title: 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.
authors.affiliation: Cardioprotection Laboratory, Auburn University School of Kinesiology, Auburn, Alabama;
authors.forename: Graham Ripley
authors.initials: GR
authors.lastname: McGinnis
authors.affiliation: Cardioprotection Laboratory, Auburn University School of Kinesiology, Auburn, Alabama;
authors.forename: Christopher
authors.initials: C
authors.lastname: Ballmann
authors.affiliation: Cardioprotection Laboratory, Auburn University School of Kinesiology, Auburn, Alabama;
authors.forename: Bridget
authors.initials: B
authors.lastname: Peters
authors.affiliation: Department of Drug Discovery and Development, Auburn University Harrison School of Pharmacy, Auburn, Alabama; and.
authors.forename: Gayani
authors.initials: G
authors.lastname: Nanayakkara
authors.affiliation: Molecular and Applied Sciences Laboratory, Auburn University School of Kinesiology, Auburn, Alabama.
authors.forename: Michael
authors.initials: M
authors.lastname: Roberts
authors.affiliation: Department of Drug Discovery and Development, Auburn University Harrison School of Pharmacy, Auburn, Alabama; and.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Amin
authors.affiliation: Cardioprotection Laboratory, Auburn University School of Kinesiology, Auburn, Alabama; jcq0001@auburn.edu.
authors.forename: John C
authors.initials: JC
authors.lastname: Quindry
mesh_terms: D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D005081:Exercise Therapy; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D019157:Ischemic Preconditioning, Myocardial; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000378:metabolism / Q000502:physiology; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000517:prevention & control; D009206:Myocardium / Q000378:metabolism; D009336:Necrosis; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D005082:Physical Exertion; D019947:Receptors, Interleukin-6 / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2
keywords: cardioprotection; myocardial infarction; myokine