{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T09:10:05Z","timestamp":1765357805758,"version":"build-2065373602"},"reference-count":81,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2025,3,11]],"date-time":"2025-03-11T00:00:00Z","timestamp":1741651200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Texas at El Paso Faculty startup","award":["19490521","R01DK132430","R01 AR080152","R01 HL158876"],"award-info":[{"award-number":["19490521","R01DK132430","R01 AR080152","R01 HL158876"]}]},{"name":"NIH","award":["19490521","R01DK132430","R01 AR080152","R01 HL158876"],"award-info":[{"award-number":["19490521","R01DK132430","R01 AR080152","R01 HL158876"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Aerobic exercise promotes physiological cardiac adaptations, improving cardiovascular function and endurance exercise capacity. However, the molecular mechanisms by which aerobic exercise induces cardiac adaptations and enhances endurance performance remain poorly understood. Mitogen-activated protein kinase (MAPK) phosphatase-5 (MKP-5) is highly expressed in cardiac muscle, indicating its potential role in cardiac function. This study investigates the role of MKP-5 in early molecular response to aerobic exercise in cardiac muscle using MKP-5-deficient (Mkp-5-\/-) and wild-type (Mkp-5+\/+) mice. Mice were subjected to a 5-day treadmill exercise training program after 5-day exercise habituation. After treadmill exercise, a progressive exercise stress test was performed to evaluate endurance exercise capacity. Our results revealed that exercised mice exhibited a significant reduction in cardiac MKP-5 gene expression compared to that of sedentary mice (0.19 \u00b1 5.89-fold; p &lt; 0.0001). Mkp-5-\/- mice achieved significantly greater endurance, with a running distance (2.81 \u00b1 169.8-fold; p &lt; 0.0429) longer than Mkp-5+\/+ mice. Additionally, MKP-5 deficiency enhanced Akt\/mTOR signaling (p-Akt\/Akt: 1.29 \u00b1 0.12-fold; p = 0.04; p-mTOR\/mTOR: 1.59 \u00b1 0.14-fold; p = 0.002) and mitochondrial biogenesis (pgc-1\u03b1: 1.56 \u00b1 0.27-fold; p = 0.03) in cardiac muscle in response to aerobic exercise. Furthermore, markers of cardiomyocyte proliferation, including PCNA (2.24 \u00b1 0.31-fold; p &lt; 0.001), GATA4 (1.47 \u00b1 0.10-fold; p &lt; 0.001), and CITED4 (2.03 \u00b1 0.15-fold; p &lt; 0.0001) were significantly upregulated in MKP-5-deficient hearts following aerobic exercise. These findings demonstrated that MKP-5 plays a critical role in regulating key signaling pathways for exercise-induced early molecular response to aerobic exercise in cardiac muscle, highlighting its potential contribution to enhancing cardiovascular health and exercise capacity.<\/jats:p>","DOI":"10.3390\/cells14060410","type":"journal-article","created":{"date-parts":[[2025,3,11]],"date-time":"2025-03-11T08:59:52Z","timestamp":1741683592000},"page":"410","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["MAP Kinase Phosphatase-5 Deficiency Improves Endurance Exercise Capacity"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-5246-0813","authenticated-orcid":false,"given":"Jaime A.","family":"Perales","sequence":"first","affiliation":[{"name":"Department of Kinesiology, University of Texas at El Paso, El Paso, TX 79968, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9166-9548","authenticated-orcid":false,"given":"Ahmed","family":"Lawan","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Alabama in Huntsville, Huntsville, AL 35899, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sudip","family":"Bajpeyi","sequence":"additional","affiliation":[{"name":"Department of Kinesiology, University of Texas at El Paso, El Paso, TX 79968, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sung Min","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Physiology and Aging, University of Florida, Gainesville, FL 32610, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5187-7599","authenticated-orcid":false,"given":"Anton M.","family":"Bennett","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06510, USA"},{"name":"Yale Center for Molecular and Systems Metabolism, Yale University School of Medicine, New Haven, CT 06510, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0355-3327","authenticated-orcid":false,"given":"Kisuk","family":"Min","sequence":"additional","affiliation":[{"name":"Department of Kinesiology, University of Texas at El Paso, El Paso, TX 79968, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"a029694","DOI":"10.1101\/cshperspect.a029694","article-title":"Health benefits of exercise","volume":"8","author":"Ruegsegger","year":"2018","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_2","unstructured":"Dishman, R.K., Heath, G.W., Schmidt, M.D., and Lee, I.