The Orphan Nuclear Receptor Nur77 Is a Determinant of Myofiber Size and Muscle Mass in Mice

Abstract

Wepreviously showed that the orphan nuclear receptor Nur77 (Nr4a1) plays an important role in the regulation of glucose ho- meostasis and oxidative metabolism in skeletal muscle. Here, we show using both gain- and loss-of-function models that Nur77 is also a regulator of muscle growth in mice. Transgenic expression of Nur77 in skeletal muscle in mice led to increases in myofi- ber size. Conversely, mice with global or muscle-specific deficiency in Nur77 exhibited reduced muscle mass and myofiber size. In contrast to Nur77 deficiency, deletion of the highly related nuclear receptor NOR1 (Nr4a3) had minimal effect on muscle mass and myofiber size.Wefurther show that Nur77 mediates its effects on muscle size by orchestrating transcriptional pro- grams that favor muscle growth, including the induction of insulin-like growth factor 1 (IGF1), as well as concomitant down- regulation of growth-inhibitory genes, including myostatin, Fbxo32 (MAFbx), and Trim63 (MuRF1). Nur77-mediated increase in IGF1 led to activation of the Akt-mTOR-S6K cascade and the inhibition of FoxO3a activity. The dependence of Nur77 on IGF1 was recapitulated in primary myoblasts, establishing this as a cell-autonomous effect. Collectively, our findings identify Nur77 as a novel regulator of myofiber size and a potential transcriptional link between cellular metabolism and muscle growth.