Adenosine A3 receptor stimulation induces protection of skeletal muscle from eccentric exercise-mediated injury

摘要

Effective therapy to reduce skeletal muscle injury associated with severe or eccentric exercise is needed. The purpose of this study was to determine whether adenosine receptor stimulation can mediate protection from eccentric exercise-induced muscle injury. Downhill treadmill exercise (−15°) was used to induce eccentric exercise-mediated skeletal muscle injury. Experiments were conducted in both normal wild-type (WT) mice and also in β-sarcoglycan knockout dystrophic mice, animals that show an exaggerated muscle damage with the stress of exercise. In the vehicle-treated WT animals, eccentric exercise increased serum creatine kinase (CK) greater than 3-fold to 358.9 ± 62.7 U/l (SE). This increase was totally abolished by stimulation of the A3 receptor. In the dystrophic β-sarcoglycan-null mice, eccentric exercise caused CK levels to reach 55,124 ± 5,558 U/l. A3 receptor stimulation in these animals reduced the CK response by nearly 50%. In the dystrophic mice at rest, 10% of the fibers were found to be damaged, as indicated by Evans blue dye staining. While this percentage was doubled after exercise, A3 receptor stimulation eliminated this increase. Neither the A1 receptor agonist 2-chloro-N⁶-cyclopentyladenosine (0.05 mg/kg) nor the A2A receptor agonist 2-p-(2-carboxyethyl)phenethylamino-5′-N-ethylcarboxamidoadenosine (0.07 mg/kg) protected skeletal muscle from eccentric exercise injury in WT or dystrophic mice. The protective effect of adenosine A3 receptor stimulation was absent in mice, in which genes for phospholipase C β2/β3 (PLCβ2/β3) and β-sarcoglycan were deleted. The present study elucidates a new protective role of the A3 receptor and PLCβ2/β3 and points to a potentially effective therapeutic strategy for eccentric exercise-induced skeletal muscle injury.