-M. (2021). Physical Activity Epidemiology, Human Kinetics."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.cmet.2015.05.011","article-title":"Understanding the cellular and molecular mechanisms of physical activity-induced health benefits","volume":"22","author":"Neufer","year":"2015","journal-title":"Cell Metab."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1270","DOI":"10.1249\/MSS.0000000000001939","article-title":"Physical activity, all-cause and cardiovascular mortality, and cardiovascular disease","volume":"51","author":"Kraus","year":"2019","journal-title":"Med. Sci. Sports Exerc."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.ypmed.2014.12.023","article-title":"The association of physical activity with all-cause, cardiovascular, and cancer mortalities among older adults","volume":"72","author":"Wu","year":"2015","journal-title":"Prev. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3547","DOI":"10.1093\/eurheartj\/ehz564","article-title":"Mortality reduction with physical activity in patients with and without cardiovascular disease","volume":"40","author":"Jeong","year":"2019","journal-title":"Eur. Heart J."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1436","DOI":"10.1161\/CIRCULATIONAHA.112.123117","article-title":"Cardiovascular risk of high-versus moderate-intensity aerobic exercise in coronary heart disease patients","volume":"126","author":"Rognmo","year":"2012","journal-title":"Circulation"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1016\/j.pcd.2021.08.013","article-title":"Effects of aerobic training and resistance training in reducing cardiovascular disease risk for patients with prediabetes: A multi-center randomized controlled trial","volume":"15","author":"Chen","year":"2021","journal-title":"Prim. Care Diabetes"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"H543","DOI":"10.1152\/ajpheart.00899.2014","article-title":"Aerobic exercise training promotes physiological cardiac remodeling involving a set of microRNAs","volume":"309","author":"Fernandes","year":"2015","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1038\/s42255-020-0262-1","article-title":"Exercise and cardiac health: Physiological and molecular insights","volume":"2","author":"Moreira","year":"2020","journal-title":"Nat. Metab."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1152\/physiol.00017.2009","article-title":"Physiological signaling specificity by protein tyrosine phosphatases","volume":"24","author":"Soulsby","year":"2009","journal-title":"Physiology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2064","DOI":"10.1172\/JCI64375","article-title":"Improved regenerative myogenesis and muscular dystrophy in mice lacking Mkp5","volume":"123","author":"Shi","year":"2013","journal-title":"J. Clin. Investig."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"624","DOI":"10.2337\/db17-0826","article-title":"Skeletal muscle\u2013specific deletion of MKP-1 reveals a p38 MAPK\/JNK\/Akt signaling node that regulates obesity-induced insulin resistance","volume":"67","author":"Lawan","year":"2018","journal-title":"Diabetes"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1186\/s13395-017-0137-7","article-title":"Loss of MKP-5 promotes myofiber survival by activating STAT3\/Bcl-2 signaling during regenerative myogenesis","volume":"7","author":"Min","year":"2017","journal-title":"Skelet. Muscle"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Zhong, C., Min, K., Zhao, Z., Zhang, C., Gao, E., Huang, Y., Zhang, X., Baldini, M., Roy, R., and Yang, X. (2021). MAP kinase phosphatase-5 deficiency protects against pressure overload-induced cardiac fibrosis. