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

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.

Metabolic Suppression by 3-Iodothyronamine Induced Muscle Cell Atrophy <i>via</i> Activation of FoxO–Proteasome Signaling and Downregulation of Akt1–S6K Signaling

“…Previous reports on skeletal muscle showed that FoxO1 activation inhibits glycolytic flux by upregulating PDK4 and promotes lipid mobilization by upregulating lipoprotein lipase and adiponectin receptor. 11,26,27) Conversely, the expression and transcriptional activity of FoxO3 are directly regulated by AMPK, which is activated by metabolic stress (e.g., low…”

“…28) Because muscle disuse cuts down the mitochondrial metabolic activity along with AMPK activation, 29) the AMPKFoxO3 axis can be one of the major signaling routes promoting expression of atrophy genes, including the ubiquitin E3 ligase and proteasome. 11) It is also worth comparing the regulatory mechanism of dexamethasone (DEX) with that of T1AM. As a synthetic glucocorticoid, DEX is well known to induce muscle atrophy.…”

“…These ligases carry unnecessary or damaged proteins to the proteasome for degradation. 10,11) In a loaded state, however, Akt1 activation leads to the phosphorylation and nuclear exclusion of the FoxOs, which subsequently suppresses muscle atrophy. 10) In addition, molecular chaperones like heat shock proteins (e.g., HSP72) have been found to play a crucial role in muscle homeostasis via both activation of the Akt1-S6K pathway and suppression of FoxO-ubiquitin-proteasome route.…”

An exclusive cellular and molecular network governs intestinal smooth muscle cell differentiation in vertebrates

“…Foxo1 belongs to the Forkhead family of transcription factors and regulates myogenic growth and differentiation, maintenance of stemness, and metabolism (Eijkelenboom and Burgering, 2013;Sanchez et al, 2014). A role for foxo1a in iSMC development has not been described previously.…”

Forkhead box O transcription factors as possible mediators in the development of major depression

“…19 role of FoxO transcription factors in mediating the muscle atrophy has been widely studied (Castets and Ruegg, 2013;Sanchez et al, 2014;Lee et al, 2012), however, the specific role of FoxO in neuronal atrophy is largely unknown. The four FoxO members found in humans, FoxO1, FoxO3a, FoxO4, and FoxO6, are all expressed in the CNS (Biggs et al, 2001;Salih et al, 2012).…”