Lafora Disease Is an Inherited Metabolic Cardiomyopathy

This work was supported by grants from the Spanish Ministry of Economy and Competitiveness (SAF2015-65722-R to Dr. Lara-Pezzi and SAF2014-59594-R to Dr. Serratosa), Autonomous Community of Madrid (2010-BMD2321, FIBROTEAM Consortium), European Union's FP7 (CardioNeT-ITN-289600, CardioNext-ITN-608027), the Spanish Carlos III Institute of Health (CPII14/00027 to Dr. Lara-Pezzi, PI13/00865 to Dr. Sanchez and RD12/0042/066 to Drs. Garcia-Pavia and Lara-Pezzi), and the National Institute of Neurological Disorders And Stroke of the National Institutes of Health (P01NS097197 to Dr. Sanchez). This work was also supported by the Plan Estatal de I+D+I 2013-2016-European Regional Development Fund (FEDER) "A way of making Europe," Spain. The Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) is supported by the Spanish Ministry of Economy and Competitiveness (MINECO) and the Pro-CNIC Foundation, and is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505).S

Early preventive treatment with Enalapril improves cardiac function and delays mortality in mice with arrhythmogenic right ventricular cardiomyopathy type 5.

Background: Arrhythmogenic right ventricular cardiomyopathy type 5 (ARVC5) is an inherited cardiac disease with complete penetrance and an aggressive clinical course caused by mutations in TMEM43 (transmembrane protein 43). There is no cure for ARVC5 and palliative treatment is started once the phenotype is present. A transgenic mouse model of ARVC5 expressing human TMEM43-S358L (TMEM43mut) recapitulates the human disease, enabling the exploration of preventive treatments. The aim of this study is to determine whether preventive treatment with heart failure drugs (β-blockers, ACE [angiotensin-converting enzyme] inhibitors, mineralocorticoid-receptor antagonists) improves the disease course of ARVC5 in TMEM43mut mice. Methods: TMEM43mut male/female mice were treated with metoprolol (β-blockers), enalapril (ACE inhibitor), spironolactone (mineralocorticoid-receptor antagonist), ACE inhibitor + mineralocorticoid-receptor antagonist, ACE inhibitor + mineralocorticoid-receptor antagonist + β-blockers or left untreated. Drugs were initiated at 3 weeks of age, before ARVC5 phenotype, and serial ECG and echocardiograms were performed. Results: TMEM43mut mice treated with enalapril showed a significantly increased median survival compared with untreated mice (26 versus 21 weeks; P=0.003). Enalapril-treated mice also exhibited increased left ventricular ejection fraction at 4 months compared with controls (37.0% versus 24.9%; P=0.004), shorter QRS duration and reduced left ventricle fibrosis. Combined regimens including enalapril also showed positive effects. Metoprolol decreased QRS voltage prematurely and resulted in a nonsignificant decrease in left ventricular ejection fraction compared with untreated TMEM43mut mice. Conclusions: Preventive enalapril-based regimens reduced fibrosis, improved ECG, echocardiographic parameters and survival of ARVC5 mice. Early metoprolol did not show positive effects and caused premature ECG abnormalities. Our findings pave the way to consider prophylactic enalapril in asymptomatic ARVC5 genetic carriers.pre-print326 K

Regulación de la actividad del tejido adiposo por la isoforma de calcineurina A CnAB1

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de lectura: 24-11-2021Esta tesis tiene embargado el acceso al texto completo hasta el 24-05-2023The phosphatase calcineurin (Cn) plays a relevant role in many physiological and pathological processes, including heart diseases. Alternative splicing of CnAβ mRNA produces the CnAβ1 variant, which is evolutionarily conserved in vertebrates. CnAβ1 presents a unique C-terminal domain that is not present in other CnA isoforms and confers this variant singular properties. In contrast to other CnA isoforms, CnAβ1 overexpression improves cardiac function after myocardial infarction in an mTORdependent manner. However, the physiological role of this calcineurin variant in adult mice is virtually unknown. To investigate the role of CnAβ1 in vivo in the context of metabolism we generated a global knockout mouse for this calcineurin variant (CnAβ1Δi12 mice). We found that CnAβ1Δi12 mice fed with a high fat diet (HFD) had reduced body weight compared to wild-type animals. This was accompanied by smaller adipocytes within epidydimal white adipose tissue (eWAT). CnAβ1Δi12 mice showed a consistent metabolic phenotype associated with the decrease of fat mass. CnAβ1Δi12 mice had more body and brown adipose tissue (BAT) temperature due to an increase in nonshivering thermogenesis in BAT. The histological analysis of BAT revealed a reduction in lipid droplets size and RT-qPCR demonstrated high expression of genes related to thermogenesis, lipolysis, fatty acid oxidation and mitochondrial biogenesis. We also observed evident browning of eWAT when mice were fed with HFD. In addition, CnAβ1Δi12 mice showed an increase in adipogenic mRNA markers in brown and white adipocytes. We found an increase in PGC1α protein levels in BAT, the main regulator of mitochondrial biogenesis. Thermoneutral exposure of CnAβ1Δi12 mice largely recovered the phenotype demonstrating that CnAβ1 is necessary for proper temperature regulation. These results suggest that CnAβ1 is a novel regulator of non-shivering thermogenesis and WAT browning and that inhibition of CnAβ1 is a promising strategy to treat obesit

Lafora Disease Is an Inherited Metabolic Cardiomyopathy

This work was supported by grants from the Spanish Ministry of Economy and Competitiveness (SAF2015-65722-R to Dr. Lara-Pezzi and SAF2014-59594-R to Dr. Serratosa), Autonomous Community of Madrid (2010-BMD2321, FIBROTEAM Consortium), European Union's FP7 (CardioNeT-ITN-289600, CardioNext-ITN-608027), the Spanish Carlos III Institute of Health (CPII14/00027 to Dr. Lara-Pezzi, PI13/00865 to Dr. Sanchez and RD12/0042/066 to Drs. Garcia-Pavia and Lara-Pezzi), and the National Institute of Neurological Disorders And Stroke of the National Institutes of Health (P01NS097197 to Dr. Sanchez). This work was also supported by the Plan Estatal de I+D+I 2013-2016-European Regional Development Fund (FEDER) "A way of making Europe," Spain. The Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) is supported by the Spanish Ministry of Economy and Competitiveness (MINECO) and the Pro-CNIC Foundation, and is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505).Ministerio de Economía y Competitividad (España)Comunidad de Madrid (España)Unión Europea. Comisión EuropeaInstituto de Salud Carlos IIINational Institutes of Health (Estados Unidos)Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)Fundación ProCNICDepto. de Medicina y Cirugía AnimalFac. de VeterinariaTRUEpu

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field