Gα _i2 Signaling Promotes Skeletal Muscle Hypertrophy, Myoblast Differentiation, and Muscle Regeneration

Abstract

Skeletal muscle atrophy results in loss of strength and an increased risk of mortality. We found that lysophosphatidic acid, which activates a G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor, stimulated skeletal muscle hypertrophy through activation of Gα(i2). Expression of a constitutively active mutant of Gα(i2) stimulated myotube growth and differentiation, effects that required the transcription factor NFAT (nuclear factor of activated T cells) and protein kinase C. In addition, expression of the constitutively active Gα(i2) mutant inhibited atrophy caused by the cachectic cytokine TNFα (tumor necrosis factor-α) by blocking an increase in the abundance of the mRNA encoding the E3 ubiquitin ligase MuRF1 (muscle ring finger 1). Gα(i2) activation also enhanced muscle regeneration and caused a switch to oxidative fibers. Our study thus identifies a pathway that promotes skeletal muscle hypertrophy and differentiation and demonstrates that Gα(i2)-induced signaling can act as a counterbalance to MuRF1-mediated atrophy, indicating that receptors that act through Gα(i2) might represent potential targets for preventing skeletal muscle wasting.

Schisandrae fructus enhances myogenic differentiation and inhibits atrophy through protein synthesis in human myotubes

“…These cells get committed to myogenic differentiation and fuse with existing muscle fibers. [56][57][58][59][60][61] In vivo skeletal muscle growth is identified by hypertrophy (increase in fiber size) and hyperplasia (increase in fiber number), [62][63][64] while in vitro myogenic differentiation can be quantified by fusion index (ratio of fused nucleus) and area (hypertrophy) of myotubes. 42,43 In addition, maintenance of myotubes is influenced by signals of skeletal muscle protein Figure 1 sF-induced differentiation in hskMcs.…”

cAMP signaling in skeletal muscle adaptation: hypertrophy, metabolism, and regeneration

“…Indeed, numerous G␣ s -coupled GPCRs of the odorant family are transcriptionally regulated during myogenesis and after skeletal muscle injury (80). Intramuscular cAMP can also be stimulated by chronic stimulation of the motor nerve by an implanted nerve cuff in rabbits and rats (131,244 (163). Although many signaling pathways may indirectly modulate intramuscular cAMP signaling via similar pathways or indirect modulation of AC activity, we will limit our discussion to ligands that directly regulate cAMP production.…”

“…Developing mouse muscle expresses G␣ s and two G␣ i isoforms (G␣ i2 and G␣ i3 ); all are downregulated after birth but strongly upregulated in denervated gastrocnemius muscle (220). In skeletal muscle, pertussis toxin-sensitive G proteins containing G␣ i signal via PKC-dependent pathways (135,163) as well as through released G␤␥ in differentiating skeletal muscle cells (61). A very exciting recent study showed that expression of G␣ i2 is sufficient to promote myofiber hypertrophy, oxidative fiber-type switching, myogenic differentiation, and muscle regeneration in mice (163).…”

“…Many studies have shown, however, that cAMP-inducing agents or genetic modification of proteins involved in cAMP signaling can also have adaptive effects on skeletal muscle by increasing myofiber size and promoting fiber-type transitions to glycolytic fibers (9,18,42,43,57,63,86,91,101,121,128,154,155,163,190,193,194,215). The prohypertrophic actions of ␤-adrenergic receptor (␤-AR) agonists and corticotropin-releasing factor receptor 2 (CRFR2) agonists have recently been harnessed to improve muscle function and ameliorate atrophy in several rodent models, including disuse (99,101,245), denervation (98, 100 -102, 127, 154, 253), aging (195,254), and muscular dystrophy (90,103,185,254,256).…”

Lysophosphatidic acid stimulates cell migration of satellite cells. A role for the sphingosine kinase/sphingosine 1‐phosphate axis

“…The mitogenic effect of LPA in myoblasts was further confirmed in a subsequent study, in which the LPA action was found to be exerted via ligation of LPA 1 /LPA 3 receptors and activation of the phosphatidylinositol-4,5-bisphosphate 3-kinase pathway [18]. Additionally, a recent study has shown that LPA, acting via Ga i2 , robustly stimulated hypertrophy of myotubes in a protein kinase C dependent manner [19].…”