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Metformin inhibits autophagy and mitophagy in cardiomyocytes
Author(s) -
Chang Michael,
Pinkhasova Polina,
Kobayashi Tamayo,
Patel Rahul,
Cohen Max,
Mehta Puja,
Zhang Yawen,
Kobayashi Satoru,
Liang Qiangrong
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.519.5
Subject(s) - mitophagy , autophagy , metformin , cardioprotection , mitochondrion , microbiology and biotechnology , pharmacology , in vivo , diabetic cardiomyopathy , chemistry , biology , endocrinology , medicine , diabetes mellitus , cardiomyopathy , apoptosis , biochemistry , heart failure , myocardial infarction
Metformin, a first‐line medication for the treatment of type 2 diabetes mellitus, has been suggested by several clinical studies to be cardioprotective. However, the mechanisms underlying metformin's cardioprotection remain debated. One current hypothesis proposes that metformin protects the heart by increasing autophagy in cardiomyocytes, leading to increased removal of protein aggregates and damaged organelles including mitochondria. In this study, we tested this hypothesis using both in vitro and in vivo models. Rat H9C2 cardiac myoblasts were treated with 3 mM metformin for 24 hours and autophagy/mitophagy were determined by Western blot analysis of LC3‐II, a well‐established marker of autophagic vesicles. Surprisingly, metformin significantly reduced LC3‐II levels in either total cell lysates or mitochondrial fractions; and lysosomal inhibitors increased LC3‐II in metformin‐treated cells to a less degree as compared with vehicle‐treated cells. These results suggest that metformin inhibited rather than stimulated autophagy and mitophagy, contrary to the current belief. This was confirmed by a novel dual fluorescent mitophagy reporter showing reduced mitochondrial fragments being degraded in the lysosomes in the presence of metformin. The reduced mitophagy was also found in the heart from the mitophagy reporter mice that received 200 mg/kg of metformin through gavage. Collectively, these results indicate that the cardioprotective benefit of metformin observed in many different models may be through mechanisms other than increased autophagy and mitophagy. Support or Funding Information This work was supported by the National Institutes of Health National Center for Research Resources. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .