Department of Internal Medicine, Geriatrics Research, Southern Illinois University School of Medicine, 801 N Rutledge St., Room 4389, 62702-4910 Springfield, IL, USA.
Exp Biol Med (Maywood). 2011 Feb;236(2):156-68. doi: 10.1258/ebm.2010.010202.
The long-lived growth hormone (GH) receptor knockout (GHRKO; KO) mice are GH-resistant due to targeted disruption of the GH receptor (Ghr) gene. Apoptosis is a physiological process in which cells play an active role in their own death and is a normal component of the development and health of multicellular organisms. Aging is associated with the progressive loss of strength of skeletal and heart muscles. Calorie restriction (CR) is a well-known experimental model to delay aging and increase lifespan. The aim of the study was to examine the expression of the following apoptosis-related genes: caspase-3, caspase-9, caspase-8, bax, bcl-2, Smac/DIABLO, p53 and cytochrome c1 (cyc1) in the skeletal muscles and hearts of female normal and GHRKO mice, fed ad libitum or subjected to 40% CR for six months, starting at two months of age. Moreover, skeletal muscle caspase-3, caspase-9, caspase-8, bax, bcl-2, Smac/DIABLO, Apaf-1, bad, phospho-bad (pbad), phospho-p53 and cytochrome c (cyc) protein expression levels were assessed. Expression of caspase-3, caspase-9, bax and Smac/DIABLO genes and proteins was decreased in GHRKO's skeletal muscles. The Apaf-1 protein expression also was diminished in this tissue. In contrast, bcl-2 and pbad protein levels were increased in skeletal muscles in knockouts. No changes were demonstrated for the examined genes' expression in GHRKO's hearts except for the increased level of cyc1 mRNA. CR did not alter the expression of the examined genes and proteins in skeletal muscles of knockouts versus normal (N) mice. In heart homogenates, CR increased caspase-3 mRNA level as compared with ad libitum mice. Decreased expression of certain proapoptotic genes and/or proteins may constitute the potential mechanism of prolonged longevity in GHRKO mice, protecting these animals from aging; this potential beneficial mechanism is not affected by CR.
长寿的生长激素(GH)受体敲除(GHRKO;KO)小鼠由于生长激素受体(Ghr)基因的靶向破坏而对 GH 产生抗性。细胞程序性死亡(细胞凋亡)是一种细胞主动参与自身死亡的生理过程,是多细胞生物发育和健康的正常组成部分。衰老与骨骼肌和心肌力量的逐渐丧失有关。热量限制(CR)是一种众所周知的延缓衰老和延长寿命的实验模型。本研究的目的是检查以下与凋亡相关的基因在正常和 GHRKO 雌性小鼠的骨骼肌和心脏中的表达:caspase-3、caspase-9、caspase-8、bax、bcl-2、Smac/DIABLO、p53 和细胞色素 c1(cyc1),这些动物在 2 个月大时开始接受 40%的 CR,持续 6 个月。此外,还评估了骨骼肌 caspase-3、caspase-9、caspase-8、bax、bcl-2、Smac/DIABLO、Apaf-1、bad、磷酸化 bad(pbad)、磷酸化 p53 和细胞色素 c(cyc)蛋白的表达水平。GHRKO 骨骼肌中 caspase-3、caspase-9、bax 和 Smac/DIABLO 基因和蛋白的表达减少。该组织中 Apaf-1 蛋白的表达也减少。相反,bcl-2 和 pbad 蛋白水平在敲除动物的骨骼肌中增加。除了 cyc1 mRNA 水平升高外,在 GHRKO 心脏中未观察到所检查基因表达的变化。与正常(N)小鼠相比,CR 未改变 KO 骨骼肌中检查基因和蛋白质的表达。在心脏匀浆中,与自由进食的小鼠相比,CR 增加了 caspase-3 mRNA 水平。某些促凋亡基因和/或蛋白表达的减少可能构成 GHRKO 小鼠长寿的潜在机制,使这些动物免受衰老的影响;这种潜在的有益机制不受 CR 的影响。