Oral Presentation Melbourne Protein Group Student Symposium 2013

GPR119 agonism regulates AMPKα and MAPK protein signalling cascades in skeletal and cardiac muscle cells (#7)

Lauren M. Cornall 1 , Michael L. Mathai 1 , Deanne H. Hryciw 2 , Andrew J. McAinch 1
  1. Biomedical and Lifestyle Diseases Unit, College of Health and Biomedicine, Victoria University, Melbourne, Vic, Australia
  2. Department of Physiology , The University of Melbourne, Melbourne, Vic, Australia

Introduction:

Obesity and type 2 diabetes mellitus (T2DM) are a significant cause of morbidity and premature mortality. GPR119 has recently been identified as a potential anti-obesity and anti-diabetic agent, having anorectic and hypoglycaemic effects. Accordingly, GPR119 agonists have rapidly been progressed to stage II clinical trials. However, the peripheral mechanisms mediating these effects are unknown. Given the role of muscle in maintaining metabolic health, we determined the effects of activating GPR119 in skeletal and cardiac muscle cells on markers of nutrient metabolism.

Methods:

C2C12 skeletal muscle myotubes and H9c2 cardiac muscle myoblasts were pre-treated for 16 hrs in the presence or absence of palmitate (50 µM C2C12;5 µM H9c2). Cells were then exposed to the GPR119 specific agonist, PSN632408 (5 µM) for 15 mins (n= 6-8/group. Protein expression was quantified by Western blotting.

Results:

In C2C12 myotubes, the ratio of phosphorylated AMPKα (Thr172)/total AMPKα protein was decreased by PSN632408 alone (p≤0.05). Palmitate-induced metabolic dysregulation attenuated the effects of GPR119 activation on AMPKα however this led to an increase in phosphorylated ACC (Ser79) protein compared to control (p≤0.05).

In H9c2 myoblasts, the ratio of phosphorylated (Thr202/Tyr204)/total ERK1/2 protein was decreased by PSN632408 alone (p≤0.05). Exposure to palmitate and PSN632408 led to a decreased expression of total JNK in cells treated compared to palmitate alone (p≤0.05). Interestingly, when palmitate was removed following the pre-treatment period, PSN632408 increased phosphorylation of JNK (Thr180/Tyr180) protein (p≤0.05).

Conclusion:

We have previously shown that PSN632408 decreases oxidative gene expression in both C2C12 and H9c2 cells. Considered with the current results these data suggest that GPR119 activation may impair nutrient metabolism in skeletal and cardiac muscle cells. Due to the role that muscle plays in maintaining systemic metabolic health, caution may be required if GPR119 agonists are further developed for the treatment of obesity and T2DM.

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

Conflicts of interest: None.