Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 35, Issue 5, Pages 831-846Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.01109-14
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Funding
- National Institutes of Health (NIH) [R01HL070070, R01DK092065, U01HL70525]
- American Diabetes Association
- JDRF [10-2009-672]
- NIH [K99R00 HL111322, T32 HL007576]
- German Research Foundation (DFG)
- Spanish Ministry of Education and Science
- AHA, Western Affiliates
- Grants-in-Aid for Scientific Research [24591094] Funding Source: KAKEN
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Sustained Akt activation induces cardiac hypertrophy (LVH), which may lead to heart failure. This study tested the hypothesis that Akt activation contributes to mitochondrial dysfunction in pathological LVH. Akt activation induced LVH and progressive repression of mitochondrial fatty acid oxidation (FAO) pathways. Preventing LVH by inhibiting mTOR failed to prevent the decline in mitochondrial function, but glucose utilization was maintained. Akt activation represses expression of mitochondrial regulatory, FAO, and oxidative phosphorylation genes in vivo that correlate with the duration of Akt activation in part by reducing FOXO-mediated transcriptional activation of mitochondrion-targeted nuclear genes in concert with reduced signaling via peroxisome proliferator-activated receptor alpha (PPAR alpha)/PGC-1 alpha and other transcriptional regulators. In cultured myocytes, Akt activation disrupted mitochondrial bioenergetics, which could be partially reversed by maintaining nuclear FOXO but not by increasing PGC-1 alpha. Thus, although short-term Akt activation may be cardioprotective during ischemia by reducing mitochondrial metabolism and increasing glycolysis, long-term Akt activation in the adult heart contributes to pathological LVH in part by reducing mitochondrial oxidative capacity.
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