of muscle cytoplasmic volume by Akt and mTOR. Deletion of S6K1 does not affect myoblast cell proliferation but reduces myoblast size to the same extent as that observed with mTOR inhibition by rapamycin. In the differentiated state, S6K1−/− myotubes have a normal number of nuclei but are smaller, and their hypertrophic response to IGF1, nutrients and membrane-targeted Akt is blunted. These growth defects reveal that mTOR requires distinct effectors for the control of muscle cell cycle and size, potentially opening new avenues of therapeutic intervention against neoplasia or muscle atrophy.

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Acknowledgements

We thank the Novartis Foundation and George Thomas laboratory for the use of S6K mutant mice. We thank J. McMullen, G. Pavlath, R. Scharfmann, G. Thomas and R. Treisman for reading the manuscript and for helpful discussions; the members of INSERM-U584 for support; Genethon (Evry) for adenovirus production; C. Cordier for expert technical assistance with the FACS analysis; M. Birnbaum for providing adenovirus expressing MyrAkt1 and kinase-inactive Akt1; and G. Thomas for providing adenovirus expressing RR-S6K1. M.P. has been a recipient of a stipend from the Fondation pour la recherche médicale, and A.S. from the INSERM and Conseil Regional d'Ile de France. This work was supported by a grant to M.P. from the INSERM Avenir programme (R01131KS) and from INSERM-Fondation pour la recherche médicale–Juvenile Diabetes Research Foundation International (4DA03H), and to A.S. and M.P. from the Association Française contre les Myopathies (9971) and from the ARC (7647).

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Competing interests

The authors declare no competing financial interests.

Correspondence to Athanassia Sotiropoulos or Mario Pende.

Supplementary information

  1. Supplementary Information

    Supplementary figures S1, S2, S3 and S4 (PDF 170 kb)

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Further reading

Figure 1: Atrophy of S6K1−/− muscles.
Figure 2: Myoblast proliferation and size show differential requirement for S6K1 activity.
Figure 3: Normal myogenesis but impaired growth of S6K1−/− cells.
Figure 4: Nutritional cues requie S6K to affect muscle mass.
Figure 5: Regulation of muscle growth and proliferation by oncogenic Akt.