Konhilas John P, Maass Alexander H, Luckey Stephen W, Stauffer Brian L, Olson Eric N, Leinwand Leslie A
Dept. of Molecular, Cellular, and Developmental Biology, Univ. of Colorado, Campus Box 347, Boulder, CO 80309-0347, USA.
Am J Physiol Heart Circ Physiol. 2004 Dec;287(6):H2768-76. doi: 10.1152/ajpheart.00292.2004. Epub 2004 Aug 19.
How an individual's sex and genetic background modify cardiac adaptation to increased workload is a topic of great interest. We systematically evaluated morphological and physiological cardiac adaptation in response to voluntary and forced exercise. We found that sex/gender is a dominant factor in exercise performance (in two exercise paradigms and two mouse strains) and that females of one of these strains have greater capacity to increase their cardiac mass in response to similar amounts of exercise. To explore the biochemical mechanisms for these differences, we examined signaling pathways previously implicated in cardiac hypertrophy. Ca2+/calmodulin-dependent protein kinase (CaMK) activity was significantly greater in males compared with females and increased after voluntary cage-wheel exposure in both sexes, but the proportional increase in CaMK activity was twofold higher in females compared with males. Phosphorylation of glycogen synthase kinase-3beta (GSK-3beta) was evident after 7 days of cage-wheel exposure in both sexes and remained elevated in females only by 21 days of exercise. Despite moderate increases in myocyte enhancer factor-2 (a downstream effector of CaMK) transcriptional activity and phosphorylation of Akt with exercise, there were no sex differences. Mitogen-activated protein kinase signaling components (p38 mitogen-activated protein kinase and extracellular regulated kinase 1/2) were not different between male and female mice and were not affected by exercise. We conclude that females have increased exercise capacity and increased hypertrophic response to exercise. We have also identified sex-specific differences in hypertrophic signaling within the cardiac myocyte that may contribute to sexual dimorphism in exercise and cardiac adaptation to exercise.
个体的性别和基因背景如何改变心脏对增加的工作负荷的适应性是一个备受关注的话题。我们系统地评估了心脏对自愿运动和强迫运动的形态学和生理学适应性。我们发现，性别是运动表现的主要因素（在两种运动模式和两种小鼠品系中），并且在这些品系之一中，雌性小鼠在进行相似运动量的运动时，增加心脏质量的能力更强。为了探究这些差异的生化机制，我们研究了先前与心肌肥大相关的信号通路。与雌性相比，雄性中钙/钙调蛋白依赖性蛋白激酶（CaMK）的活性显著更高，并且在两性自愿接触笼轮后均增加，但雌性中CaMK活性的比例增加是雄性的两倍。在笼轮接触7天后，两性中糖原合酶激酶-3β（GSK-3β）的磷酸化均明显，并且仅在运动21天后，雌性中的该磷酸化仍保持升高。尽管运动后肌细胞增强因子-2（CaMK的下游效应物）的转录活性和Akt的磷酸化适度增加，但不存在性别差异。丝裂原活化蛋白激酶信号成分（p38丝裂原活化蛋白激酶和细胞外调节激酶1/2）在雄性和雌性小鼠之间没有差异，并且不受运动影响。我们得出结论，雌性具有更高的运动能力以及对运动更强的肥大反应。我们还确定了心肌细胞内肥大信号的性别特异性差异，这可能导致运动中的性别二态性以及心脏对运动的适应性。
