Perales Jaime A, Lawan Ahmed, Bajpeyi Sudip, Han Sung Min, Bennett Anton M, Min Kisuk
Department of Kinesiology, University of Texas at El Paso, El Paso, TX 79968, USA.
Department of Biological Sciences, University of Alabama in Huntsville, Huntsville, AL 35899, USA.
Cells. 2025 Mar 11;14(6):410. doi: 10.3390/cells14060410.
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 () and wild-type () 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 ± 5.89-fold; < 0.0001). mice achieved significantly greater endurance, with a running distance (2.81 ± 169.8-fold; < 0.0429) longer than mice. Additionally, MKP-5 deficiency enhanced Akt/mTOR signaling (p-Akt/Akt: 1.29 ± 0.12-fold; = 0.04; p-mTOR/mTOR: 1.59 ± 0.14-fold; = 0.002) and mitochondrial biogenesis (: 1.56 ± 0.27-fold; = 0.03) in cardiac muscle in response to aerobic exercise. Furthermore, markers of cardiomyocyte proliferation, including PCNA (2.24 ± 0.31-fold; < 0.001), GATA4 (1.47 ± 0.10-fold; < 0.001), and CITED4 (2.03 ± 0.15-fold; < 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.
有氧运动可促进心脏的生理性适应，改善心血管功能和耐力运动能力。然而，有氧运动诱导心脏适应并提高耐力表现的分子机制仍知之甚少。丝裂原活化蛋白激酶（MAPK）磷酸酶-5（MKP-5）在心肌中高表达，表明其在心脏功能中可能发挥的作用。本研究使用MKP-5基因敲除（）和野生型（）小鼠，研究MKP-5在心肌对有氧运动的早期分子反应中的作用。在进行5天的运动适应性训练后，小鼠接受为期5天的跑步机运动训练计划。跑步机运动后，进行渐进性运动应激试验以评估耐力运动能力。我们的结果显示，与久坐不动的小鼠相比，运动小鼠的心脏MKP-5基因表达显著降低（0.19±5.89倍；<0.0001）。基因敲除小鼠的耐力显著增强，跑步距离（2.81±169.8倍；<0.0429）比野生型小鼠更长。此外，MKP-5基因缺失增强了有氧运动后心肌中的Akt/mTOR信号传导（p-Akt/Akt：1.29±0.12倍；=0.04；p-mTOR/mTOR：1.59±0.14倍；=0.002）和线粒体生物发生（：1.56±0.27倍；=0.03）。此外，有氧运动后，MKP-5基因敲除心脏中心肌细胞增殖标志物，包括增殖细胞核抗原（PCNA，2.24±0.31倍；<0.001）、GATA4（1.47±0.10倍；<0.001）和CITED4（2.03±0.15倍；<0.0001）显著上调。这些发现表明，MKP-5在调节运动诱导的心肌对有氧运动的早期分子反应的关键信号通路中起关键作用，突出了其对增强心血管健康和运动能力的潜在贡献。
