The Hippo pathway member Yap plays a key role in influencing fate decisions in muscle satellite cells

Abstract

SummarySatellite cells are the resident stem cells of skeletal muscle. Mitotically quiescent in mature muscle, they can be activated to proliferate and generate myoblasts to supply further myonuclei to hypertrophying or regenerating muscle fibres, or self-renew to maintain the resident stem cell pool. Here, we identify the transcriptional co-factor Yap as a novel regulator of satellite cell fate decisions. Yap expression increases during satellite cell activation and Yap remains highly expressed until after the differentiation versus self-renewal decision is made. Constitutive expression of Yap maintains Pax7 + and MyoD + satellite cells and satellite cell-derived myoblasts, promotes proliferation but prevents differentiation. In contrast, Yap knockdown reduces the proliferation of satellite cell-derived myoblasts by <40%. Consistent with the cellular phenotype, microarrays show that Yap increases expression of genes associated with Yap inhibition, the cell cycle, ribosome biogenesis and that it represses several genes associated with angiotensin signalling. We also identify known regulators of satellite cell function such as BMP4, CD34 and Myf6 (Mrf4) as genes whose expression is dependent on Yap activity. Finally, we confirm in myoblasts that Yap binds to Tead transcription factors and co-activates MCAT elements which are enriched in the proximal promoters of Yap-responsive genes.

Muscle protein synthesis, mTORC1/MAPK/Hippo signaling, and capillary density are altered by blocking of myostatin and activins

“…During muscle differentiation in C 2 C 12 cells, YAP phosphorylation at this site is strongly increased, which was important for myoblast differentiation (57). A recent study from the same group showed that YAP expression increased when satellite cells were activated but decreased when differentiation started and that the constitutive expression of YAP promoted proliferation but prevented differentiation (26). In contrast, knocking down YAP strongly decreased the proliferation of myoblasts (26).…”

“…One of those is Hippo signaling (13,22). In vitro studies suggest its importance at least in muscle cell proliferation and differentiation (26,57). However, no in vivo studies of Hippo signaling have been conducted in skeletal muscle.…”

Cellular micro-environments reveal defective mechanosensing responses and elevated YAP signaling in LMNA-mutated muscle precursors

“…However, it has been shown that precise control of this pathway is essential for proper muscle differentiation and homeostasis; indeed, overexpression of YAP in C2C12 myoblasts inhibits their differentiation (Watt et al, 2010;Judson et al, 2012). In addition, sustained YAP activity in muscle fibers induces muscle atrophy and myopathy (Judson et al, 2013), thus supporting the importance of YAP regulation in muscle cells.…”

“…YAP is expressed in almost all cell types including skeletal muscles (Jeong et al, 2010;Watt et al, 2010;Judson et al, 2012). Mechanical cues of the microenvironment, such as substrate stiffness and topographic features, are crucial regulators of YAP-TAZ pathway and this regulation takes place through the regulation of the actomyosin cytoskeletal system (Dupont et al, 2011;Mendez and Janmey, 2012).…”

“…YAP is a crucial member of the Hippo pathway, and is expressed in almost all cell types (Mendez and Janmey, 2012), including skeletal muscles (Jeong et al, 2010;Watt et al, 2010;Judson et al, 2012). Although YAP recapitulates some aspects of MKL1-SRF regulation, its regulation appears distinct and seems to take place through regulation of the actomyosin cytoskeletal network instead of the ratio between F-actin and G-actin (Mendez and Janmey, 2012).…”