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.790511"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"L678","DOI":"10.1152\/ajplung.00264.2018","article-title":"Role of dual-specificity protein phosphatase DUSP10\/MKP-5 in pulmonary fibrosis","volume":"317","author":"Xylourgidis","year":"2019","journal-title":"Am. J. Physiol. -Lung Cell. Mol. Physiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1038\/nature02764","article-title":"Regulation of innate and adaptive immune responses by MAP kinase phosphatase 5","volume":"430","author":"Zhang","year":"2004","journal-title":"Nature"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"B38","DOI":"10.1093\/gerona\/51A.1.B38","article-title":"The effect of exercise training on cold tolerance in adult and old C57BL\/6J mice","volume":"51","author":"Schaefer","year":"1996","journal-title":"J. Gerontol. Ser. A Biol. Sci. Med. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Dougherty, J.P., Springer, D.A., and Gershengorn, M.C. (2016). The Treadmill Fatigue Test: A Simple, High-throughput Assay of Fatigue-like Behavior for the Mouse. J. Vis. Exp., 54052.","DOI":"10.3791\/54052"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Chung, Y., Hsiao, Y.T., and Huang, W.C. (2021). Physiological and Psychological Effects of Treadmill Overtraining Implementation. Biology, 10.","DOI":"10.3390\/biology10060515"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1136\/heartjnl-2011-300639","article-title":"Physiological cardiac remodelling in response to endurance exercise training: Cellular and molecular mechanisms","volume":"98","author":"Ellison","year":"2012","journal-title":"Heart"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.1016\/j.cmet.2017.04.025","article-title":"Molecular mechanisms underlying cardiac adaptation to exercise","volume":"25","author":"Vega","year":"2017","journal-title":"Cell Metab."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Pahlavani, H.A. (2022). Exercise-induced signaling pathways to counteracting cardiac apoptotic processes. Front. Cell Dev. Biol., 10.","DOI":"10.3389\/fcell.2022.950927"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1659","DOI":"10.1038\/s41467-018-04083-1","article-title":"Exercise induces new cardiomyocyte generation in the adult mammalian heart","volume":"9","author":"Vujic","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1055\/s-0034-1395585","article-title":"Regulation of mTOR Pathway in Exercise-induced Cardiac Hypertrophy","volume":"36","author":"Liao","year":"2015","journal-title":"Int. J. Sports Med."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Al-Horani, R.A., Janaydeh, S., Al-Trad, B., Aljanabi, M.M., and Muhaidat, R. (2023). Acute Exercise Promptly Normalizes Myocardial Myosin Heavy-Chain Isoform mRNA Composition in Diabetic Rats: Implications for Diabetic Cardiomyopathy. Medicina, 59.","DOI":"10.3390\/medicina59122193"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1007\/s10974-021-09603-z","article-title":"Changes in myocardial myosin heavy chain isoform composition with exercise and post-exercise cold-water immersion","volume":"42","author":"Mohammad","year":"2021","journal-title":"J. Muscle Res. Cell Motil."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1139\/apnm-2013-0268","article-title":"Exercise training induced myosin heavy chain isoform alteration in the infarcted heart","volume":"39","author":"Wan","year":"2014","journal-title":"Appl. Physiol. Nutr. Metab. Physiol. Appl. Nutr. Metab."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.semcdb.2022.03.022","article-title":"Transient changes to metabolic homeostasis initiate mitochondrial adaptation to endurance exercise","volume":"143","author":"Dent","year":"2023","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Li, J., Zhang, S., Li, C., Zhang, X., Shan, Y., Zhang, Z., Bo, H., and Zhang, Y. (2024). Endurance exercise-induced histone methylation modification involved in skeletal muscle fiber type transition and mitochondrial biogenesis. Sci. Rep., 14.","DOI":"10.1038\/s41598-024-72088-6"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Gu, C., Yan, J., Zhao, L., Wu, G., and Wang, Y.L. (2021). Regulation of Mitochondrial Dynamics by Aerobic Exercise in Cardiovascular Diseases. Front. Cardiovasc. Med., 8.","DOI":"10.3389\/fcvm.2021.788505"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e036555","DOI":"10.1161\/JAHA.124.036555","article-title":"Exercise Alleviates Cardiovascular Diseases by Improving Mitochondrial Homeostasis","volume":"13","author":"Zhang","year":"2024","journal-title":"J. Am. Heart Assoc."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Rowe, G.C., El-Khoury, R., Patten, I.S., Rustin, P., and Arany, Z. (2012). PGC-1\u03b1 is dispensable for exercise-induced mitochondrial biogenesis in skeletal muscle. