Inhibition of autophagy in the heart induces age-related cardiomyopathy.
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 Atg5 (autophagy-related gene 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 further 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 6 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 3 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 has a crucial role in maintaining cardiac structure and function.
Taneike
Manabu
M
Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka Japan.
Yamaguchi
Osamu
O
Nakai
Atsuko
A
Hikoso
Shungo
S
Takeda
Toshihiro
T
Mizote
Isamu
I
Oka
Takafumi
T
Tamai
Takahito
T
Oyabu
Jota
J
Murakawa
Tomokazu
T
Nishida
Kazuhiko
K
Shimizu
Takahiko
T
Hori
Masatsugu
M
Komuro
Issei
I
Takuji Shirasawa
Takuji Shirasawa
TS
Mizushima
Noboru
N
Otsu
Kinya
K
D000375:Aging / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D001343:Autophagy; D000071187:Autophagy-Related Protein 5; D009202:Cardiomyopathies / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism / Q000648:ultrastructure; D009206:Myocardium / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D009928:Organ Specificity; D014463:Ultrasonography
C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D008869:Microtubule-Associated Proteins