The Role of Sex Differences in Autophagy in the Heart During Coxsackievirus B3-Induced Myocarditis

Koenig, Andreas; Sateriale, Adam; Budd, Ralph C.; Huber, Sally A.; Buskiewicz, Iwona

doi:10.1007/s12265-013-9525-5

Cited by 29 publications

(18 citation statements)

References 99 publications

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“…), although the nature of the sex effect can differ depending upon cell type, tissue and organism (Koenig et al . ). At the cardiac level, the existence of sex differences in autophagy‐related gene expression was proposed and it was demonstrated that glycogen autophagy is more sensitive to metabolic stress in the hearts of female mice (Reichelt et al .…”

Section: Discussionmentioning

confidence: 97%

Endolysosomal two‐pore channels regulate autophagy in cardiomyocytes

García-Rúa

Feijóo‐Bandín

Rodríguez-Penas

et al. 2016

The Journal of Physiology

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Key pointsr Two-pore channels (TPCs) were identified as a novel family of endolysosome-targeted calcium release channels gated by nicotinic acid adenine dinucleotide phosphate, as also as intracellular Na + channels able to control endolysosomal fusion, a key process in autophagic flux.r Autophagy, an evolutionarily ancient response to cellular stress, has been implicated in the pathogenesis of a wide range of cardiovascular pathologies, including heart failure.r We report direct evidence indicating that TPCs are involved in regulating autophagy in cardiomyocytes, and that TPC knockout mice show alterations in the cardiac lysosomal system. TPC downregulation implies a decrease in the viability of cardiomyocytes under starvation conditions. In cardiac tissues from both humans and rats, TPC transcripts and protein levels were higher in females than in males, and correlated negatively with markers of autophagy.r We conclude that the endolysosomal channels TPC1 and TPC2 are essential for appropriate basal and induced autophagic flux in cardiomyocytes, and also that they are differentially expressed in male and female hearts.Abstract Autophagy participates in physiological and pathological remodelling of the heart. The endolysosomal two-pore channels (TPCs), TPC1 and TPC2, have been implicated in the regulation of autophagy. The present study aimed to investigate the role of TPC1 and TPC2 in basal and induced cardiac autophagic activity. In cultured cardiomyocytes, starvation induced a significant increase in TPC1 and TPC2 transcripts and protein levels that paralleled the increase in autophagy identified by increased LC3-II and decreased p62 levels. Small interfering RNA depletion of TPC2 alone or together with TPC1 increased both LC3II and p62 levels under basal conditions and in response to serum starvation, suggesting that, under conditions of severe energy depletion (serum plus glucose starvation), changes in the autophagic flux (as assessed by use of bafilomycin A1) occurred either when TPC1 or TPC2 were downregulated. The knockdown of TPCs diminished cardiomyocyte viability under starvation and simulated ischaemia. Electron micrographs of hearts from TPC1/2 double knockout mice showed that cardiomyocytes contained large numbers of immature lysosomes with diameters significantly smaller than those of wild-type mice. In cardiac tissues from humans and rats, TPC1 and TPC2 transcripts and protein levels were higher in females than in males. Furthermore, transcript levels of TPCs correlated negatively with p62 levels in heart tissues. TPC1 and TPC2 are essential for appropriate basal and induced autophagic flux in cardiomyocytes (i.e. there is a negative effect on cell viability under stress conditions in their absence) and they are differentially expressed in male and female human and murine hearts, where they correlate with markers of autophagy.

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Section: Discussionmentioning

confidence: 97%

Endolysosomal two‐pore channels regulate autophagy in cardiomyocytes

García-Rúa

Feijóo‐Bandín

Rodríguez-Penas

et al. 2016

The Journal of Physiology

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“…83 Sex-dependent differences in autophagic responses have been shown before. [84][85][86][87] In a mouse model of cancer-induced cardiac atrophy, Cosper et al 84 found that males have a more severe phenotype than females, including greater cardiac autophagy. Sexual dimorphism was also found in neuronal response to nutrient deprivation with neurons from males but not females undergoing autophagy.…”

