Moderate Modulation of Cardiac PGC-1α Expression Partially Affects Age-Associated Transcriptional Remodeling of the Heart

Aging is associated with a decline in cardiac function due to a decreased myocardial reserve. This adverse cardiac remodeling comprises of a variety of changes, including a reduction in mitochondrial function and a decline in the expression of the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a central regulator of mitochondrial biogenesis and metabolic adaptation in the myocardium. To study the etiological involvement of PGC-1α in cardiac aging, we used mouse models mimicking the modest down- and upregulation of this coactivator in the old and the exercised heart, respectively. Young mice with reduced cardiac expression of PGC-1α recapitulated part of the age-related impairment in mitochondrial gene expression, but otherwise did not aggravate the aging process. Inversely however, moderate overexpression of PGC-1α counteracts numerous key age-related remodeling changes, e.g., by improving blood pressure, age-associated apoptosis, and collagen accumulation, as well as in the expression of many, but not all cardiac genes involved in mitochondrial biogenesis, dynamics, metabolism, calcium handling and contractility. Thus, while the reduction of PGC-1α in the heart is insufficient to cause an aging phenotype, moderate overexpression reduces pathological remodeling of older hearts and could thereby contribute to the beneficial effects of exercise on cardiac function in aging

A novel SCN5A mutation, F1344S, identified in a patient with Brugada syndrome and fever-induced ventricular fibrillation

Objective Brugada syndrome (BS) is an inherited electrical cardiac disorder characterized by right bundle branch block pattern and ST segment elevation in leads V1 to V3 on surface electrocardiogram that can potentially lead to malignant ventricular tachycardia and sudden cardiac death. About 20% of patients have mutations in the only so far identified gene, SCN5A, which encodes the α-subunit of the human cardiac voltage-dependent sodium channel (hNav1.5). Fever has been shown to unmask or trigger the BS phenotype, but the associated molecular and the biophysical mechanisms are still poorly understood. We report on the identification and biophysical characterization of a novel heterozygous missense mutation in SCN5A, F1344S, in a 42-year-old male patient showing the BS phenotype leading to ventricular fibrillation during fever. Methods The mutation was reproduced in vitro using site-directed mutagenesis and characterized using the patch clamp technique in the whole-cell configuration. Results The biophysical characterization of the channels carrying the F1344S mutation revealed a 10mV mid-point shift of the G/V curve toward more positive voltages during activation. Raising the temperature to 40.5°C further shifted the mid-point activation by 18mV and significantly changed the slope factor in Nav1.5/F1344S mutant channels from − 6.49 to − 10.27mV. Conclusions Our findings indicate for the first time that the shift in activation and change in the slope factor at a higher temperature mimicking fever could reduce sodium currents' amplitude and trigger the manifestation of the BS phenotyp

The Wellesley News (06-10-1957)

https://repository.wellesley.edu/wcnews/1157/thumbnail.jp

Cardiac mTOR complex 2 preserves ventricular function in pressure-overload hypertrophy

Mammalian target of rapamycin (mTOR), a central regulator of growth and metabolism, has tissue-specific functions depending on whether it is part of mTOR complex 1 (mTORC1) or mTORC2. We have previously shown that mTORC1 is required for adaptive cardiac hypertrophy and maintenance of function under basal and pressure-overload conditions. In the present study, we aimed to identify functions of mTORC2 in the heart.; Using tamoxifen-inducible cardiomyocyte-specific gene deletion, we generated mice deficient for cardiac rapamycin-insensitive companion of mTOR (rictor), an essential and specific component of mTORC2. Under basal conditions, rictor deficiency did not affect cardiac growth and function in young mice and also had no effects in adult mice. However, transverse aortic constriction caused dysfunction in the rictor-deficient hearts, whereas function was maintained in controls after 1 week of pressure overload. Adaptive increases in cardiac weight and cardiomyocyte cross-sectional area, fibrosis, and hypertrophic and metabolic gene expression were not different between the rictor-deficient and control mice. In control mice, maintained function was associated with increased protein levels of rictor, protein kinase C (PKC)βII, and PKCδ, whereas rictor ablation abolished these increases. Rictor deletion also significantly decreased PKCε at baseline and after pressure overload. Our data suggest that reduced PKCε and the inability to increase PKCβII and PKCδ abundance are, in accordance with their known function, responsible for decreased contractile performance of the rictor-deficient hearts.; Our study demonstrates that mTORC2 is implicated in maintaining contractile function of the pressure-overloaded male mouse heart

