The Role Of Map Kinase Phosphatase-5 In Cardiac Adaptation To Endurance Exercise

PURPOSE: Endurance exercise induces numerous beneficial effects on the cardiovascular systemand promotes cardioprotection against heart disease. It has been established that the mitogen-activated protein kinases (MAPKs) improve cardiac function in response to endurance exercise.However, molecular mechanisms of how MAPK signaling pathways regulate the cardiacadaptation to endurance exercise remain unclear. The MAPKs are highly conservedserine/threonine protein kinases that participate in a variety of fundamental cellular processes incardiac muscle. The MAPKs are negatively regulated by MAP kinase phosphatases (MKPs)through direct dephosphorylation. Recently, growing evidence suggests the importance of MKP-5 signaling in physiological and pathological processes. The purpose of this study is to investigatethe role of MKP-5 in cardiac muscle adaptation to endurance exercise. METHODS: To test ourpurpose, 8-week old male wild type (Mkp-5+/+) and MKP-5 deficient (Mkp-5-/-) mice weresubjected to endurance treadmill exercise with 70 ~ 75% of VO2max (15 m/min), 60 min/day, 5 daysafter one week of exercise habituation. Exercise stress test was performed to determine enduranceexercise capacity following endurance exercise training. To investigate cardiac adaptation toendurance exercise, the phosphoinositide 3-kinase (PI3K)-protein kinase B (Akt)-mammaliantarget of rapamycin (mTOR) pathways were assessed in exercised hearts from Mkp-5+/+and Mkp-5-/- mice by immunoblotting. RESULTS: We found that MKP-5 gene expression is dramaticallydownregulated by 81% in cardiac muscle following endurance exercise as compared to non-exercised mice (P < 0.0001). Mkp-5-/- mice exhibited 3-fold increased running distance comparedto Mkp-5+/+ mice (Mean: 632.8 vs 224.7 meters; P = 0.00429). We found that the phosphorylationof PI3K (P = 0.0078), Akt (P = 0.002), mTOR (P = 0.0001), and 4E-BP1 (P = 0.012) was significantlyincreased in MKP-5 deficient-hearts following endurance exercise as compared to the exercisedhearts of wild type mice. CONCULSION: Taken together, our results implicate that MKP-5 maybe an important biological target to improve cardiac function in response to exercise.