Inhibition of autophagy in the heart induces age-related cardiomyopathy

Manabu Taneike, Osamu Yamaguchi, Atsuko Nakai, Shungo Hikoso, Toshihiro Takeda, Isamu Mizote, Takafumi Oka, Takahito Tamai, Jota Oyabu, Tomokazu Murakawa, Kazuhiko Nishida, Takahiko Shimizu, Masatsugu Hori, Issei Komuro, Takuji Shirasawa, Noboru Mizushima, Kinya Otsu

Research output: Contribution to journalArticlepeer-review

368 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)600-606
Number of pages7
Issue number5
Publication statusPublished - 1 Jul 2010


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