Interleukin-6 mediates exercise preconditioning against myocardial ischemia reperfusion injury

Abstract

Interleukin-6 (IL-6) is a pleiotropic cytokine that protects against cardiac ischemia-reperfusion (I/R) injury following pharmacological and ischemic preconditioning (IPC), but the affiliated role in exercise preconditioning is unknown. Our study purpose was to characterize exercise-induced IL-6 cardiac signaling (aim 1) and evaluate myocardial preconditioning (aim 2). In aim 1, C57 and IL-6(-/-) mice underwent 3 days of treadmill exercise for 60 min/day at 18 m/min. Serum, gastrocnemius, and heart were collected preexercise, immediately postxercise, and 30 and 60 min following the final exercise session and analyzed for indexes of IL-6 signaling. For aim 2, a separate cohort of exercise-preconditioned (C57 EX and IL-6(-/-) EX) and sedentary (C57 SED and IL-6(-/-) SED) mice received surgical I/R injury (30 min I, 120 min R) or a time-matched sham operation. Ischemic and perfused tissues were examined for necrosis, apoptosis, and autophagy. In aim 1, serum IL-6 and IL-6 receptor (IL-6R), gastrocnemius, and myocardial IL-6R were increased following exercise in C57 mice only. Phosphorylated (p) signal transducer and activator of transcription 3 was increased in gastrocnemius and heart in C57 and IL-6(-/-) mice postexercise, whereas myocardial iNOS and cyclooxygenase-2 were unchanged in the exercised myocardium. Exercise protected C57 EX mice against I/R-induced arrhythmias and necrosis, whereas arrhythmia score and infarct outcomes were higher in C57 SED, IL-6(-/-) SED, and IL-6(-/-) EX mice compared with SH. C57 EX mice expressed increased p-p44/42 MAPK (Thr(202)/Tyr(204)) and p-p38 MAPK (Thr(180)/Tyr(182)) compared with IL-6(-/-) EX mice, suggesting pathway involvement in exercise preconditioning. Findings indicate exercise exerts cardioprotection via IL-6 and strongly implicates protective signaling originating from the exercised skeletal muscle.

Acute Changes in Inflammatory Biomarker Levels in Recreational Runners Participating in a Marathon or Half-Marathon

“…Previous researchers suggest that aerobic exercise can provoke an IL-6 response from muscle cells, and this finding may be associated with exercise-associated metabolic changes, adaptation to training, and possibly preconditioning individuals against myocardial ischemia-reperfusion injury [9, 11, 13]. It has further been proposed that such responses can be related to the intensity of the exercise and mediate both autocrine and paracrine benefits of training [9, 11].…”

Stat proteins as intracellular regulators of resistance to myocardial injury in the context of cardiac remodeling and targeting for therapy

“…Such remarkable findings could signify that keeping our skeletal muscles in good shape helps our myocardium in its cardioprotective aspect via elevation of circulating IL-6. 34 Somewhat in line with the findings of McGinnis et al, it was revealed that if ischemia/reperfusion events are triggered in a remote organ, the myocardium can acquire a higher resistance to ischemic injury as a result. 34,35 Under remote ischemic preconditioning (RIPC), there was decrease of serum troponin I levels with an accompanying increase of STAT5 phosphorylation in patients undergoing coronary artery bypass surgery in comparison with control patients without RIPC.…”

“…34 Somewhat in line with the findings of McGinnis et al, it was revealed that if ischemia/reperfusion events are triggered in a remote organ, the myocardium can acquire a higher resistance to ischemic injury as a result. 34,35 Under remote ischemic preconditioning (RIPC), there was decrease of serum troponin I levels with an accompanying increase of STAT5 phosphorylation in patients undergoing coronary artery bypass surgery in comparison with control patients without RIPC. 35 In a pig experimental model of remote ischemic preconditioning, it was proved that RIPC limited infarct size and augmented STAT3 phosphorylation while STAT5 remained decreased in the early phase of reperfusion in both the RIPC and control groups.…”

“…33 Before discussing the relationships of STAT3 with pharmacological agents, it is worth noting what STAT3 has in common with "sports". 34 STAT3 plays a role in the prophylaxis and prevention of cardiac insufficiency with linkage to physical exercise. 34 Namely, after physical activity (precisely, the treadmill exercise of mice), the phosphorylated (p) signal transducer and activator of transcription 3 was increased in the gastrocnemius and heart muscles, with an elevation of serum IL-6 and IL-6 receptor (IL-6R), and IL-6R of gastrocnemius and heart muscle origin.…”

“…34 STAT3 plays a role in the prophylaxis and prevention of cardiac insufficiency with linkage to physical exercise. 34 Namely, after physical activity (precisely, the treadmill exercise of mice), the phosphorylated (p) signal transducer and activator of transcription 3 was increased in the gastrocnemius and heart muscles, with an elevation of serum IL-6 and IL-6 receptor (IL-6R), and IL-6R of gastrocnemius and heart muscle origin. Such remarkable findings could signify that keeping our skeletal muscles in good shape helps our myocardium in its cardioprotective aspect via elevation of circulating IL-6.…”