Functional significance and morphological characterization of starvation-induced autophagy in the adult heart.

Abstract

To examine the functional significance and morphological characteristics of starvation-induced autophagy in the adult heart, we made green fluorescent protein-microtubule-associated protein 1-light chain 3 (LC3) transgenic mice starve for up to 3 days. Electron microscopy revealed round, homogenous, electron-dense lipid droplet-like vacuoles that initially appeared in cardiomyocytes as early as 12 hours after starvation; these vacuoles were identified as lysosomes based on cathepsin D-immunopositive reactivity and acid phosphatase activity. The increase in the number of lysosomes depended on the starvation interval; typical autophagolysosomes with intracellular organelles also appeared, and their numbers increased at the later phases of starvation. Myocardial expression of autophagy-related proteins, LC3-II, cathepsin D, and ubiquitin, increased, whereas both myocardial ATP content and starvation integral decreased. Treatment with bafilomycin A1, an autophagy inhibitor, did not affect cardiac function in normally fed mice but significantly depressed cardiac function and caused significant left ventricular dilatation in mice starved for 3 days. The cardiomyocytes were occupied with markedly accumulated lysosomes in starved mice treated with bafilomycin A1, and both the myocardial amino acid content, which was increased during starvation, and the myocardial ATP content were severely decreased, potentially contributing to cardiac dysfunction. The present findings suggest a critical role of autophagy in the maintenance of cardiac function during starvation in the adult.

• Authors: Hiromitsu Kanamori, Genzou Takemura, Rumi Maruyama, Kazuko Goto, Akiko Tsujimoto, Atsushi Ogino, Longhu Li, Itta Kawamura, Toshiaki Takeyama, Tomonori Kawaguchi, Kenshi Nagashima, Takako Fujiwara, Hisayoshi Fujiwara, Mitsuru Seishima, Shinya Minatoguchi
• Journal: The American journal of pathology (Am J Pathol) Vol. 174 Issue 5 Pg. 1705-14 (May 2009) ISSN: 1525-2191 [Electronic] United States
• PMID: 19342365 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• LC3 protein, rat
• Macrolides
• Microtubule-Associated Proteins
• Ubiquitin
• enhanced green fluorescent protein
• Green Fluorescent Proteins
• bafilomycin A1
• Adenosine Triphosphate
• Cathepsin D
• Proton-Translocating ATPases

Topics

• Adenosine Triphosphate (metabolism)
• Animals
• Apoptosis (drug effects, physiology)
• Autophagy
• Body Weight (drug effects)
• Cathepsin D (metabolism)
• Enzyme Inhibitors (pharmacology)
• Fluorescent Antibody Technique
• Green Fluorescent Proteins (genetics)
• Heart Function Tests
• Immunoenzyme Techniques
• Lysosomes (metabolism, ultrastructure)
• Macrolides (pharmacology)
• Mice
• Mice, Transgenic
• Microtubule-Associated Proteins (physiology)
• Myocytes, Cardiac (cytology, metabolism, ultrastructure)
• Proton-Translocating ATPases (antagonists & inhibitors)
• Rats
• Ubiquitin (metabolism)
• Vacuoles (metabolism, ultrastructure)
• Ventricular Dysfunction, Left (metabolism)