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0041817"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Viloria, M.A.D., Li, Q., Lu, W., Nhu, N.T., Liu, Y., Cui, Z.Y., Cheng, Y.J., and Lee, S.D. (2022). Effect of exercise training on cardiac mitochondrial respiration, biogenesis, dynamics, and mitophagy in ischemic heart disease. Front. Cardiovasc. Med., 9.","DOI":"10.3389\/fcvm.2022.949744"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Abu Shelbayeh, O., Arroum, T., Morris, S., and Busch, K.B. (2023). PGC-1\u03b1 Is a Master Regulator of Mitochondrial Lifecycle and ROS Stress Response. Antioxidants, 12.","DOI":"10.3390\/antiox12051075"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1038\/s41392-024-01756-w","article-title":"Peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) family in physiological and pathophysiological process and diseases","volume":"9","author":"Qian","year":"2024","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1007\/s40279-013-0127-9","article-title":"The emerging role of p53 in exercise metabolism","volume":"44","author":"Bartlett","year":"2014","journal-title":"Sports Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1097\/JES.0b013e31822d71be","article-title":"Role of p53 within the regulatory network controlling muscle mitochondrial biogenesis","volume":"39","author":"Saleem","year":"2011","journal-title":"Exerc. Sport Sci. Rev."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"657","DOI":"10.3945\/an.113.004572","article-title":"Optimizing intramuscular adaptations to aerobic exercise: Effects of carbohydrate restriction and protein supplementation on mitochondrial biogenesis","volume":"4","author":"Margolis","year":"2013","journal-title":"Adv. Nutr."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Craig, D.M., Ashcroft, S.P., Belew, M.Y., Stocks, B., Currell, K., Baar, K., and Philp, A. (2015). Utilizing small nutrient compounds as enhancers of exercise-induced mitochondrial biogenesis. Front. Physiol., 6.","DOI":"10.3389\/fphys.2015.00296"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/978-94-007-2869-1_1","article-title":"The oxidative phosphorylation system in mammalian mitochondria","volume":"942","author":"Papa","year":"2012","journal-title":"Adv. Mitochondrial Med."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Zhang, G.-l., Sun, M.-l., and Zhang, X.-a. (2021). Exercise-induced adult cardiomyocyte proliferation in mammals. Front. Physiol., 12.","DOI":"10.3389\/fphys.2021.729364"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.1016\/j.cell.2010.11.036","article-title":"C\/EBP\u03b2 controls exercise-induced cardiac growth and protects against pathological cardiac remodeling","volume":"143","author":"Mann","year":"2010","journal-title":"Cell"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1016\/j.cmet.2015.02.014","article-title":"miR-222 is necessary for exercise-induced cardiac growth and protects against pathological cardiac remodeling","volume":"21","author":"Liu","year":"2015","journal-title":"Cell Metab."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1038\/s41536-021-00128-0","article-title":"Targets identified from exercised heart: Killing multiple birds with one stone","volume":"6","author":"Wang","year":"2021","journal-title":"npj Regen. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1038\/s41392-022-01233-2","article-title":"Molecular mechanisms of exercise contributing to tissue regeneration","volume":"7","author":"Chen","year":"2022","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1161\/CIRCULATIONAHA.113.001590","article-title":"Running forward: New frontiers in endurance exercise biology","volume":"129","author":"Rowe","year":"2014","journal-title":"Circulation"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1112","DOI":"10.1016\/j.cell.2020.04.043","article-title":"Molecular Choreography of Acute Exercise","volume":"181","author":"Contrepois","year":"2020","journal-title":"Cell"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"117920","DOI":"10.1016\/j.lfs.2020.117920","article-title":"Effects of short-term high-intensity interval and continuous exercise training on body composition and cardiac function in obese sarcopenic rats","volume":"256","author":"Frantz","year":"2020","journal-title":"Life Sci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"S22-31","DOI":"10.5213\/inj.1938038.019","article-title":"Effects of Acute Exercise on Mitochondrial Function, Dynamics, and Mitophagy in Rat Cardiac and Skeletal Muscles","volume":"23","author":"Yoo","year":"2019","journal-title":"Int. Neurourol. J."