Obese mice exposed to psychosocial stress display cardiac and hippocampal dysfunction associated with local brain-derived neurotrophic factor depletion

Introduction: Obesity and psychosocial stress (PS) co-exist in individuals of Western society. Nevertheless, how PS impacts cardiac and hippocampal phenotype in obese subjects is still unknown. Nor is it clear whether changes in local brain-derived neurotrophic factor (BDNF) account, at least in part, for myocardial and behavioral abnormalities in obese experiencing PS. Methods: In adult male WT mice, obesity was induced via a high-fat diet (HFD). The resident-intruder paradigm was superimposed to trigger PS. In vivo left ventricular (LV) performance was evaluated by echocardiography and pressure-volume loops. Behaviour was indagated by elevated plus maze (EPM) and Y-maze. LV myocardium was assayed for apoptosis, fibrosis, vessel density and oxidative stress. Hippocampus was analyzed for volume, neurogenesis, GABAergic markers and astrogliosis. Cardiac and hippocampal BDNF and TrkB levels were measured by ELISA and WB. We investigated the pathogenetic role played by BDNF signaling in additional cardiac-selective TrkB (cTrkB) KO mice. Findings: When combined, obesity and PS jeopardized LV performance, causing prominent apoptosis, fibrosis, oxidative stress and remodeling of the larger coronary branches, along with lower BDNF and TrkB levels. HFD/PS weakened LV function similarly in WT and cTrkB KO mice. The latter exhibited elevated LV ROS emission already at baseline. Obesity/PS augmented anxiety-like behaviour and impaired spatial memory. These changes were coupled to reduced hippocampal volume, neurogenesis, local BDNF and TrkB content and augmented astrogliosis. Interpretation: PS and obesity synergistically deteriorate myocardial structure and function by depleting cardiac BDNF/TrkB content, leading to augmented oxidative stress. This comorbidity triggers behavioral deficits and induces hippocampal remodeling, potentially via lower BDNF and TrkB levels. FUND: J.A. was in part supported by Rotary Foundation Global Study Scholarship. G.K. was supported by T32 National Institute of Health (NIH) training grant under award number 1T32AG058527. S.C. was funded by American Heart Association Career Development Award (19CDA34760185). G.A.R.C. was funded by NIH (K01HL133368-01). APB was funded by a Grant from the Friuli Venezia Giulia Region entitled: Heart failure as the Alzheimer disease of the heart; therapeutic and diagnostic opportunities . M.C. was supported by PRONAT project (CNR). N.P. was funded by NIH (R01 HL136918) and by the Magic-That-Matters fund (JHU). V.L. was in part supported by institutional funds from Scuola Superiore Sant\u27Anna (Pisa, Italy), by the TIM-Telecom Italia (WHITE Lab, Pisa, Italy), by a research grant from Pastificio Attilio Mastromauro Granoro s.r.l. (Corato, Italy) and in part by ETHERNA project (Prog. n. 161/16, Fondazione Pisa, Italy). Funding source had no such involvement in study design, in the collection, analysis, interpretation of data, in the writing of the report; and in the decision to submit the paper for publication

WASP-Arp2/3-dependent actin polymerization influences fusogen localization during cell-cell fusion in Caenorhabditis elegans embryos

Cell-cell fusion is essential for development and physiology. Actin polymerization was implicated in the Caenorhabditis elegans fusogen EFF-1 engagement in a reconstituted Drosophila cell culture system, and the actin-binding protein spectraplakin links EFF-1 to the actin cytoskeleton and promotes cell-cell fusions in C. elegans larvae. However, it remains unclear whether and how fusogens and the actin cytoskeleton are coordinated in C. elegans embryos. Here, we used live imaging analysis of GFP knock-in and RNAi embryos to study the embryonic cell-cell fusions in C. elegans. Our results show that the inhibition of WASP-Arp2/3-dependent actin polymerization delays cell-cell fusions. EFF-1 is primarily distributed in intracellular vesicles in embryonic fusing cells, and we find that the perturbation of actin polymerization reduces the number of EFF-1-postive vesicles. Thus, the actin cytoskeleton differently promotes cell-cell fusion by regulating fusogen localization to the fusing plasma membrane in larvae or to intracellular vesicles in embryos

The Relation of Moderate Alcohol Consumption to Hyperuricemia in a Rural General Population

