Biology subjects

Stoner, M. W.

Publications and source records attributed to Stoner, M. W..

10 recordsLinked to original sources

bioRxiv2025

Essential Role for Trf2 in Cardiac Development and Function

Telomere Repeat-binding Factor 2 (Trf2) is essential for protecting our telomeres. While Trf2 global deletion is lethal, its role in organ-specific development, particularly in the heart, remains less understood. In this study, we investigated the role of Trf2 in cardiac development and function. Our studies reveal that cardiomyocyte (CM)-specific loss of Trf2 leads to profound defects in heart morphology, including impaired ventricular wall formation and compromised CM proliferation, concurrent with no CM telomere length attrition. Further, in vivo functional assessment and molecular analyses of CM-Trf2 deficient ventricles revealed severe cardiac dysfunction and, interestingly, altered nuclear envelope gene expression, respectively. Our work provides new insights into the essential role of Trf2 in heart development and function, and potential avenues for therapeutic intervention targeting telomere biology.

developmental biology↗

bioRxiv2025

Adropin protects against cardiac metabolic remodeling and dysfunction in HFpEF

Cardiometabolic heart failure with preserved ejection fraction (HFpEF) is a heterogenous metabolic disease, which in the heart presents as left ventricle diastolic dysfunction, ventricular stiffness, and myocardial structural remodeling. Deleterious changes in cardiac metabolism are central to HFpEF pathophysiology, and proposed treatments for the disease have focused on repairing these defects. In this study, we used a preclinical mouse model that recapitulates cardiometabolic HFpEF to elucidate the molecular mechanisms driving cardiac dysfunction, and tested whether recombinant Adropin (a liver- and brain-derived endogenous peptide hormone) could reverse observed defects. We show that long-term treatment with Adropin reversed multiple markers of HFpEF-related cardiac dysfunction (including fibrosis, diastolic dysfunction, and cardiomyocyte hypertrophy). Using untargeted metabolomics, we found that Adropin treatment reduced hexosamine biosynthesis pathway activity, leading to a reduction in the O-GlcNAcylation of the cardiac fatty acid oxidation enzyme long chain acyl-CoA dehydrogenase (LCAD). Reducing LCAD O-GlcNAcylation increased LCAD activity in vitro, and reduced the accumulation of long-chain acylcarnitines in HFpEF mouse hearts in vivo. Our results suggest that Adropin may restore cardiac metabolic function in HFpEF, and that targeting this pathway may be a novel therapeutic avenue for this disease. CLINICAL PERSPECTIVE- Adropin is a circulating liver- and brain-derived peptide that regulates energy metabolism in the heart and other high metabolic-demand tissues. The plasma abundance of Adropin is decreased in diabetic, hypertensive, and aged individuals; all comorbid risk factors for the development of heart failure with preserved ejection (HFpEF). We therefore examined the potential role of Adropin in HFpEF pathophysiology. - Patients with HFpEF display significant reductions in circulating Adropin levels, matching those seen in comorbid diseases. In a mouse model of HFpEF, treatment with recombinant Adropin reduced diastolic dysfunction, cardiac fibrosis, and cardiomyocyte hypertrophy. - These data suggest that targeting the Adropin pathway may represent a new therapeutic approach in HFpEF.

physiology↗

bioRxiv2025

Cardiac-specific deletion of GCN5L1 promotes fatty liver disease in HFpEF

The prevalence of cardiometabolic heart failure with preserved ejection fraction (HFpEF) continues to grow, representing over half of heart failure cases in the United States. As no specific medication for HFpEF exists, treatment guidelines focus on the management of comorbidities related to metabolic syndrome (e.g. obesity, diabetes, hypertension) that promote the disease1. These same comorbidities also drive pathology in non-cardiac tissues, and the links between cardiometabolic disease presentations in different organs are increasingly being recognized. Preclinical studies on the potential crosstalk between HFpEF and metabolic disease in the liver (e.g. metabolic dysfunction-associated liver disease; MASLD) have focused on how liver dysfunction may affect the heart, particularly through the release of secreted liver proteins. This may reflect the situation in the clinic, where incident MASLD is a risk factor for future HFpEF development. Here, in contrast to this developing paradigm of liver-initiated cardiac disease, we report for the first time a defect in cardiac metabolism related to the mitochondrial metabolic protein GCN5L1 that drives hepatic steatosis and MASLD in HFpEF.

physiology↗

bioRxiv2023

GCN5L1-mediated acetylation prevents Rictor degradation in cardiac cells after hypoxic stress

