Introduction:

Preliminary data suggests a putative role for GPR43 in regulating systemic health via processes including adipogenesis, inflammation and secretion of gastrointestinal peptides. This suggests GPR43 may have a role in weight control. Given muscle is a major determinant of systemic metabolic health and energy balance, we sought to characterise the effect of activating GPR43 in skeletal and cardiac muscle cells.

Methods:

C₂C₁₂ skeletal muscle myotubes and H9c2 cardiac muscle myoblasts were exposed to a GPR43 specific phenylacetamide (PA) agonist (70 nM – 7 uM) for 15 mins (n=5-8/group). Protein expression was quantified by Western blotting. Metabolic activity of C₂C₁₂ and H9c2 cells treated with PA was determined via MTT assay (n=10-12/group).

Results:

In C₂C₁₂ myotubes 70 nM PA significantly up-regulated total JNK and AMPKα proteins compared to control (p≤0.05). There was no change in the phosphorylation of these markers or the abundance of total or phosphorylated ERK1/2 protein at any dose used. Metabolic activity in C₂C₁₂ myotubes was decreased at 70 nM and 7 µM PA compared to control (p≤0.05). Interestingly, PA treatment did not alter protein expression or metabolic activity in H9c2 myoblasts.

Conclusion:

These data suggest GPR43 may have a specific role in mediating skeletal muscle metabolic function. Decrements in metabolic activity in C₂C₁₂ myotubes imply GPR43 agonism may impinge upon nutrient metabolism in skeletal muscle. This has the potential to promote aberrations of systemic metabolic health. Thus, targeting GPR43 may form a novel means of treating obesity and type 2 diabetes mellitus in which skeletal muscle fatty acid and glucose metabolism is perturbed. Further work is needed to clarify the signaling pathways mediating decreased metabolic activity and how this relates to functional changes in nutrient metabolism.

LMC was supported by a scholarship (PB 10M 5472) from the National Heart Foundation of Australia.