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Proc Natl Acad Sci U S A. 2014 Nov 4;111(44):15756-61. doi: 10.1073/pnas.1417898111. Epub 2014 Oct 21.

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

Author information

1
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115; Department of Cell Biology, Harvard Medical School, Boston, MA 02115;
2
Endocrine Research Unit, Division of Endocrinology, The Mayo Clinic, Rochester, MN 55905;
3
Department of Cell Biology, Harvard Medical School, Boston, MA 02115;
4
Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI 53706;
5
Department of Physiology and Pharmacology, Karolinska Institute, S-171 77, Stockholm, Sweden;
6
Novartis Institutes for Biomedical Research, Cambridge, MA 02139; and.
7
Division of Newborn Medicine, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115.
8
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115; Department of Cell Biology, Harvard Medical School, Boston, MA 02115; Bruce_Spiegelman@dfci.harvard.edu.

Abstract

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha 4 (PGC-1α4) 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.

KEYWORDS:

GPR56; Gα12/13; mTOR; muscle hypertrophy; overload

PMID:
25336758
PMCID:
PMC4226111
DOI:
10.1073/pnas.1417898111
[Indexed for MEDLINE]
Free PMC Article

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