G protein-coupled receptor 56 regulates mechanical overload-induced muscle hypertrophy

James P. White, Christiane D. Wrann, Rajesh R. Rao, Sreekumaran K. Nair, Mark P. Jedrychowski, Jae Sung You, Vicente Martínez-Redondo, Steven P. Gygi, Jorge L. Ruas, Troy A. Hornberger, Zhidan Wu, David J. Glass, Xianhua Piao, Bruce M. Spiegelman

Research output: Contribution to journalArticlepeer-review

58 Scopus citations


Peroxisome proliferator-activated receptor gamma coactivator 1-alpha 4 (PGC-1α 4) is a protein isoform derived by alternative splicing of the PGC1α mRNA and has been shown to promote muscle hypertrophy. We show here that G protein-coupled receptor 56 (GPR56) is a transcriptional target of PGC-1α4 and is induced in humans by resistance exercise. Furthermore, the anabolic effects of PGC-1α4 in cultured murine muscle cells are dependent on GPR56 signaling, because knockdown of GPR56 attenuates PGC-1α4-induced muscle hypertrophy in vitro. Forced expression of GPR56 results in myotube hypertrophy through the expression of insulin-like growth factor 1, which is dependent on Gα12/13 signaling. A murine model of overload-induced muscle hypertrophy is associated with increased expression of both GPR56 and its ligand collagen type III, whereas genetic ablation of GPR56 expression attenuates overload-induced muscle hypertrophy and associated anabolic signaling. These data illustrate a signaling pathway through GPR56 which regulates muscle hypertrophy associated with resistance/loading-type exercise.

Original languageEnglish (US)
Pages (from-to)15756-15761
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number44
StatePublished - Nov 4 2014


  • GPR56
  • Gα12/13
  • MTOR
  • Muscle hypertrophy
  • Overload

ASJC Scopus subject areas

  • General


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