Abstract 18841: Despite Impaired Autophagic Flux Cardiac and Mitochondrial Functions are Preserved in Aged Mice Lacking Insulin Receptors in the Whole Heart
Introduction: Ageing-dependent cardiovascular diseases have been associated with decreases turnover of long-lived molecules and cellular organelles, known as autophagy. Insulin signaling plays an important role in both cell survival and development. However, the effects of insulin signaling on mammalian aging have been little investigated.
Hypothesis: The insulin receptor is pivotal for preserving cardiac function in aging by up-regulating autophagy.
Methods: In order to address this, male mice lacking insulin receptors in the whole heart (TIRKO) and their aged-matched wild-type (WT) mice were studied at 12 weeks (young-Y) and 60 weeks (mildly old-MO) of age.
Results: Despite signs of perivascular fibrosis, MO-TIRKO mice showed a 20% decrease in cardiomyocyte hypertrophy and preserved cardiac and mitochondrial function (maintained cardiac output and increased ATP/O ratios) as compares to age-matched WT. To investigate if autophagy plays a role in this matter, we measured the autophagy in heart homogenates (LC3II/I expression ratio). Interestingly, LC3II/I ratio was 50% decreased in both Y and MO-TIRKO mice, whereas MO-WT mice showed a 50% increase in this ratio. These differences were represented by a 2 fold increase LC3I levels in Y and MO-TIRKO mice, whereas LC3II levels were unchanged. This data was supported by a 50% reduction in ATG3 expression. As expected, P62 levels were also increased in TIRKO mice regardless of age. To further study autophagy flux, we generated LC3-mcherry TIRKO mice. Following either 6, 12, 24 and 48 hours of fasting, 12 weeks-old LC3 mcherry-TIRKO mice showed 40% less LC3-mcherry puncta/cell, while WT mice showed a linear increase of puncta numbers with fasting.
Conclusion: Taken together, these results suggest that TIRKO mice are indeed protected against age-induced cardiac and mitochondrial dysfunction, despite lower autophagic flux.
Author Disclosures: K.P. Pires: Research Grant; Modest; Assessoria de Cooperacao Internacional Coordenacao de Cooperacao Bilateral Programa CSF-Programa Ciência sem Fronteiras (COCBI). C. Black: None. B. Henrie: None. S. Pei: None. S. Boudina: Research Grant; Modest; PMCID: PMC3883087, NIHMSID: NIHMS527962.
- © 2014 by American Heart Association, Inc.