Section: Malesmentioning

confidence: 99%

Sexual dimorphism in activation of placental autophagy in obese women with evidence for fetal programming from a placenta-specific mouse model

et al. 2016

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(2016) Sexual dimorphism in activation of placental autophagy in obese women with evidence for fetal programming from a placenta-specific mouse model, Autophagy, 12:5, 752-769, DOI: 10.1080/15548627.2016 ABSTRACTThe incidence of maternal obesity and its co-morbidities (diabetes, cardiovascular disease) continues to increase at an alarming rate, with major public health implications. In utero exposure to maternal obesity has been associated with development of cardiovascular and metabolic diseases in the offspring as a result of developmental programming. The placenta regulates maternal-fetal metabolism and shows significant changes in its function with maternal obesity. Autophagy is a cell-survival process, which is responsible for the degradation of damaged organelles and misfolded proteins. Here we show an activation of autophagosomal formation and autophagosome-lysosome fusion in placentas of males but not females from overweight (OW) and obese (OB) women vs. normal weight (NW) women. However, total autophagic activity in these placentas appeared to be decreased as it showed an increase in SQSTM1/p62 and a decrease in lysosomal biogenesis. A mouse model with a targeted deletion of the essential autophagy gene Atg7 in placental tissue showed significant placental abnormalities comparable to those seen in human placenta with maternal obesity. These included a decrease in expression of mitochondrial genes and antioxidants, and decreased lysosomal biogenesis. Strikingly, the knockout mice were developmentally programmed as they showed an increased sensitivity to high-fat diet-induced obesity, hyperglycemia, hyperinsulinemia, increased adiposity, and cardiac remodeling. In summary, our results indicate a sexual dimorphism in placental autophagy in response to maternal obesity. We also show that autophagy plays an important role in placental function and that inhibition of placental autophagy programs the offspring to obesity, and to metabolic and cardiovascular diseases.

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“…In humans, women show less apoptosis and less maladaptive remodeling relative to men in response to acute coronary ischemia [206]. Under normal conditions men’s hearts have increased expression of CARBONIC ANHYDRASE 3 , a gene associated with hypertrophy and heart failure, and decreased expression of APOJ/CLUSTERIN , an autophagy regulator thought to be protective upon inflammatory injury [207]. Studies of human cells and rodent models indicate that estrogen is generally protective but may not be responsible for all the sex differences in heart stress responses.…”

Section: Sex-specific Autophagy and Apoptosis In Mammalian Cells And mentioning

confidence: 99%

Mitochondrial maintenance failure in aging and role of sexual dimorphism

Tower¹

2015

Archives of Biochemistry and Biophysics

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Gene expression changes during aging are partly conserved across species, and suggest that oxidative stress, inflammation and proteotoxicity result from mitochondrial malfunction and abnormal mitochondrial-nuclear signaling. Mitochondrial maintenance failure may result from trade-offs between mitochondrial turnover versus growth and reproduction, sexual antagonistic pleiotropy and genetic conflicts resulting from uni-parental mitochondrial transmission, as well as mitochondrial and nuclear mutations and loss of epigenetic regulation. Aging phenotypes and interventions are often sex-specific, indicating that both male and female sexual differentiation promote mitochondrial failure and aging. Studies in mammals and invertebrates implicate autophagy, apoptosis, AKT, PARP, p53 and FOXO in mediating sex-specific differences in stress resistance and aging. The data support a model where the genes Sxl in Drosophila, sdc-2 in C. elegans, and Xist in mammals regulate mitochondrial maintenance across generations and in aging. Several interventions that increase life span cause a mitochondrial unfolded protein response (UPRmt), and UPRmt is also observed during normal aging, indicating hormesis. The UPRmt may increase life span by stimulating mitochondrial turnover through autophagy, and/or by inhibiting the production of hormones and toxic metabolites. The data suggest that metazoan life span interventions may act through a common hormesis mechanism involving liver UPRmt, mitochondrial maintenance and sexual differentiation.

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The Role of Sex Differences in Autophagy in the Heart During Coxsackievirus B3-Induced Myocarditis

Cited by 29 publications

References 99 publications

Endolysosomal two‐pore channels regulate autophagy in cardiomyocytes

Endolysosomal two‐pore channels regulate autophagy in cardiomyocytes

Sexual dimorphism in activation of placental autophagy in obese women with evidence for fetal programming from a placenta-specific mouse model

Mitochondrial maintenance failure in aging and role of sexual dimorphism

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