Skeletal muscle atrophy is one of the major side effects of high dose or sustained usage of glucocorticoids. Pyroptosis is a novel form of pro-inflammatory programmed cell death that may contribute to skeletal muscle injury. Trimetazidine, a well-known anti-anginal agent, can improve skeletal muscle performance both in humans and mice. We here showed that dexamethasone-induced atrophy, as evidenced by the increase of muscle atrophy F-box (Atrogin-1) and muscle ring finger 1 (MuRF1) expression, and the decrease of myotube diameter in C2C12 myotubes. Dexamethasone also induced pyroptosis, indicated by upregulated pyroptosis-related protein NLR family pyrin domain containing 3 (NLRP3), Caspase-1, and gasdermin-D (GSDMD). Knockdown of NLRP3 or GSDMD attenuated dexamethasone-induced myotube pyroptosis and atrophy. Trimetazidine treatment ameliorated dexamethasone-induced muscle pyroptosis and atrophy both in vivo and in vitro. Activation of NLRP3 using LPS and ATP not only increased the cleavage and activation of Caspase-1 and GSDMD, but also increased the expression levels of atrophy markers MuRF1 and Atrogin-1 in trimetazidine-treated C2C12 myotubes. Mechanically, dexamethasone inhibited the phosphorylation of PI3K/AKT/FoxO3a, which could be attenuated by trimetazidine. Conversely, co-treatment with a PI3K/AKT inhibitor, picropodophyllin, remarkably increased the expression of NLRP3 and reversed the protective effects of trimetazidine against dexamethasone-induced C2C12 myotube pyroptosis and atrophy. Taken together, our study suggests that NLRP3/GSDMD-mediated pyroptosis might be a novel mechanism for dexamethasone-induced skeletal muscle atrophy. Trimetazidine might be developed as a potential therapeutic agent for the treatment of dexamethasone-induced muscle atrophy.

Obesity has reached epidemic proportions globally. Although modern adoption of a sedentary lifestyle coupled with energy-dense nutrition is considered to be the main cause of obesity epidemic, genetic preposition contributes significantly to the imbalanced energy metabolism in obesity. However, the variants of genetic loci identified from large-scale genetic studies do not appear to fully explain the rapid increase in obesity epidemic in the last four to five decades. Recent advancements of next-generation sequencing technologies and studies of tissue-specific effects of epigenetic factors in metabolic organs have significantly advanced our understanding of epigenetic regulation of energy metabolism in obesity. The epigenome, including DNA methylation, histone modifications, and RNA-mediated processes, is characterized as mitotically or meiotically heritable changes in gene function without alteration of DNA sequence. Importantly, epigenetic modifications are reversible. Therefore, comprehensively understanding the landscape of epigenetic regulation of energy metabolism could unravel novel molecular targets for obesity treatment. In this review, we summarize the current knowledge on the roles of DNA methylation, histone modifications such as methylation and acetylation, and RNA-mediated processes in regulating energy metabolism. We also discuss the effects of lifestyle modifications and therapeutic agents on epigenetic regulation of energy metabolism in obesity.

Meteorin‐like (Metrnl) is a novel adipokine that is highly expressed in white adipose tissue. Metrnl stimulates energy expenditure and improves glucose tolerance in rodents. However, whether Metrnl plays a role in coronary artery disease (CAD) remains to be elucidated. The present study aimed to investigate the association of serum Metrnl with CAD in Chinese patients. A total of 193 patients with CAD and 156 control subjects were enrolled in this study. Serum Metrnl concentration was measured by enzyme‐linked immunosorbent assay. Anthropometric phenotypes, fasting glucose, serum lipids, and inflammatory cytokines were measured. Serum Metrnl was lower in CAD patients when compared to those controls (132.41 vs 173.17 pg/mL, P < 0.001). Serum Metrnl was negatively correlated with metabolic parameters, including body mass index, total cholesterol, and low‐density lipoprotein cholesterol as well as inflammatory markers including high‐sensitivity C‐reactive protein, IL‐1β, and IL‐11 even after adjustment for potential confounding variables (P < 0.05). In multivariable logistic regression analyses, compared to those in the highest tertile of serum Metrnl levels, subjects in the lowest tertile had the highest risks for CAD (adjusted OR = 2.63, 95% CI = 1.46‐4.27, P = 0.001). After adjustment for potential confounding variables, serum Metrnl was also decreased as the number of stenosed vessels increased (P < 0.001). Furthermore, decreased Metrnl level was negatively correlated with the severity of CAD quantified by the Gensini score. This first case‐control study shows significant associations of serum Metrnl with the presence and severity of CAD, suggesting Metrnl might be a new promising therapeutic target for CAD.

