Inhibition of autophagy in the heart induces age-related cardiomyopathy
Inhibition of autophagy in the heart induces age-related cardiomyopathy
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DOI：
10.4161/auto.6.5.11947
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发表时间：
2010-07-01
期刊：
影响因子：
13.3
通讯作者：
Otsu, Kinya
中科院分区：
文献类型：
--
作者：
Taneike, Manabu;Yamaguchi, Osamu;Otsu, Kinya
构成性自噬对于控制蛋白质和细胞器的质量以维持细胞功能具有重要意义。受损的蛋白质和细胞器在衰老的器官中积累。我们之前报道过心脏特异性基因Atg5（自噬相关基因）缺陷的小鼠，在胚胎发生早期将该基因剔除，正常出生，并显示出正常的心脏功能和结构，直到10周大。在本研究中，为了确定心脏中atg5缺乏症的长期后果，我们对心脏特异性atg5缺乏症小鼠进行了额外12个月的监测。首先，我们检查了野生型小鼠心脏中自噬的年龄相关变化。从LC3-II（微管相关蛋白1轻链3-II）水平的降低来看，6、14或26月龄小鼠的心脏自噬水平低于10周龄小鼠。接下来，我们研究了心脏特异性atg5缺陷小鼠的心功能和寿命。缺乏atg5的小鼠在6个月后开始死亡。与对照组小鼠相比，atg5缺陷小鼠在10月龄时左心室尺寸显著增加，左心室缩短率显著降低，而在3月龄时表现出相似的腔室大小和收缩功能。超微结构分析显示，3月龄和10月龄atg5缺陷小鼠肌节结构紊乱，线粒体塌陷，线粒体呼吸功能下降。这些结果表明，持续本构性自噬在维持心脏结构和功能中起着至关重要的作用。
Constitutive autophagy is important for control of the quality of proteins and organelles to maintain cell function. Damaged proteins and organelles accumulate in aged organs. We have previously reported that cardiac-specific gene Atg5 (autophagy-related 5)-deficient mice, in which the gene was floxed out early in embryogenesis, were born normally, and showed normal cardiac function and structure up to 10 weeks old. In the present study, to determine the longer-term consequences of Atg5-deficiency in the heart, we monitored cardiac-specific Atg5-deficient mice for an additional 12 months. First, we examined the age-associated changes of autophagy in the wild-type mouse heart. The level of autophagy, as indicated by decreased LC3-II (microtubule-associated protein 1 light chain 3-II) levels, in the hearts of 6-, 14- or 26-month-old mice was lower than that of 10-week-old mice. Next, we investigated the cardiac function and life span in cardiac-specific Atg5-deficient mice. The Atg5-deficient mice began to die after the age of six months. Atg5-deficient mice exhibited a significant increase in left ventricular dimension and decrease in fractional shortening of the left ventricle at the age of 10 months, compared to control mice, while they showed similar chamber size and contractile function at the age of three months. Ultrastructural analysis revealed a disorganized sarcomere structure and collapsed mitochondria in 3- and 10-month-old Atg5-deficient mice, with decreased mitochondrial respiratory functions. These results suggest that continuous constitutive autophagy plays a crucial role in maintaining cardiac structure and function.