A Novel Skeletal Muscle Cytoprotective Action of Adenosine A3 Receptors

Abstract

Adenosine (Ado) can protect skeletal muscle from ischemic injury, in addition to its cardio- and vasculo-protective effect. However, identity of the Ado receptor and the mechanism mediating skeletal muscle protection is unknown. Using a quantitative mouse hindlimb ischemia-reperfusion injury model, the objective here was to assess the protective role of Ado receptor subtypes. Ado A3 receptor-selective agonist Cl-IBMECA reduced skeletal muscle injury, an effect that was blocked by the A3 receptor antagonist MRS1191 (% injury, vehicle: 28±5.9% vs. Cl-IBMECA: 5.4±3.8%, Cl-IBMECA & MRS1191: 21.5±3.5%, mean±SE, 7–22 mice, ANOVA & comparisons, Cl-IBMECA vs. all others, P<0.05). The A1 receptor agonist CCPA was also protective and and was selectively antagonized by the A1 receptor blocker DPCPX (CCPA: 10.8±1.8%, DPCPX &CCPA: 22±3.3%, 7–12 mice, P<0.05). The protection induced by Cl-IBMECA and another A3 receptor agonist MRS3558 was completely abrogated in phospholipase C β2/3-null mice while that caused by CCPA remained unaffected in these animals (8–10 mice). The study demonstrated a novel potent protective effect of A3 receptors in skeletal muscle and implicates phospholipase C β in mediating this protection. The data add to the cyto-protective actions of adenosine and suggest that the A3 receptor is a novel therapeutic target in ameliorating skeletal muscle injury.