Yes‐Associated Protein is up‐regulated by mechanical overload and is sufficient to induce skeletal muscle hypertrophy

Abstract

Edited by Ned Mantei Keywords:Mammalian/mechanistic target of rapamycin complex 1 Mechanotransduction Yes-Associated Protein Synergist ablation Hippo pathway TEA domain a b s t r a c t Mechanically-induced skeletal muscle growth is regulated by mammalian/mechanistic target of rapamycin complex 1 (mTORC1). Yes-Associated Protein (YAP) is a mechanically-sensitive, and growth-related, transcriptional co-activator that can regulate mTORC1. Here we show that, in skeletal muscle, mechanical overload promotes an increase in YAP expression; however, the time course of YAP expression is markedly different from that of mTORC1 activation. We also show that the overexpression of YAP induces hypertrophy via an mTORC1-independent mechanism. Finally, we provide preliminary evidence of possible mediators of YAP-induced hypertrophy (e.g. increased MyoD and c-Myc expression, and decreased Smad2/3 activity and muscle ring finger 1 (MuRF1) expression).

S100A7 induction is repressed by YAP via the Hippo pathway in A431 cells

“…Similar to repression function of YAP/TEAD in this present study, a recent study has also provided direct evidence that YAP/TAZ-TEAD function as transcriptional co-repressors via recruitment of the nucleosome remodeling and histone deacetylase (NuRD) complex to target gene, and this repressor function requires TEAD1/3/4 transcription [22]. In addition, the YAP/TEAD has been proposed to mediate the repressor activity of Smad3 in human ES cells [30]. Conversely, YAP-TAED recruits the NcoA6 H3K4 methyltransferase complex and SWI/SNF chromatin-remodeling complex for target gene activation [31, 32].…”

Hippo Pathway and Skeletal Muscle Mass Regulation in Mammals: A Controversial Relationship

“…Imposing a significant burden to the plantaris by agonist ablation, a higher expression of Yap was found together with a higher transcriptional activity of TEADs into the plantaris, thereby highlighting Yap sensitivity to mechanical loading on the muscle (Goodman et al, 2015). This phenomenon was accompanied by an increase in Akt phosphorylation in a similar pattern as Yap expression and by hypertrophy that persisted following inhibition of mTOR by rapamycin injection.…”

“…Corroborating previous results (Wang et al, 2015b), it seems that Yap can induce hypertrophy independently of mTOR. This hypertrophy was probably due, at least in part, to a low expression of MuRF-1 and a high expression of MyoD and c-Myc (Goodman et al, 2015). …”

Ribosome Biogenesis is Necessary for Skeletal Muscle Hypertrophy

“…Further, the significant increase in both UBF protein and Rb hyperphosphorylation levels at this later time point were insensitive to mTORC1 inhibition. More recently, Goodman and coworkers provided intriguing evidence showing that YAP was capable of driving c-Myc expression in a rapamycin-independent manner (13). Similar to what has been described in cardiac hypertrophy, it appears that mTORC1 regulation of translational efficiency is important in mediating the initial events of ribosome biogenesis and that more long-term, c-Myc regulation of ribosome biogenesis may be necessary to sustain a full hypertrophic response (16).…”