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

Abstract

Skeletal muscle mass reflects a dynamic turnover between net protein synthesis and degradation. In addition, satellite cell inclusion may contribute to increase muscle mass while fiber loss results in a reduction of muscle mass. Since 2010, a few studies looked at the involvement of the newly discovered Hippo pathway in the regulation of muscle mass. In line with its roles in other organs, it has been hypothesized that the Hippo pathway could play a role in different regulatory mechanisms in skeletal muscle as well, namely proliferation and renewal of satellite cells, differentiation, death, and growth of myogenic cells. While the Hippo components have been identified in skeletal muscle, their role in muscle mass regulation has been less investigated and conflicting results have been reported. Indeed, the first studies described both atrophic and hypertrophic roles of the Hippo pathway and its effectors Yap/Taz using different biochemical approaches. Further, investigation is therefore warranted to determine the role of the Hippo pathway in the regulation of skeletal muscle mass. New components of the pathway will probably emerge and unsuspected roles will likely be discovered due to its numerous interactions with different cellular processes. This mini-review aims to summarize the current literature concerning the roles of the Hippo pathway in the regulation of muscle mass and to develop the hypothesis that this pathway could contribute to muscle mass adaptation after exercise.

Keywords: Taz; Yap; growth; mTOR; size.

Figure 1

Canonical Hippo pathway. Core components of the Hippo pathway in mammals. Mst1/2 is phosphorylated by upstream regulators and binding with Sav enhances its affinity for Lats1/2, which in turn binds with Mob1. Activation of Mst1/2 and Lats1/2 results in phosphorylation and inactivation of Yap/Taz. See text for abbreviations.

Figure 2

Regulation and functions of the Hippo pathway. Hippo pathway core components, Mst1/2 and Lats1/2, are regulated by membrane protein (NF2, AMOT), membrane receptors (GPCR and downstream effectors Rho GTPases), metabolites (epinephrine, glucagon, LPA and S1P), low ATP levels and extracellular matrix. When phosphorylated (1) at S127 (S89 for Taz), Yap is bound to 14-3-3 protein for cytoplasmic retention; (2) at S381 (S311 for Taz), β-TRCP is recruited and Yap/Taz is ubiquitinated for proteasomal degradation. In the non-phosphorylated state, Yap translocates into the nucleus, and binds to TEAD proteins to induce transcription of several genes (CGTF, Gli2, diap1, Birc5, Birc2, FGF1, AREG, Ankrd1, and LAT1). Yap can bind an unknown transcription factor to induce transcription of Myc. Finally Yap can directly bind proteins like RUNX, ErbB4, and p73. See text for abbreviations.