Een robuust en maatschappelijk gedragen energiesysteem MMIP 13

De energietransitie zal de komende decennia grote veranderingen teweeg brengen in onze maatschappij. Industrie, gebouwde omgeving, landbouw, mobiliteit en de energiesector zullen grootschalig gaan verduurzamen. Verduurzamingstrajecten kennen echter veel onzekerheden en zijn vaak afhankelijk van elkaar. Deze complexiteit krijgt nog een extra dimensie omdat er ook afhankelijkheden zijn tussen de verschillende sectoren. De energietransitie is niet alleen een technologisch vraagstuk, maar is ook sociaal economisch, maatschappelijk, ruimtelijk en ecologisch van aard. Voor deze systeemproblematiek is vaak geen eenduidige eigenaar. In dit proces speelt het energiesysteem een centrale rol. Het zal de komende jaren een fundamentele verandering ondergaan: fossiele brandstoffen zullen stap voor stap worden vervangen door grote hoeveelheden duurzame, (intermitterende) bronnen, de vraag naar energie zal gaan veranderen, de grenzen tussen energiedragers zullen vervagen, er zullen (onderling verbonden) energiesystemen ontstaan op alle schaalniveaus (woning, wijk, regio, nationaal, internationaal), nieuwe spelers zullen in de energiemarkt hun intrede doen. Kortom het energiesysteem wordt steeds complexer. Dit betekent dat een transitieproces nodig is dat het mogelijk maakt om, vanuit een systeemperspectief, adequaat, hoogwaardig en efficiënt besluiten te kunnen nemen over en invulling te geven aan de inrichting en werking van een betaalbaar en geaccepteerd energiesysteem waarbij de betrouwbaarheid, leveringszekerheid en veiligheidop het zelfde niveau blijven als vandaag de dag. Het Meerjarig Missiegedreven InnovatieProgramma (MMIP) 13 ontwikkelt hiervoor kennis en innovaties. De 6 deelprogramma’s van dit MMIP richten zich op verschillende aspecten van de uitdaging rond het integrale energiesysteem. Het programma kent zowel technische als economische en sociale aspecten

Pelvic floor muscle function in a general female population in relation with age and parity and the relation between voluntary and involuntary contractions of the pelvic floor musculature

Contains fulltext : 80525.pdf (publisher's version ) (Closed access

Infectious Diseases and Basal Ganglia Calcifications: A Cross-Sectional Study in Patients with Fahr's Disease and Systematic Review

Background: It is unclear whether patients with basal ganglia calcifications (BGC) should undergo infectious disease testing as part of their diagnostic work-up. We investigated the occurrence of possibly associated infections in patients with BGC diagnosed with Fahr's disease or syndrome and consecutively performed a systematic review of published infectious diseases associated with BGC. Methods: In a cross-sectional study, we evaluated infections in non-immunocompromised patients aged ≥ 18 years with BGC in the Netherlands, who were diagnosed with Fahr's disease or syndrome after an extensive multidisciplinary diagnostic work-up. Pathogens that were assessed included the following: Brucella sp., cytomegalovirus, human herpesvirus type 6/8, human immunodeficiency virus (HIV), Mycobacterium tuberculosis, rubella virus, and Toxoplasma gondii. Next, a systematic review was performed using MEDLINE and Embase (2002-2023). Results: The cross-sectional study included 54 patients (median age 65 years). We did not observe any possible related infections to the BGC in this population. Prior infection with Toxoplasma gondii occurred in 28%, and in 94%, IgG rubella antibodies were present. The positive tests were considered to be incidental findings by the multidisciplinary team since these infections are only associated with BGC when congenitally contracted and all patients presented with adult-onset symptoms. The systematic search yielded 47 articles, including 24 narrative reviews/textbooks and 23 original studies (11 case series, 6 cross-sectional and 4 cohort studies, and 2 systematic reviews). Most studies reported congenital infections associated with BGC (cytomegalovirus, HIV, rubella virus, Zika virus). Only two studies reported acquired pathogens (chronic active Epstein-Barr virus and Mycobacterium tuberculosis). The quality of evidence was low. Conclusions: In our cross-sectional study and systematic review, we found no convincing evidence that acquired infections are causing BGC in adults. Therefore, we argue against routine testing for infections in non-immunocompromised adults with BGC in Western countries

A Proton Leak Current through the Cardiac Sodium Channel Is Linked to Mixed Arrhythmia and the Dilated Cardiomyopathy Phenotype

Cardiac Na+ channels encoded by the SCN5A gene are essential for initiating heart beats and maintaining a regular heart rhythm. Mutations in these channels have recently been associated with atrial fibrillation, ventricular arrhythmias, conduction disorders, and dilated cardiomyopathy (DCM)