Attenuation of apoptosis in vitro and ischemia/reperfusion injury in vivo in mouse skeletal muscle by P2Y6 receptor activation

  • Pharmacol Res. 2008 Sep-Oct;58(3-4):232-9. doi: 10.1016/j.phrs.2008.08.004.
Liaman K Mamedova  1 ,  Ruibo Wang ,  Pedro Besada ,  Bruce T Liang ,  Kenneth A Jacobson
Affiliations
  • 1. Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0810, USA.
PMID: 18805489 DOI: 10.1016/j.phrs.2008.08.004
Abstract

Activation of the G(q)-coupled P2Y(6) receptor heterologously expressed in astrocytes significantly attenuates Apoptosis induced by tumor necrosis factor alpha (TNFalpha). We have extended the analysis of P2Y(6) receptor-induced cytoprotection to mouse skeletal muscle cells endogenously expressing this receptor. The endogenous P2Y(6) receptor agonist UDP and synthetic agonist MRS2693 protected C2C12 skeletal muscle cells against Apoptosis in a concentration-dependent manner (0.1-10 nM) as determined by propidium iodide staining, histochemical analysis using hematoxylin and Hoechst 33258, and DNA fragmentation. The insurmountable P2Y(6) receptor antagonist MRS2578 blocked the protection. TNFalpha-induced Apoptosis in C2C12 cells correlated with activation of the transcription factor NF-kappaB. The NF-kappaB activation was attenuated by 10nM MRS2693, which activated the antiapoptic ERK1/2 pathway. In an in vivo mouse hindlimb model, MRS2693 protected against skeletal muscle ischemia/reperfusion injury. The P2Y(6) receptor is a novel cytoprotective receptor that deserves further exploration in ameliorating skeletal muscle injury.

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