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

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.GPR56 | mTOR | Gα12/13 | muscle hypertrophy | overload

Stachel-independent modulation of GPR56/ADGRG1 signaling by synthetic ligands directed to its extracellular region

“…Furthermore, several aGPCRs, including GPR56, are found partially uncleaved in vivo (20,36,42). For example, GPR56 in skeletal muscle was found to be almost completely uncleaved (42), although it plays critical roles in skeletal muscle cells (11,43). Together, these observations suggest that Stachel-independent mechanisms may play important roles in aGPCR signaling.…”

“…For example, the aGPCR GPR56/ADGRG1 is involved in cortex development, oligodendrocyte development, muscle cell development, innate immunity, and cancer progression (11)(12)(13)(14)(15)(16)(17). Recent studies have highlighted the role of GPR56 in promoting progression of acute myeloid leukemia (18) and progastrin-dependent colon cancer (19) and suggested that a GPR56 inhibitor would be clinically desirable.…”

Gα13 ablation reprograms myofibers to oxidative phenotype and enhances whole-body metabolism

“…A recent study has shown that coexpression of inactive Gα13 and Gα12 mutants can reverse GPR56-induced C2C12 myotube hypertrophy (50). However, the role of Gα13 in skeletal muscle had never been studied in vivo.…”

The hitchhiker’s guide to PGC-1α isoform structure and biological functions

“…The 14 kb upstream alternative Pgc-1α gene promoter is highly sensitive to stimulation, and most exercise interventions, from high-to low-intensity endurance training [57] to resistance training [36] seem to activate it to some extent. The classical proximal promoter seems to be less inducible but consistently responsive to high-intensity endurance exercise [57] or freewheel running [33,58]. Pre-treatment of exercised animals with a β-adrenergic antagonist impairs Pgc-1α-b and Pgc-1α-c induction but does not affect the induction of Pgc-1α1 [32].…”