Insulin receptor substrate signaling suppresses neonatal autophagy in the heart

Riehle, Christian; Wende, Adam R.; Sena, Sandra; Pires, Karla Maria Pereira; Pereira, Renata O.; Zhu, Yi; Bugger, Heiko; Frank, Deborah J.; Bevins, Jack; Chen, Dong; Perry, Cynthia N.; Dong, X. Charlie; Valdez, Steven; Rech, Monika; Sheng, Xiaoming; Weimer, Bart C.; Gottlieb, Roberta A.; White, Morris F.; Abel, E. Dale

doi:10.1172/jci71171

Cited by 106 publications

(101 citation statements)

References 59 publications

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“…Additionally, a mismatch between the amount of fatty acids transported inside the cell and ␤-oxidation can result in lipotoxicity and ceramide formation, resulting in increased apoptosis (32). Impaired insulin signaling may also lead to mitochondrial dysfunction (8), dysregulated calcium cycling (11,48), altered cardiomyocyte size and remodeling (6,15), and unrestrained autophagy (37).…”

Section: Discussionmentioning

confidence: 99%

Partial deletion of ROCK2 protects mice from high-fat diet-induced cardiac insulin resistance and contractile dysfunction

Soliman

Nyamandi

Garcia-Patino

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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KM. Partial deletion of ROCK2 protects mice from high-fat diet-induced cardiac insulin resistance and contractile dysfunction. Am J Physiol Heart Circ Physiol 309: H70 -H81, 2015. First published April 24, 2015 doi:10.1152/ajpheart.00664.2014.-Obesity is associated with cardiac insulin resistance and contractile dysfunction, which contribute to the development of heart failure. The RhoA-Rho kinase (ROCK) pathway has been reported to modulate insulin resistance, but whether it is implicated in obesity-induced cardiac dysfunction is not known. To test this, wild-type (WT) and ROCK2 ϩ/Ϫ mice were fed normal chow or a high-fat diet (HFD) for 17 wk. Whole body insulin resistance, determined by an insulin tolerance test, was observed in HFD-WT, but not HFD-ROCK2 ϩ/Ϫ , mice. The echocardiographically determined myocardial performance index, a measure of global systolic and diastolic function, was significantly increased in HFD-WT mice, indicating a deterioration of cardiac function. However, no change in myocardial performance index was found in hearts from HFD-ROCK2 ϩ/Ϫ mice. Speckle-tracking-based strain echocardiography also revealed regional impairment in left ventricular wall motion in hearts from HFD-WT, but not HFD-ROCK2 ϩ/Ϫ , mice. Activity of ROCK1 and ROCK2 was significantly increased in hearts from HFD-WT mice, and GLUT4 expression was significantly reduced. Insulin-induced phosphorylation of insulin receptor substrate (IRS) Tyr 612 , Akt, and AS160 was also impaired in these hearts, while Ser 307 phosphorylation of IRS was increased. In contrast, the increase in ROCK2, but not ROCK1, activity was prevented in hearts from HFD-ROCK2 ϩ/Ϫ mice, and cardiac levels of TNF␣ were reduced. This was associated with normalization of IRS phosphorylation, downstream insulin signaling, and GLUT4 expression. These data suggest that increased activation of ROCK2 contributes to obesityinduced cardiac dysfunction and insulin resistance and that inhibition of ROCK2 may constitute a novel approach to treat this condition. ROCK2; insulin signaling; heart; insulin receptor substrate phosphorylation

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Section: Discussionmentioning

confidence: 99%

Partial deletion of ROCK2 protects mice from high-fat diet-induced cardiac insulin resistance and contractile dysfunction

Soliman

Nyamandi

Garcia-Patino

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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“…The mTOR complex 1 (mTORC1) regulates autophagy via insulin-dependent and -independent mechanisms ( 26,27 ). Phosphorylation of mTOR was signifi cantly lower ( ‫ف‬ 34%) in HFD-fed hearts ( Fig.…”

Section: High Fat Feeding Increases Autophagosome Abundance In the Hementioning

confidence: 99%

Lipid-induced NOX2 activation inhibits autophagic flux by impairing lysosomal enzyme activity

Jaishy

Zhang

Chung

et al. 2015

Journal of Lipid Research

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This article is available online at http://www.jlr.org deposition of toxic lipid intermediates in the heart that may have deleterious effects ("lipotoxicity") on myocardial structure and function ( 2 ). Studies using mouse models of increased myocardial lipid availability showed that increasing lipid accumulation directly in cardiomyocytes (CMs) was suffi cient to induce lipotoxic cardiomyopathy and premature cell death independently of systemic or neurohumoral effects of obesity ( 3-5 ). However, gaps remain in our mechanistic understanding of the interactions between lipid accumulation and cardiac dysfunction and the impact of lipotoxicity on cardiac autophagy has been relatively understudied.Macroautophagy (hereafter "autophagy") is a catabolic process wherein cytoplasmic materials are delivered to lysosomes in double-membrane structures called autophagosomes for degradation ( 6 ). Autophagy regulates lipid metabolism in multiple tissues ( 7-9 ). Impaired autophagy Abstract Autophagy is a catabolic process involved in maintaining energy and organelle homeostasis. The relationship between obesity and the regulation of autophagy is cell type specifi c. Despite adverse consequences of obesity on cardiac structure and function, the contribution of altered cardiac autophagy in response to fatty acid overload is incompletely understood. Here, we report the suppression of autophagosome clearance and the activation of NADPH oxidase (Nox)2 in both high fat-fed murine hearts and palmitate-treated H9C2 cardiomyocytes (CMs). Defective autophagosome clearance is secondary to superoxidedependent impairment of lysosomal acidifi cation and enzyme activity in palmitate-treated CMs. Inhibition of Nox2 prevented superoxide overproduction, restored lysosome acidifi cation and enzyme activity, and reduced autophagosome accumulation in palmitate-treated CMs. Palmitate-induced Nox2 activation was dependent on the activation of classical protein kinase Cs (PKCs), specifi cally PKC ␤ II. These fi ndings reveal a novel mechanism linking lipotoxicity with a PKC ␤ -Nox2-mediated impairment in pH-dependent lysosomal enzyme activity that diminishes autophagic turnover in CMs. Obesity is an independent risk factor for CVD ( 1 ). A prominent factor in obesity-related cardiomyopathy is the ectopic

