Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, New Jersey Medical School, Rutgers University, 185 South Orange Avenue, MSB G609, Newark, NJ, 07103, USA.
Department of Kinesiology and Health, Rutgers University, New Brunswick, NJ, USA.
Basic Res Cardiol. 2017 Sep 8;112(6):59. doi: 10.1007/s00395-017-0648-8.
Exercise training is key to healthful longevity. Since exercise training compliance is difficult, it would be useful to have a therapeutic substitute that mimicked exercise training. We compared the effects of exercise training in wild-type (WT) littermates with adenylyl cyclase type 5 knock out (AC5 KO) mice, a model of enhanced exercise performance. Exercise performance, measured by maximal distance and work to exhaustion, was increased in exercise-trained WT to levels already attained in untrained AC5 KO. Exercise training in AC5 KO further enhanced their exercise performance. The key difference in untrained AC5 KO and exercise-trained WT was the β-adrenergic receptor signaling, which was decreased in untrained AC5 KO compared to untrained WT but was increased in WT with exercise training. Despite this key difference, untrained AC5 KO and exercise-trained WT mice shared similar gene expression, determined by deep sequencing, in their gastrocnemius muscle with 183 genes commonly up or down-regulated, mainly involving muscle contraction, metabolism and mitochondrial function. The SIRT1/PGC-1α pathway partially mediated the enhanced exercise in both AC5 KO and exercise-trained WT mice, as reflected in the reduced exercise responses after administering a SIRT1 inhibitor, but did not abolish the enhanced exercise performance in the AC5 KO compared to untrained WT. Increasing oxidative stress with paraquat attenuated exercise performance more in untrained WT than untrained AC5 KO, reflecting the augmented oxidative stress protection in AC5 KO. Blocking nitric oxide actually reduced the enhanced exercise performance in untrained AC5 KO and trained WT to levels below untrained WT, demonstrating the importance of this mechanism. These results suggest that AC5 KO mice, without exercise training, share similar mechanisms responsible for enhanced exercise capacity with chronic exercise training, most importantly increased nitric oxide, and demonstrate more reserve with the addition of exercise training. A novel feature of the enhanced exercise performance in untrained AC5 KO mice is their decreased sympathetic tone, which is also beneficial to patients with cardiovascular disease.
运动训练是健康长寿的关键。由于运动训练的依从性很差，因此拥有一种模拟运动训练的治疗替代物将非常有用。我们比较了运动训练对野生型（WT）同窝仔鼠与腺苷酸环化酶 5 敲除（AC5 KO）鼠的影响，后者是运动表现增强的模型。通过最大距离和疲劳功测量，运动训练的 WT 运动表现增加到未训练的 AC5 KO 已经达到的水平。在未训练的 AC5 KO 中，运动训练进一步增强了它们的运动表现。未训练的 AC5 KO 和运动训练的 WT 的关键区别在于β-肾上腺素能受体信号，与未训练的 WT 相比，未训练的 AC5 KO 中β-肾上腺素能受体信号降低，但运动训练后 WT 中β-肾上腺素能受体信号增加。尽管存在这一关键差异，但未训练的 AC5 KO 和运动训练的 WT 小鼠在其比目鱼肌中的基因表达相似，通过深度测序确定，有 183 个基因共同上调或下调，主要涉及肌肉收缩、代谢和线粒体功能。SIRT1/PGC-1α 通路部分介导了 AC5 KO 和运动训练的 WT 小鼠的增强运动，这反映在给予 SIRT1 抑制剂后运动反应降低，但与未训练的 WT 相比，SIRT1 抑制剂并未消除 AC5 KO 中的增强运动表现。用百草枯增加氧化应激会使未训练的 WT 比未训练的 AC5 KO 运动表现下降更多，反映了 AC5 KO 中增强的氧化应激保护。阻断一氧化氮实际上会降低未训练的 AC5 KO 和训练的 WT 的增强运动表现，使其降至未训练的 WT 以下，证明了这种机制的重要性。这些结果表明，未经运动训练的 AC5 KO 小鼠与慢性运动训练一样，具有增强运动能力的相似机制，最重要的是增加一氧化氮，并且在加入运动训练后具有更多的储备。未经训练的 AC5 KO 小鼠增强运动表现的一个新特征是其交感神经张力降低，这对心血管疾病患者也有益。