Acute ischemic stroke (AIS) is a major public health problem in China. Impaired angiogenesis plays crucial roles in the development of ischemic cerebral injury. Recent studies have identified that microRNAs (miRNAs) are important regulators of angiogenesis, but little is known the exact effects of angiogenesis-associated miRNAs in AIS. In the present study, we detected the expression levels of angiogenesis-associated miRNAs in AIS patients, middle cerebral artery occlusion (MCAO) rats, and oxygen-glucose deprivation/reoxygenation (OGD/R) human umbilical vein endothelial cells (HUVECs). MiR-191 was increased in the plasma of AIS patients, OGD/R HUVECs, and the plasma and brain of MCAO rats. Over-expression of miR-191 promoted apoptosis, but reduced the proliferation, migration, tube-forming and spheroid sprouting activity in HUVECs OGD/R model. Mechanically, vascular endothelial zinc finger 1 (VEZF1) was identified as the direct target of miR-191, and could be regulated by miR-191 at post-translational level. In vivo studies applying miR-191 antagomir demonstrated that inhibition of miR-191 reduced infarction volume in MCAO rats. In conclusion, our data reveal a novel role of miR-191 in promoting ischemic brain injury through inhibiting angiogenesis via targeting VEZF1. Therefore, miR-191 may serve as a biomarker or a therapeutic target for AIS.

Background: Acute myocardial infarction (AMI) is one of the leading causes of cardiovascular morbidity and mortality worldwide. Pyroptosis is a form of inflammatory cell death that plays a major role in the development and progression of cardiac injury in AMI. However, the underlying mechanisms for the activation of pyroptosis during AMI are not fully elucidated. Methods and Results: Here we show that RBP4 (retinol‐binding protein 4), a previous identified proinflammatory adipokine, was increased both in the myocardium of left anterior descending artery ligation‐induced AMI mouse model and in ischemia‐hypoxia‒induced cardiomyocyte injury model. The upregulated RBP4 may contribute to the activation of cardiomyocyte pyroptosis in AMI because overexpression of RBP4 activated NLRP3 (nucleotide‐binding oligomerization domain‐like receptor family pyrin domain‐containing 3) inflammasome, promoted the precursor cleavage of Caspase‐1, and subsequently induced GSDMD (gasdermin‐D)‐dependent pyroptosis. In contrast, knockdown of RBP4 alleviated ischemia‐hypoxia‒induced activation of NLRP3 inflammasome signaling and pyroptosis in cardiomyocytes. Mechanistically, coimmunoprecipitation assay showed that RBP4 interacted directly with NLRP3 in cardiomyocyte, while genetic knockdown or pharmacological inhibition of NLRP3 attenuated RBP4‐induced pyroptosis in cardiomyocytes. Finally, knockdown of RBP4 in heart decreased infarct size and protected against AMI‐induced pyroptosis and cardiac dysfunction in mice. Conclusions: Taken together, these findings reveal RBP4 as a novel modulator promoting cardiomyocyte pyroptosis via interaction with NLRP3 in AMI. Therefore, targeting cardiac RBP4 might represent a viable strategy for the prevention of cardiac injury in patients with AMI.

Background: Unintentional weight loss (cachexia) has been associated with poor outcomes in chronic heart failure (CHF). Meteorin‐like (Metrnl) is a novel myokine with protective effects on cardiovascular diseases. However, the change of Metrnl concentrations and its role in elderly patients with CHF remains unclear. The aim of this study was to evaluate the association of serum Metrnl with weight loss and outcomes in elderly patients with CHF.Methods: A total of 931 consecutive elderly patients (aged 60 years and older) with CHF and 135 age‐matched and sex‐matched control subjects were enrolled. Serum Metrnl concentration was measured by enzyme‐linked immunosorbent assay. Body weight was measured at baseline and 12 months.Results: Median of serum Metrnl levels was lower in CHF patients when compared with controls [201.31 (184.95–261.16) pg/mL vs. 168.68 (103.15–197.54) pg/mL, P < 0.001]. Patients with the lowest levels of Metrnl had higher N‐terminal pro brain natriuretic peptide (NT‐proBNP) levels but lower left ventricular eject fraction (LVEF) and estimated glomerular filtration rate (P < 0.001). Lower serum Metrnl was associated with a higher risk of >5% weight loss from baseline to 12 months [odds ratio = 6.13, 95% confidence interval (CI) = 2.57–14.62 per log decrease; P < 0.001]. Serum Metrnl levels were decreased as LVEF decreased (P < 0.001) and were positively correlated with LVEF (r = 0.267, P < 0.001) but negatively correlated with NT‐proBNP levels (r = −0.257, P < 0.001). Cox regression analysis suggested that lower serum Metrnl was associated with higher cardiovascular mortality [hazard ratio (HR) = 6.71, 95% CI = 3.41–13.18 per log decrease; P < 0.001], CHF rehospitalization (HR = 3.07, 95% CI = 1.82–5.17 per log decrease; P < 0.001), and the combined major adverse cardiac event(s) (MACEs) (HR = 5.38, 95% CI = 3.51–8.25 per log decrease; P < 0.001). The Kaplan–Meier survival curves showed that low concentration of Metrnl was a prognostic indicator of MACEs in patients with CHF.Conclusions: Our study suggests that lower serum Metrnl level is correlated with weight loss and the severity of cardiac dysfunction in elderly patients with CHF.