Myocardial autophagic energy stress responses—macroautophagy, mitophagy, and glycophagy

Delbridge, L.; Mellor, Kimberley M.; Taylor, David J.; Gottlieb, Roberta A.

doi:10.1152/ajpheart.00002.2015

Cited by 62 publications

(48 citation statements)

References 114 publications

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“…However, p62 (sequestosome‐1), which accumulates when autophagy is inhibited, was significantly elevated in diabetic compared with control mice (Figure 7B). This is consistent with previous reports that autophagy is decreased in type 1 diabetic models 30, 31. In contrast, 2 established CMA targets, GAPDH and hexokinase II,33, 34 trended towards a decrease in diabetic mice.…”

Section: Resultssupporting

confidence: 92%

Cardiac Insulin Signaling Regulates Glycolysis Through Phosphofructokinase 2 Content and Activity

Humphries

Matsuzaki

Vadvalkar

et al. 2017

JAHA

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BackgroundThe healthy heart has a dynamic capacity to respond and adapt to changes in nutrient availability. Diabetes mellitus disrupts this metabolic flexibility and promotes cardiomyopathy through mechanisms that are not completely understood. Phosphofructokinase 2 (PFK‐2) is a primary regulator of cardiac glycolysis and substrate selection, yet its regulation under normal and pathological conditions is unknown. This study was undertaken to determine how changes in insulin signaling affect PFK‐2 content, activity, and cardiac metabolism.Methods and ResultsStreptozotocin‐induced diabetes mellitus, high‐fat diet feeding, and fasted mice were used to identify how decreased insulin signaling affects PFK‐2 and cardiac metabolism. Primary adult cardiomyocytes were used to define the mechanisms that regulate PFK‐2 degradation. Both type 1 diabetes mellitus and a high‐fat diet induced a significant decrease in cardiac PFK‐2 protein content without affecting its transcript levels. Overnight fasting also induced a decrease in PFK‐2, suggesting it is rapidly degraded in the absence of insulin signaling. An unbiased metabolomic study demonstrated that decreased PFK‐2 in fasted animals is accompanied by an increase in glycolytic intermediates upstream of phosphofructokianse‐1, whereas those downstream are diminished. Mechanistic studies using cardiomyocytes showed that, in the absence of insulin signaling, PFK‐2 is rapidly degraded via both proteasomal‐ and chaperone‐mediated autophagy.ConclusionsThe loss of PFK‐2 content as a result of reduced insulin signaling impairs the capacity to dynamically regulate glycolysis and elevates the levels of early glycolytic intermediates. Although this may be beneficial in the fasted state to conserve systemic glucose, it represents a pathological impairment in diabetes mellitus.

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Section: Resultssupporting

confidence: 92%

Cardiac Insulin Signaling Regulates Glycolysis Through Phosphofructokinase 2 Content and Activity

Humphries

Matsuzaki

Vadvalkar

et al. 2017

JAHA

View full text Add to dashboard Cite

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“…Hence, based on our in vitro study results, it is conceivable that high glucose activate Beclin-1, which in turn leads to increased autophagy. At the same time, Beclin-1 inactivates Bcl-2 [reviewed in [37,38]], suggesting that autophagy might play a different role in the pathogenesis of type-2 versus type-1 diabetic cardiomyopathy although future studies are warranted to confirm this hypothesis.…”

Section: Discussionmentioning

confidence: 99%

Type-2 diabetes increases autophagy in the human heart through promotion of Beclin-1 mediated pathway

Munasinghe

Riu

Dixit

et al. 2016

International Journal of Cardiology

101

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“…Whereas altered protein quality control mechanisms have been long correlated to neurological diseases, 3 only a few cardiac diseases are known to be associated with defective autophagy. These include Danon disease, 4, 5 LEOPARD syndrome, 6 Vici syndrome, 7, 8 desmin-related cardiomyopathy, 9–11 diabetic cardiomyopathy, 12 dilated cardiomyopathy (DCM) caused by lamin A/C ( LMNA ) mutations, 13, 14 and left ventricular non-compaction (LVNC) caused by pleckstrin homology domain-containing family M, member 2 (PLEKHM2 ) mutations. 15 In most of these cardiomyopathies there is a defect in a gene encoding a protein, which is involved in the ALP, either by acting directly on it or by inducing protein accumulation.…”

mentioning

confidence: 99%

Activation of Autophagy Ameliorates Cardiomyopathy in Mybpc3 -Targeted Knockin Mice

Singh

Zech

Geertz

et al. 2017

Circ: Heart Failure

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Background Alterations in autophagy have been reported in hypertrophic cardiomyopathy (HCM) caused by Danon disease, Vici syndrome or LEOPARD syndrome, but not in HCM caused by mutations in genes encoding sarcomeric proteins, which account for most of HCM cases. MYBPC3, encoding cardiac myosin-binding protein C, is the most frequently mutated HCM gene. Methods and Results We evaluated autophagy in HCM patients carrying MYBPC3 mutations and in a Mybpc3-targeted knock-in (KI) HCM mouse model, as well as the effect of autophagy modulators on the development of cardiomyopathy in KI mice. Microtubule-associated protein 1 light chain 3 (LC3)-II protein levels were higher in HCM septal myectomies than in non-failing control hearts and in 60-week-old KI than wild-type (WT) mouse hearts. In contrast to WT, autophagic flux was blunted and associated with accumulation of residual bodies and glycogen in hearts of 60-week-old KI mice. We found that Akt-mTORC1 signaling was increased, and treatment with 2.24 mg/kgxd rapamycin or 40% caloric restriction for 9 weeks partially rescued cardiomyopathy or heart failure and restored autophagic flux in KI mice. Conclusions Altogether, we found that i) autophagy is altered in HCM patients with MYBPC3 mutations, ii) autophagy is impaired in Mybpc3-targeted KI mice and iii) activation of autophagy ameliorated the cardiac disease phenotype in this mouse model. We propose that activation of autophagy might be an attractive option alone or in combination with another therapy to rescue HCM caused by MYBPC3 mutations.

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Myocardial autophagic energy stress responses—macroautophagy, mitophagy, and glycophagy

Abstract: Delbridge LM, Mellor KM, Taylor DJ, Gottlieb RA. Myocardial autophagic energy stress responses-macroautophagy, mitophagy, and glycophagy.

Cited by 62 publications

References 114 publications

Cardiac Insulin Signaling Regulates Glycolysis Through Phosphofructokinase 2 Content and Activity

Cardiac Insulin Signaling Regulates Glycolysis Through Phosphofructokinase 2 Content and Activity

Type-2 diabetes increases autophagy in the human heart through promotion of Beclin-1 mediated pathway

Activation of Autophagy Ameliorates Cardiomyopathy in Mybpc3 -Targeted Knockin Mice

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