FoxO3 hastens autophagy and shrinks the heart but does not curtail pathological hypertrophy in adult mice

Extract

This editorial refers to ‘FoxO3 induces reversible cardiac atrophy and autophagy in a transgenic mouse model’ by T.G. Schips et al., pp. 587–597, this issue.

The FoxO subfamily of Forkhead box transcription factors regulate many target genes that are involved in diverse cellular processes. FoxO proteins show partial functional redundancy due to the conserved DNA-binding domain, but also exhibit isoform specificity with regard to cellular function.¹ Three of the four FoxO isoforms—FoxO1, FoxO3, and FoxO4, but not FoxO6—are expressed in the heart. The biological functions of FoxO proteins in the heart have been mainly revealed by studies on FoxO1 and FoxO3 using either cultured cardiomyocytes or loss-of-function animal models. Combined loss of FoxO1 and FoxO3 in the heart does not affect cardiac development,¹ suggesting functional redundancy of FoxO proteins in regulating cardiac development. Indeed, loss of all three FoxO isoforms is required for an oncogenic phenotype in mice.² So far, a viable animal model of FoxO gain-of-function is lacking, hindering a better understanding on the pathophysiological significance of FoxO proteins in adult hearts.