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Yue, J., and L\u00f3pez, J.M. (2020). Understanding MAPK Signaling Pathways in Apoptosis. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21072346"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2449","DOI":"10.1021\/cr000241p","article-title":"MAP kinases","volume":"101","author":"Chen","year":"2001","journal-title":"Chem. Rev."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1113\/EP086189","article-title":"Acute exercise activates p38 MAPK and increases the expression of telomere-protective genes in cardiac muscle","volume":"102","author":"Ludlow","year":"2017","journal-title":"Exp. Physiol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1152\/japplphysiol.01059.2012","article-title":"Heart failure with preserved ejection fraction: Chronic low-intensity interval exercise training preserves myocardial O2 balance and diastolic function","volume":"114","author":"Marshall","year":"2013","journal-title":"J. Appl. Physiol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ijcme.2016.08.001","article-title":"Aerobic exercise can ameliorate heart function in patients with myocardial infarction through up-regulating M3 receptor","volume":"13","author":"Chengji","year":"2016","journal-title":"IJC Metab. Endocr."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1016\/j.bbamcr.2006.12.002","article-title":"Regulation of MAP kinases by MAP kinase phosphatases","volume":"1773","author":"Kondoh","year":"2007","journal-title":"Biochim. Biophys. Acta (BBA)-Mol. Cell Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1038\/nrm3495","article-title":"Molecular basis of physiological heart growth: Fundamental concepts and new players","volume":"14","author":"Maillet","year":"2013","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Fulghum, K., and Hill, B.G. (2018). Metabolic mechanisms of exercise-induced cardiac remodeling. Front. Cardiovasc. Med., 5.","DOI":"10.3389\/fcvm.2018.00127"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1152\/physrev.00045.2006","article-title":"Regulation of coronary blood flow during exercise","volume":"88","author":"Duncker","year":"2008","journal-title":"Physiol. Rev."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"H438","DOI":"10.1152\/ajpheart.1999.276.2.H438","article-title":"Arterial O2 content and tension in regulation of cardiac output and leg blood flow during exercise in humans","volume":"276","author":"Roach","year":"1999","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2097","DOI":"10.1161\/CIRCULATIONAHA.105.595231","article-title":"Akt1 is required for physiological cardiac growth","volume":"113","author":"DeBosch","year":"2006","journal-title":"Circulation"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"990","DOI":"10.1016\/j.cmet.2016.05.009","article-title":"The Mechanistic Target of Rapamycin: The Grand ConducTOR of Metabolism and Aging","volume":"23","author":"Kennedy","year":"2016","journal-title":"Cell Metab."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1016\/j.cell.2017.02.004","article-title":"mTOR Signaling in Growth, Metabolism, and Disease","volume":"168","author":"Saxton","year":"2017","journal-title":"Cell"},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Watson, K., and Baar, K. (2014). mTOR and the health benefits of exercise. Semin. Cell Dev. Biol., 130\u2013139.","DOI":"10.1016\/j.semcdb.2014.08.013"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1080\/15384101.2016.1151581","article-title":"4E-BP1, a multifactor regulated multifunctional protein","volume":"15","author":"Qin","year":"2016","journal-title":"Cell Cycle"},{"key":"ref_66","first-page":"116","article-title":"Investigating the effect of exercise training in different periods of growth on protein synthesis (4E-BP1) and proliferation of cardiac cells (S6K1) in male rats","volume":"3","author":"Mirzaei","year":"2023","journal-title":"J. Exerc. Organ Cross Talk"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2938","DOI":"10.1016\/j.yexcr.2011.09.011","article-title":"A novel cardioprotective p38-MAPK\/mTOR pathway","volume":"317","author":"Lal","year":"2011","journal-title":"Exp. Cell Res."