Background: although alcohol abuse is known to increase serum uric acid, the relation between moderate drinking and uric acid have remained poorly understood. We performed this study to evaluate whether different alcohol consumption level has different effects on the risk of hyperuricemia based on a rural general population. Method: multi-stage cluster sampling method was used to select a representative sample of individuals aged 35 years or older. Participants were asked to provide information about their alcohol consumption. Data regarding the demographic and lifestyle characteristics and the blood biochemical indexes of these participants were collected by well-trained personnel. Results: in total, 11,039 participants aged 35 years or older were included (4997 men and 6042 women). The prevalence of hyperuricemia in the different male alcohol consumption groups was 11.9% in non-drinkers, 12.6% in moderate drinkers, and 16.3% in heavy drinkers (p < 0.001). In females, the rates were 6.3% in non-drinkers, 8.1% in moderate drinkers, and 6.6% for heavy drinkers (p = 0.818). In males, multivariate logistic regression analyses shows heavy drinkers had an approximately 1.7-fold higher risk of hyperuricemia (OR: 1.657, 95% CI: 1.368 to 2.007, p < 0.001) than non-drinkers; moderate drinkers did not experience a significant increase in risk (OR: 1.232, 95% CI: 0.951 to 1.596, p = 0.114)). Multivariate logistic regression analyses of females showed that, compared with non-drinkers, neither moderate nor heavy drinkers had a significantly increased risk of hyperuricemia (OR: 1.565, 95% CI: 0.521 to 4.695, p = 0.425 for heavy drinkers; OR: 0.897, 95% CI: 0.117 to 6.855, p = 0.916 for moderate drinkers). Conclusions: heavy alcohol consumption increased the risk of hyperuricemia for males but not for females. Among both males and females, moderate alcohol consumption did not increase the risk of hyperuricemia

The spectrin-based membrane skeleton is asymmetric and remodels during neural development in C. elegans

Perturbation of spectrin-based membrane mechanics causes hereditary elliptocytosis and spinocerebellar ataxia, but the underlying cellular basis of pathogenesis remains unclear. Here, we introduced conserved disease-associated spectrin mutations into the Caenorhabditis elegans genome and studied the contribution of spectrin to neuronal migration and dendrite formation in developing larvae. The loss of spectrin resulted in ectopic actin polymerization outside of the existing front and secondary membrane protrusions, leading to defective neuronal positioning and dendrite morphology in adult animals. Spectrin accumulated in the lateral region and rear of migrating neuroblasts and redistributes from the soma into the newly formed dendrites, indicating that the spectrin-based membrane skeleton is asymmetric and remodels to regulate actin assembly and cell shape during development. We affinity-purified spectrin from C. elegans and showed that its binding partner ankyrin functions with spectrin. Asymmetry and remodeling of the membrane skeleton might enable spatiotemporal modulation of membrane mechanics for distinct developmental events

Heart Failure-Related Hyperphosphorylation in the Cardiac Troponin I C Terminus Has Divergent Effects on Cardiac Function In Vivo

BACKGROUND: In human heart failure, Ser199 (equivalent to Ser200 in mouse) of cTnI (cardiac troponin I) is significantly hyperphosphorylated, and in vitro studies suggest that it enhances myofilament calcium sensitivity and alters calpain-mediated cTnI proteolysis. However, how its hyperphosphorylation affects cardiac function in vivo remains unknown

PGC-1α Regulates Expression of Myocardial Mitochondrial Antioxidants and Myocardial Oxidative Stress After Chronic Systolic Overload

Mitochondria are a principal site for generation of reactive oxygen species (ROS) in the heart. Peroxisome proliferator activated receptor γ coactivator 1α (PGC-1α) plays an important role in regulating mitochondrial biogenesis and myocardial metabolism, but whether PGC-1α can simultaneously upregulate myocardial mitochondrial antioxidants has not been studied. In the present study, we examined the effect of PGC-1α deficiency (PGC-1α−/−) on oxidative stress and expression of a group of mitochondrial antioxidants in normal hearts and in hearts exposed to chronic systolic pressure overload produced by transverse aortic constriction (TAC). We found that PGC-1α−/− caused moderate but significant decreases of myocardial mitochondrial antioxidant enzymes such as SOD2, and thioredoxin (Trx2), but had no effect on expression of myocardial oxidative stress markers and left ventricular (LV) function under basal conditions. However, in response to TAC for 6 weeks, PGC-1α−/− mice showed greater increases of myocardial oxidative stress markers 3’-nitrotyrosine and 4-hydroxynonenal, more severe LV hypertrophy and dilatation, pulmonary congestion, and a greater reduction of LV fractional shortening and dP/dtmax than did wild-type hearts. SOD mimetic MnTMPyP treatment (6 mg/kg/day) significantly attenuated TAC-induced LV hypertrophy and dysfunction in PGC-1α−/− mice. These data indicate that PGC-1α plays an important role in regulating expression of myocardial mitochondrial antioxidants SOD2 and Trx2 and in protecting hearts against TAC-induced myocardial oxidative stress, hypertrophy, and dysfunction. Antioxid. Redox Signal. 13, 1011–1022