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FoxO transcription factors: their roles in the maintenance of skeletal muscle homeostasis

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Abstract

Forkhead box class O family member proteins (FoxOs) are highly conserved transcription factors with important roles in cellular homeostasis. The four FoxO members in humans, FoxO1, FoxO3, FoxO4, and FoxO6, are all expressed in skeletal muscle, but the first three members are the most studied in muscle. In this review, we detail the multiple modes of FoxO regulation and discuss the central role of these proteins in the control of skeletal muscle plasticity. FoxO1 and FoxO3 are key factors of muscle energy homeostasis through the control of glycolytic and lipolytic flux, and mitochondrial metabolism. They are also key regulators of protein breakdown, as they modulate the activity of several actors in the ubiquitin–proteasome and autophagy–lysosomal proteolytic pathways, including mitochondrial autophagy, also called mitophagy. FoxO proteins have also been implicated in the regulation of the cell cycle, apoptosis, and muscle regeneration. Depending of their activation level, FoxO proteins can exhibit ambivalent functions. For example, a basal level of FoxO factors is necessary for cellular homeostasis and these proteins are required for adaptation to exercise. However, exacerbated activation may occur in the course of several diseases, resulting in metabolic disorders and atrophy. A better understanding of the precise functions of these transcriptions factors should thus lead to the development of new therapeutic approaches to prevent or limit the muscle wasting that prevails in numerous pathological states, such as immobilization, denervated conditions, neuromuscular disease, aging, AIDS, cancer, and diabetes.

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Acknowledgments

This work was supported by the Faculty of Sport Sciences of the University of Montpellier 1 and by INRA’s PHASE division. The authors thank Dr. P. Glaviole for helpful discussions.

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The authors declare no conflicts of interest, financial or otherwise.

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Authors and Affiliations

  1. INRA, UMR866 Dynamique Musculaire Et Métabolisme, Université Montpellier 1, 2 Place Viala, 34060, Montpellier, France

    Anthony M. J. Sanchez, Robin B. Candau & Henri Bernardi

  2. Faculté des Sciences du Sport, Université Montpellier 1, 700 avenue du Pic Saint Loup, 34090, Montpellier, France

    Anthony M. J. Sanchez & Robin B. Candau

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  1. Anthony M. J. Sanchez
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  2. Robin B. Candau
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Correspondence to Anthony M. J. Sanchez.

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Sanchez, A.M.J., Candau, R.B. & Bernardi, H. FoxO transcription factors: their roles in the maintenance of skeletal muscle homeostasis. Cell. Mol. Life Sci. 71, 1657–1671 (2014). https://doi.org/10.1007/s00018-013-1513-z

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  • DOI: https://doi.org/10.1007/s00018-013-1513-z

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