Abstract
The Yes-associated protein (YAP) is a core effector of the Hippo pathway, which regulates proliferation and apoptosis in organ development. YAP function has been extensively characterized in epithelial cells and tissues, but its function in adult skeletal muscle remains poorly defined. Here we show that YAP positively regulates basal skeletal muscle mass and protein synthesis. Mechanistically, we show that YAP regulates muscle mass via interaction with TEAD transcription factors. Furthermore, YAP abundance and activity in muscles is increased following injury or degeneration of motor nerves, as a process to mitigate neurogenic muscle atrophy. Our findings highlight an essential role for YAP as a positive regulator of skeletal muscle size. Further investigation of interventions that promote YAP activity in skeletal muscle might aid the development of therapeutics to combat muscle wasting and neuromuscular disorders.
Highlights
The Yes-associated protein (YAP) is a core effector of the Hippo pathway, which regulates proliferation and apoptosis in organ development
Levels of YAP at serine 112 (YAPS112) declined between embryonic day 17 (E17) and adult stages, but no difference in the ratio of YAPS112/YAP was observed, suggesting that YAP abundance diminished in concert with reduced Hippo pathway activity during this time (Fig. 1a, Supplementary Fig. 1b,c)
While YAP and the Hippo pathway predominately control organ size in epithelial tissues by altering the rates of cell proliferation and the activation of stem cells[1,2,23], our findings provide the first evidence to show that the key Hippo pathway transcriptional regulatory protein, YAP, can regulate the size of post-mitotic adult skeletal muscle fibres, by way of increasing protein synthesis
Summary
The Yes-associated protein (YAP) is a core effector of the Hippo pathway, which regulates proliferation and apoptosis in organ development. The overexpression of the mammalian homologue of the Hippo kinase (MST1)—which inactivates YAP—leads to atrophy of fast-twitch muscle fibres via FoxO-dependent transcription of the ubiquitin ligase Atrogin-1 (Fbxo32), and activation of autophagy[20]. These observations support the hypothesis that YAP may contribute to controlling the growth and remodelling of adult mammalian skeletal musculature in instances of physiological adaptation and disease. Using gain- and loss-of-function approaches, our findings demonstrate that YAP, the core effector of the Hippo pathway, is a mediator of size in adult skeletal muscle fibres, and an effector of processes that promote protein synthesis. We have established that the abundance of YAP in muscles is increased following disruption of the interaction between motor nerves and muscle fibres, and provide the first evidence of a functional role for YAP and TEAD in the preservation of muscle mass in conditions of atrophy associated with disruption of the NMJ
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