Cardiomyocyte apoptosis and cardiac fibrosis are the leading causes of mortality in patients with ischemic heart disease. As such, these processes represent potential therapeutic targets to treat heart failure resulting from ischemic insult. We previously demonstrated that the mitochondrial acetyltransferase protein GCN5L1 regulates cardiomyocyte cytoprotective signaling in ischemia- reperfusion injury in vivo and hypoxia-reoxygenation injury in vitro. The current study investigated the mechanism underlying GCN5L1-mediated regulation of the Akt/mTORC2 cardioprotective signaling pathway. Rictor protein levels in cardiac tissues from human ischemic heart disease patients were significantly decreased relative to non-ischemic controls. Rictor protein levels were similarly decreased in cardiac AC16 cells following hypoxic stress, while mRNA levels remained unchanged. The reduction in Rictor protein levels after hypoxia was enhanced by the knockdown of GCN5L1, and was blocked by GCN5L1 overexpression. These findings correlated with changes in Rictor lysine acetylation, which were mediated by GCN5L1 acetyltransferase activity. Rictor degradation was regulated by proteasomal activity, which was antagonized by increased Rictor acetylation. Finally, we found that GCN5L1 knockdown restricted cytoprotective Akt signaling, in conjunction with decreased mTOR abundance and activity. In summary, these studies suggest that GCN5L1 promotes cardioprotective Akt/mTORC2 signaling by maintaining Rictor protein levels through enhanced lysine acetylation.

cell biology↗

bioRxiv2022

Reduced acetylation of TFAM promotes bioenergetic dysfunction in the failing heart

General Control of Amino-Acid Synthesis 5-like 1 (GCN5L1) was previously identified as a key regulator of protein lysine acetylation in mitochondria. Subsequent studies demonstrated that GCN5L1 regulates the acetylation status and activity of mitochondrial fuel substrate metabolism enzymes. However, the role of GCN5L1 in response to chronic hemodynamic stress is largely unknown. Here, we show that cardiomyocyte-specific GCN5L1 knockout mice (cGCN5L1 KO) display exacerbated pressure overload-induced heart failure progression following transaortic constriction (TAC). Mitochondrial DNA and mitochondrial electron transport chain protein levels were decreased in cGCN5L1 KO hearts after TAC, and isolated neonatal cardiomyocytes with reduced GCN5L1 expression had lower bioenergetic output in response to hypertrophic stress. Loss of GCN5L1 expression led to a decrease in the acetylation status of mitochondrial transcription factor A (TFAM) after TAC in vivo, which was linked to a reduction in mtDNA levels in vitro. Together, these data suggest that GCN5L1 may protect from hemodynamic stress by maintaining mitochondrial bioenergetic output. HighlightsO_LIReduced GCN5L1 expression in the failing heart promotes contractile dysfunction C_LIO_LIMitochondrial DNA (mtDNA) levels are reduced in cardiomyocyte-specific GCN5L1 knockout mice following hemodynamic stress C_LIO_LIGCN5L1 knockdown reduces, and GCN5L1 overexpression increases, bioenergetic output in hypertrophic cardiomyocytes C_LIO_LIGCN5L1-mediated acetylation of TFAM promotes increased mtDNA levels C_LI

physiology↗

bioRxiv2022

G-PROTEIN COUPLED RECEPTOR 19 (GPR19) KNOCKOUT MICE DISPLAY SEX-DEPENDENT METABOLIC DYSFUNCTION

G-protein coupled receptors (GPCRs) mediate signal transduction from the cellular surface to intracellular metabolic pathways. While the function of many GPCRs has been delineated previously, a significant number require further characterization to elucidate their cellular function. G-protein coupled receptor 19 (GPR19) is a poorly characterized class A GPCR which has been implicated in the regulation of circadian rhythm, tumor metastasis, and mitochondrial homeostasis. In this report, we use a novel knockout (KO) mouse model to examine the role of GPR19 in whole-body metabolic regulation. We show that loss of GPR19 promotes increased energy expenditure and decreased activity in both male and female mice. However, only male GPR19 KO mice display glucose intolerance in response to a high fat diet (HFD). Loss of GPR19 expression in male mice, but not female mice, resulted in diet-induced hepatomegaly, which was associated with decreased expression of key fatty acid oxidation genes in male GPR19 KO livers. Overall, our data suggest that loss of GPR19 impacts whole-body energy metabolism in diet-induced obese mice in a sex-dependent manner.

physiology↗

bioRxiv2021

Diet-induced obese mice are resistant to improvements in cardiac function resulting from short-term adropin treatment

