Carter Christy S, Giovannini Silvia, Seo Dong-Oh, DuPree Jameson, Morgan Drake, Chung Hae Young, Lees Hazel, Daniels Michael, Hubbard Gene B, Lee Shuko, Ikeno Yuji, Foster Thomas C, Buford Thomas W, Marzetti Emanuele
Department of Aging and Geriatric Research, Institute on Aging, University of Florida, Gainesville, FL 32610, USA.
Age (Dordr). 2011 Jun;33(2):167-83. doi: 10.1007/s11357-010-9196-y. Epub 2010 Dec 14.
The primary purpose of the present set of studies was to provide a direct comparison of the effects of the angiotensin-converting enzyme inhibitor enalapril and the angiotensin receptor blocker losartan on body composition, physical performance, and muscle quality when administered late in life to aged rats. Overall, enalapril treatment consistently attenuated age-related increases in adiposity relative to both placebo and losartan. The maximal effect was achieved after 3 months of treatment (between 24 and 27 months of age), at a dose of 40 mg/kg and was observed in the absence of any changes in physical activity, body temperature, or food intake. In addition, the reduction in fat mass was not due to changes in pathology given that enalapril attenuated age-related increases in tumor development relative to placebo- and losartan-treated animals. Both enalapril and losartan attenuated age-related decreases in grip strength, suggesting that changes in body composition appear dissociated from improvements in physical function and may reflect a differential impact of enalapril and losartan on muscle quality. To link changes in adiposity to improvements in skeletal muscle quality, we performed gene array analyses to generate hypotheses regarding cell signaling pathways altered with enalapril treatment. Based on these results, our primary follow-up pathway was mitochondria-mediated apoptosis of myocytes. Relative to losartan- and placebo-treated rats, only enalapril decreased DNA fragmentation and caspase-dependent apoptotic signaling. These data suggest that attenuation of the severity of skeletal muscle apoptosis promoted by enalapril may represent a distinct mechanism through which this compound improves muscle strength/quality.
本系列研究的主要目的是直接比较血管紧张素转换酶抑制剂依那普利和血管紧张素受体阻滞剂氯沙坦在老年大鼠生命后期给药时对身体成分、身体机能和肌肉质量的影响。总体而言，与安慰剂和氯沙坦相比，依那普利治疗持续减弱了与年龄相关的肥胖增加。在治疗3个月后（24至27月龄之间），以40mg/kg的剂量达到最大效果，且在身体活动、体温或食物摄入量无任何变化的情况下观察到该效果。此外，脂肪量的减少并非由于病理学变化，因为与安慰剂和氯沙坦治疗的动物相比，依那普利减弱了与年龄相关的肿瘤发生增加。依那普利和氯沙坦均减弱了与年龄相关的握力下降，这表明身体成分的变化似乎与身体机能的改善无关，可能反映了依那普利和氯沙坦对肌肉质量的不同影响。为了将肥胖的变化与骨骼肌质量的改善联系起来，我们进行了基因阵列分析，以生成关于依那普利治疗后改变的细胞信号通路的假设。基于这些结果，我们的主要后续研究途径是线粒体介导的心肌细胞凋亡。与氯沙坦和安慰剂治疗的大鼠相比，只有依那普利减少了DNA片段化和半胱天冬酶依赖性凋亡信号。这些数据表明，依那普利促进的骨骼肌凋亡严重程度的减弱可能代表了该化合物改善肌肉力量/质量的独特机制。