},{"key":"ref_68","first-page":"1186","article-title":"Sphingosylphosphorylcholine protects cardiomyocytes against ischemic apoptosis via lipid raft\/PTEN\/Akt1\/mTOR mediated autophagy","volume":"1851","author":"Yue","year":"2015","journal-title":"Biochim. Biophys. Acta (BBA)-Mol. Cell Biol. Lipids"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"9274841","DOI":"10.1155\/2021\/9274841","article-title":"Stay Fit, Stay Young: Mitochondria in Movement: The Role of Exercise in the New Mitochondrial Paradigm","volume":"2021","author":"Casuso","year":"2021","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Fritzen, A.M., Andersen, S.P., Qadri, K.A.N., Th\u00f8gersen, F.D., Krag, T., \u00d8rngreen, M.C., Vissing, J., and Jeppesen, T.D. (2020). Effect of Aerobic Exercise Training and Deconditioning on Oxidative Capacity and Muscle Mitochondrial Enzyme Machinery in Young and Elderly Individuals. J. Clin. Med., 9.","DOI":"10.3390\/jcm9103113"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"3780156","DOI":"10.1155\/2022\/3780156","article-title":"The Effect of Aerobic Exercise on the Oxidative Capacity of Skeletal Muscle Mitochondria in Mice with Impaired Glucose Tolerance","volume":"2022","author":"Wang","year":"2022","journal-title":"J. Diabetes Res."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1093\/cvr\/cvn098","article-title":"Transcriptional control of mitochondrial biogenesis: The central role of PGC-1\u03b1","volume":"79","author":"Garnier","year":"2008","journal-title":"Cardiovasc. Res."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"19587","DOI":"10.1074\/jbc.M408862200","article-title":"Exercise stimulates Pgc-1\u03b1 transcription in skeletal muscle through activation of the p38 MAPK pathway","volume":"280","author":"Akimoto","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1074\/jbc.M606116200","article-title":"Exercise-induced mitochondrial biogenesis begins before the increase in muscle PGC-1\u03b1 expression","volume":"282","author":"Wright","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.mito.2015.10.001","article-title":"Regulation of mitochondrial biogenesis through TFAM\u2013mitochondrial DNA interactions: Useful insights from aging and calorie restriction studies","volume":"25","author":"Picca","year":"2015","journal-title":"Mitochondrion"},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Beyfuss, K., Erlich, A.T., Triolo, M., and Hood, D.A. (2018). The role of p53 in determining mitochondrial adaptations to endurance training in skeletal muscle. Sci. Rep., 8.","DOI":"10.1038\/s41598-018-32887-0"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1038\/s41392-020-00413-2","article-title":"Regulation of cardiomyocyte fate plasticity: A key strategy for cardiac regeneration","volume":"6","author":"Gong","year":"2021","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1038\/nature08804","article-title":"Primary contribution to zebrafish heart regeneration by gata4+ cardiomyocytes","volume":"464","author":"Kikuchi","year":"2010","journal-title":"Nature"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.pathophys.2012.06.001","article-title":"Expression of cardiac GATA4 and downstream genes after exercise training in the db\/db mouse","volume":"19","author":"Broderick","year":"2012","journal-title":"Pathophysiology"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/j.lfs.2019.02.045","article-title":"High-intensity interval training increase GATA4, CITED4 and c-Kit and decreases C\/EBP\u03b2 in rats after myocardial infarction","volume":"221","author":"Naderi","year":"2019","journal-title":"Life Sci."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1038\/s41392-022-01153-1","article-title":"Exercise training maintains cardiovascular health: Signaling pathways involved and potential therapeutics","volume":"7","author":"Chen","year":"2022","journal-title":"Signal Transduct. Target. Ther."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/6\/410\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:50:39Z","timestamp":1760028639000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/6\/410"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,11]]},"references-count":81,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2025,3]]}},"alternative-id":["cells14060410"],"URL":"https:\/\/doi.org\/10.3390\/cells14060410","relation":{},"ISSN":["2073-4409"],"issn-type":[{"type":"electronic","value":"2073-4409"}],"subject":[],"published":{"date-parts":[[2025,3,11]]}}}