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Enhanced cardiac Akt/protein kinase B signaling contributes to pathological cardiac hypertrophy in part by impairing mitochondrial function via transcriptional repression of mitochondrion-targeted nuclear genes.


ABSTRACT: 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 ? (PPAR?)/PGC-1? 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?. 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.

SUBMITTER: Wende AR 

PROVIDER: S-EPMC4323486 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Enhanced cardiac Akt/protein kinase B signaling contributes to pathological cardiac hypertrophy in part by impairing mitochondrial function via transcriptional repression of mitochondrion-targeted nuclear genes.

Wende Adam R AR   O'Neill Brian T BT   Bugger Heiko H   Riehle Christian C   Tuinei Joseph J   Buchanan Jonathan J   Tsushima Kensuke K   Wang Li L   Caro Pilar P   Guo Aili A   Sloan Crystal C   Kim Bum Jun BJ   Wang Xiaohui X   Pereira Renata O RO   McCrory Mark A MA   Nye Brenna G BG   Benavides Gloria A GA   Darley-Usmar Victor M VM   Shioi Tetsuo T   Weimer Bart C BC   Abel E Dale ED  

Molecular and cellular biology 20141222 5


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  ...[more]

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