Muscle function and homeostasis require cytokine inhibition of AKT activity in <i>Drosophila</i>.

Abstract

<i>Unpaired</i> ligands are secreted signals that act via a GP130-like receptor, <i>domeless</i>, to activate JAK/STAT signalling in <i>Drosophila</i>. Like many mammalian cytokines, <i>unpaireds</i> can be activated by infection and other stresses and can promote insulin resistance in target tissues. However, the importance of this effect in non-inflammatory physiology is unknown. Here, we identify a requirement for <i>unpaired</i>-JAK signalling as a metabolic regulator in healthy adult <i>Drosophila</i> muscle. Adult muscles show basal JAK-STAT signalling activity in the absence of any immune challenge. Plasmatocytes (<i>Drosophila</i> macrophages) are an important source of this tonic signal. Loss of the <i>dome</i> receptor on adult muscles significantly reduces lifespan and causes local and systemic metabolic pathology. These pathologies result from hyperactivation of AKT and consequent deregulation of metabolism. Thus, we identify a cytokine signal that must be received in muscle to control AKT activity and metabolic homeostasis.