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“…A 1.4-F micromanometer-tipped pressure catheter (Millar Instruments, Houston, TX) was retrogradely introduced into the left ventricle via the right carotid artery. Hemodynamic measurements were obtained and analyzed as previously described using LabChart7 Pro software (ADInstruments, Colorado Springs, CO) (20,21).…”

Section: Animals Cirs1ko Mice (␣Mhc-crementioning

confidence: 99%

“…Citrate synthase (CS) and hydroxyacyl-coenzyme A (hydroxyacyl-CoA) dehydrogenase (HADH) enzyme activities were determined as previously described (21). For measurement of skeletal muscle CS activity, absorbance was monitored at 412 nm using an Ultrospec 3000 spectrophotometer (Amersham Pharmacia Biotech, NJ) with a total reaction volume of 1 ml.…”

Section: Mitochondrial Function In Saponin-permeabilized Cardiac Fibersmentioning

confidence: 99%

Insulin Receptor Substrates Are Essential for the Bioenergetic and Hypertrophic Response of the Heart to Exercise Training

Riehle

Wende

Zhu

et al. 2014

Molecular and Cellular Biology

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Insulin and insulin-like growth factor 1 (IGF-1) receptor signaling pathways differentially modulate cardiac growth under resting conditions and following exercise training. These effects are mediated by insulin receptor substrate 1 (IRS1) and IRS2, which also differentially regulate resting cardiac mass. To determine the role of IRS isoforms in mediating the hypertrophic and metabolic adaptations of the heart to exercise training, we subjected mice with cardiomyocyte-specific deletion of either IRS1 (CIRS1 knockout [CIRS1KO] mice) or IRS2 (CIRS2KO mice) to swim training. CIRS1KO hearts were reduced in size under basal conditions, whereas CIRS2KO hearts exhibited hypertrophy. Following exercise swim training in CIRS1KO and CIRS2KO hearts, the hypertrophic response was equivalently attenuated, phosphoinositol 3-kinase (PI3K) activation was blunted, and prohypertrophic signaling intermediates, such as Akt and glycogen synthase kinase 3␤ (GSK3␤), were dephosphorylated potentially on the basis of reduced Janus kinase-mediated inhibition of protein phosphatase 2a (PP2A). Exercise training increased peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1␣) protein content, mitochondrial capacity, fatty acid oxidation, and glycogen synthesis in wild-type (WT) controls but not in IRS1-and IRS2-deficient hearts. PGC-1␣ protein content remained unchanged in CIRS1KO but decreased in CIRS2KO hearts. These results indicate that although IRS isoforms play divergent roles in the developmental regulation of cardiac size, these isoforms exhibit nonredundant roles in mediating the hypertrophic and metabolic response of the heart to exercise. C ardiac hypertrophy is the growth response of the heart to increased workload and has been categorized as physiological or pathological hypertrophy. Cardiac hypertrophy is considered pathological if contractile dysfunction occurs after an initial phase of compensation, which ultimately results in heart failure. Common causes for pathological hypertrophy are valvular disease and hypertension. In contrast, physiological hypertrophy is characterized by adaptive myocyte growth with a new steady state and preserved contractile function, as exemplified by the response to chronic exercise training, also known as "athlete's heart" (1). The differences between physiological and pathological cardiac hypertrophy have been attributed in part to differences in intracellular signaling pathways. For example, insulin receptor-and insulinlike growth factor 1 (IGF-1) receptor-mediated signaling to phosphatidylinositol 3-kinase (PI3K) and Akt1 have been implicated in physiological cardiac hypertrophy, whereas activation of G protein-coupled pathways, such as angiotensin II and adrenergic signaling, has been associated with pathological hypertrophy (2, 3).We previously reported that cardiomyocyte-selective deletion of the insulin receptor (CIRKO) reduced heart size by 20 to 30% (4), whereas under basal conditions IGF-1 receptor deletion was without effect (5). CIRKO hearts exhibit increased ...

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Insulin receptor substrate signaling suppresses neonatal autophagy in the heart

Cited by 106 publications

References 59 publications

Partial deletion of ROCK2 protects mice from high-fat diet-induced cardiac insulin resistance and contractile dysfunction

Partial deletion of ROCK2 protects mice from high-fat diet-induced cardiac insulin resistance and contractile dysfunction

Lipid-induced NOX2 activation inhibits autophagic flux by impairing lysosomal enzyme activity

Insulin Receptor Substrates Are Essential for the Bioenergetic and Hypertrophic Response of the Heart to Exercise Training

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