Previous studies have shown that treatment with recombinant adropin, a circulating peptide secreted by the liver and brain, restores glucose utilization in the hearts of diet-induced obese mice. This restoration of fuel substrate flexibility, which is lost in obese and diabetic animals, has the potential to improve contractile function in the diabetic heart. Using an ex vivo approach, we examined whether short-term adropin treatment could enhance cardiac function in a mouse model of diet-induced obesity. Our study showed that acute adropin treatment reduces inhibitory phosphorylation of pyruvate dehydrogenase in primary neonatal cardiomyocytes, and leads to moderate improvements in ex vivo cardiac function in mice fed a low fat diet. Conversely, short-term exposure to adropin led to a small decrease in cardiac function in mice fed a long-term high fat diet. Insulin treatment did not significantly alter cardiac function in adropin treated hearts from either low or high fat diet mice, however acute adropin treatment did moderately restore downstream insulin signaling in high fat diet fed mice. Overall, these data suggest that in an ex vivo setting, acute adropin treatment alone is not sufficient to promote improved cardiac function in obese animals.

physiology↗

bioRxiv2021

GPER-dependent estrogen signaling increases cardiac GCN5L1 expression and MCAD activity

Reversible lysine acetylation regulates the activity of cardiac metabolic enzymes, including those controlling fuel substrate metabolism. Mitochondrial-targeted GCN5L1 and SIRT3 have been shown to regulate the acetylation status of mitochondrial enzymes, which results in alterations to the relative oxidation rates of fatty acids, glucose, and other fuels for contractile activity. However, the role that lysine acetylation plays in driving metabolic differences between male and female hearts is not currently known. In this study, we report that estrogens induce the expression of GCN5L1 via GPER agonism in cardiac cells, which increases the enzymatic activity and acetylation status of the fatty acid oxidation enzyme medium chain acyl-CoA dehydrogenase (MCAD).

physiology↗

bioRxiv2021

Inhibitory Acetylation of Pyruvate Dehydrogenase Promotes Diastolic Dysfunction in Mice

Left ventricular diastolic dysfunction is a structural and functional condition that precedes the development of heart failure with preserved ejection fraction (HFpEF). The etiology of diastolic dysfunction includes alterations in fuel substrate metabolism that negatively impact cardiac bioenergetics, and may precipitate the eventual transition to heart failure. To date, the molecular mechanisms that regulate early changes in fuel metabolism leading to diastolic dysfunction remain unclear. In this report, we use a diet-induced obesity model and quantitative acetylproteomics in aged mice to show that inhibitory lysine acetylation of the pyruvate dehydrogenase (PDH) complex promotes energetic deficits and diastolic dysfunction in mouse hearts. Cardiomyocyte-specific deletion of the mitochondrial lysine acetylation regulatory protein GCN5L1 prevented hyperacetylation of the PDH complex subunit PDHA1, allowing aged obese mice to continue using pyruvate as a bioenergetic substrate in the heart. Our findings suggest that changes in mitochondrial protein lysine acetylation represent a key metabolic component of diastolic dysfunction that precedes the development of heart failure.

physiology↗

bioRxiv2019

Cardiomyocyte-Specific Deletion of GCN5L1 Limits Cardiac Contractile Decline in Obese Pre-Diabetic Mice

Reduced substrate flexibility, and a shift towards increased cardiac fatty acid utilization, is a key feature of obesity and diabetes. We previously reported that increased acetylation of several mitochondrial FAO enzymes, regulated in part via increased abundance of the mitochondrial acetyltransferase GCN5L1, correlated with increased FAO enzyme activity in the heart. The focus of the current study was to investigate whether decreased acetylation, via cardiomyocyte-specific deletion of GCN5L1 (GCN5L1 cKO), regulates cardiac energy metabolism following exposure to a high fat diet (HFD). Excess dietary fat led to similar cardiac hypertrophy in wildtype and GCN5L1 cKO mice. We show that acetylation of pyruvate dehydrogenase (PDH) was significantly reduced in HFD GCN5L1 cKO hearts, which correlated with its increased enzymatic activity relative to HFD wildtype controls. The acetylation of both electron transport chain Complex I protein NDUFB8, and manganese superoxide dismutase 2 (SOD2), was significantly reduced by GCN5L1 deletion in HFD animals, resulting in decreased lipid peroxidation. Finally, we show that in contrast to wildtype mice, GCN5L1 cKO hearts maintain ex vivo contractility and workload in response to a HFD. In summary, we show that GCN5L1 deletion limits cardiac functional decline observed in HFD mice, by increasing fuel substrate flexibility and limiting reactive oxygen species damage.

physiology↗