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

Adam R. Wende, Brian T. O'Neill, Heiko Bugger, Christian Riehle, Joseph Tuinei, Jonathan Buchanan, Kensuke Tsushima, Li Wang, Pilar Caro, Guo Aili, Crystal Sloan, Bum Jun Kim, Xiaohui Wang, Renata O. Pereira, Mark A. McCrory, Brenna G. Nye, Gloria A. Benavides, Victor M. Darley-Usmar, Tetsuo Shioi, Bart C WeimerE. Dale Abela

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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 α (PPARα)/PGC-1α 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-1α. 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.

Original languageEnglish (US)
Pages (from-to)831-846
Number of pages16
JournalMolecular and Cellular Biology
Volume35
Issue number5
DOIs
StatePublished - 2015

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Proto-Oncogene Proteins c-akt
Cardiomegaly
Mitochondria
Fatty Acids
Peroxisome Proliferator-Activated Receptors
Oxidative Phosphorylation
Glycolysis
Muscle Cells
Energy Metabolism
Transcriptional Activation
Genes
Ischemia
Heart Failure
Glucose

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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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.; O'Neill, Brian T.; Bugger, Heiko; Riehle, Christian; Tuinei, Joseph; Buchanan, Jonathan; Tsushima, Kensuke; Wang, Li; Caro, Pilar; Aili, Guo; Sloan, Crystal; Kim, Bum Jun; Wang, Xiaohui; Pereira, Renata O.; McCrory, Mark A.; Nye, Brenna G.; Benavides, Gloria A.; Darley-Usmar, Victor M.; Shioi, Tetsuo; Weimer, Bart C; Abela, E. Dale.

In: Molecular and Cellular Biology, Vol. 35, No. 5, 2015, p. 831-846.

Research output: Contribution to journalArticle

Wende, AR, O'Neill, BT, Bugger, H, Riehle, C, Tuinei, J, Buchanan, J, Tsushima, K, Wang, L, Caro, P, Aili, G, Sloan, C, Kim, BJ, Wang, X, Pereira, RO, McCrory, MA, Nye, BG, Benavides, GA, Darley-Usmar, VM, Shioi, T, Weimer, BC & Abela, ED 2015, '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', Molecular and Cellular Biology, vol. 35, no. 5, pp. 831-846. https://doi.org/10.1128/MCB.01109-14
Wende, Adam R. ; O'Neill, Brian T. ; Bugger, Heiko ; Riehle, Christian ; Tuinei, Joseph ; Buchanan, Jonathan ; Tsushima, Kensuke ; Wang, Li ; Caro, Pilar ; Aili, Guo ; Sloan, Crystal ; Kim, Bum Jun ; Wang, Xiaohui ; Pereira, Renata O. ; McCrory, Mark A. ; Nye, Brenna G. ; Benavides, Gloria A. ; Darley-Usmar, Victor M. ; Shioi, Tetsuo ; Weimer, Bart C ; Abela, E. Dale. / 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. In: Molecular and Cellular Biology. 2015 ; Vol. 35, No. 5. pp. 831-846.
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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 α (PPARα)/PGC-1α 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-1α. 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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AU - Riehle, Christian

AU - Tuinei, Joseph

AU - Buchanan, Jonathan

AU - Tsushima, Kensuke

AU - Wang, Li

AU - Caro, Pilar

AU - Aili, Guo

AU - Sloan, Crystal

AU - Kim, Bum Jun

AU - Wang, Xiaohui

AU - Pereira, Renata O.

AU - McCrory, Mark A.

AU - Nye, Brenna G.

AU - Benavides, Gloria A.

AU - Darley-Usmar, Victor M.

AU - Shioi, Tetsuo

AU - Weimer, Bart C

AU - Abela, E. Dale

PY - 2015

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