School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada.
PLoS One. 2010 Feb 24;5(2):e9386. doi: 10.1371/journal.pone.0009386.
Caloric restriction (CR) extends lifespan through a reduction in oxidative stress, delays the onset of morbidity and prolongs lifespan. We previously reported that long-term CR hastened clinical onset, disease progression and shortened lifespan, while transiently improving motor performance in G93A mice, a model of amyotrophic lateral sclerosis (ALS) that shows increased free radical production. To investigate the long-term CR-induced pathology in G93A mice, we assessed the mitochondrial bioenergetic efficiency and oxidative capacity (CS--citrate synthase content and activity, cytochrome c oxidase--COX activity and protein content of COX subunit-I and IV and UCP3-uncoupling protein 3), oxidative damage (MDA--malondialdehyde and PC--protein carbonyls), antioxidant enzyme capacity (Mn-SOD, Cu/Zn-SOD and catalase), inflammation (TNF-alpha), stress response (Hsp70) and markers of apoptosis (Bax, Bcl-2, caspase 9, cleaved caspase 9) in their skeletal muscle. At age 40 days, G93A mice were divided into two groups: Ad libitum (AL; n = 14; 7 females) or CR (n = 13; 6 females), with a diet equal to 60% of AL. COX/CS enzyme activity was lower in CR vs. AL male quadriceps (35%), despite a 2.3-fold higher COX-IV/CS protein content. UCP3 was higher in CR vs. AL females only. MnSOD and Cu/Zn-SOD were higher in CR vs. AL mice and CR vs. AL females. MDA was higher (83%) in CR vs. AL red gastrocnemius. Conversely, PC was lower in CR vs. AL red (62%) and white (30%) gastrocnemius. TNF-alpha was higher (52%) in CR vs. AL mice and Hsp70 was lower (62%) in CR vs. AL quadriceps. Bax was higher in CR vs. AL mice (41%) and CR vs. AL females (52%). Catalase, Bcl-2 and caspases did not differ. We conclude that CR increases lipid peroxidation, inflammation and apoptosis, while decreasing mitochondrial bioenergetic efficiency, protein oxidation and stress response in G93A mice.
热量限制（CR）通过降低氧化应激来延长寿命，延迟发病并延长寿命。我们之前报道过，长期 CR 加速了临床发病、疾病进展并缩短了寿命，而在 G93A 小鼠中短暂改善了运动表现，G93A 小鼠是一种肌萎缩侧索硬化症（ALS）模型，其自由基产生增加。为了研究长期 CR 在 G93A 小鼠中引起的病理学变化，我们评估了线粒体生物能效率和氧化能力（CS-柠檬酸合酶含量和活性、细胞色素 c 氧化酶-COX 活性以及 COX 亚基-I 和-IV 和 UCP3-解偶联蛋白 3 的蛋白含量）、氧化损伤（MDA-丙二醛和 PC-蛋白羰基）、抗氧化酶能力（Mn-SOD、Cu/Zn-SOD 和过氧化氢酶）、炎症（TNF-α）、应激反应（Hsp70）和凋亡标志物（Bax、Bcl-2、caspase 9、裂解 caspase 9）在其骨骼肌中。在 40 天时，将 G93A 小鼠分为两组：自由进食（AL；n = 14；7 只雌性）或 CR（n = 13；6 只雌性），饮食量相当于 AL 的 60%。尽管 COX-IV/CS 蛋白含量高 2.3 倍，但 CR 男性股四头肌中的 COX/CS 酶活性仍低于 AL（35%）。仅在 CR 雌性中 UCP3 高于 AL。MnSOD 和 Cu/Zn-SOD 在 CR 中高于 AL 小鼠和 CR 中高于 AL 雌性。CR 中的 MDA 高于 AL 红色比目鱼肌（83%）。相反，CR 中的 PC 低于 AL 红色（62%）和白色（30%）比目鱼肌。CR 中的 TNF-α高于 AL 小鼠（52%），CR 中的 Hsp70低于 AL 股四头肌（62%）。CR 中的 Bax 高于 AL 小鼠（41%）和 CR 中的 AL 雌性（52%）。过氧化氢酶、Bcl-2 和半胱天冬酶没有差异。我们的结论是，CR 增加了脂质过氧化、炎症和细胞凋亡，同时降低了 G93A 小鼠的线粒体生物能效率、蛋白质氧化和应激反应。
