The Hippo signal transduction network for exercise physiologists

Abstract

The ubiquitous transcriptional co-activators Yap (gene symbol Yap1) and Taz (gene symbol Wwtr1) regulate gene expression mainly by co-activating the Tead transcription factors. Yap and Taz lie at the centre of the Hippo signalling network and are not only regulated by the Hippo kinase cassette itself but also by a plethora of exercise-associated signals and signalling modules. These include mechanotransduction, the AKT-mTORC1 network, SMAD transcription factors, hypoxia, glucose, AMPK, adrenaline/epinephrine and angiotensin II through G protein-coupled receptors, and interleukin 6 (Il-6). Consequently exercise should alter Hippo signalling in several organs to mediate at least some aspects of organ-specific adaptations to exercise. Consistent with this idea Tead1 over expression in muscle fibres has been shown to promote a fast-to-slow fibre type switch whereas Yap in muscle fibres and cardiomyocytes promotes skeletal muscle and cardiac hypertrophy, respectively. Finally TEAD1, YAP1, VGLL2, VGLL3 and VGLL4 have all been linked in genome wide-association studies to body height, a key factor in sports.