Article
Cell Biology
Paula Ketilly Nascimento Alves, Antje Schauer, Antje Augstein, Anita Maennel, Peggy Barthel, Dirk Joachim, Janet Friedrich, Maria-Elisa Prieto, Anselmo Sigari Moriscot, Axel Linke, Volker Adams
Summary: This study investigated the effect of leucine supplementation on myocardial function and key signaling pathways in a rat model of HFpEF. The results showed that leucine supplementation improved diastolic function, reduced remodeling processes, and was associated with HDAC4/TGF-beta 1/Collagenase downregulation, suggesting its potential use in the treatment of HFpEF.
Article
Pharmacology & Pharmacy
Daniel Priksz, Nora Lampe, Arpad Kovacs, Melissa Herwig, Mariann Bombicz, Balazs Varga, Tician Wilisicz, Judit Szilvassy, Aniko Posa, Rita Kiss, Rudolf Gesztelyi, Arnold Raduly, Reka Szekeres, Marcel Sieme, Zoltan Papp, Attila Toth, Nazha Hamdani, Zoltan Szilvassy, Bela Juhasz
Summary: BGP-15 treatment improves diastolic function, reduces cardiomyocyte stiffness, and restores titin compliance in a rabbit model of atherosclerotic cardiomyopathy by increasing the activity of the cGMP-PKG pathway. The findings suggest that BGP-15 may have potential clinical utility in the treatment of diastolic dysfunction.
BRITISH JOURNAL OF PHARMACOLOGY
(2022)
Article
Cardiac & Cardiovascular Systems
Genri Numata, Eiki Takimoto, Taro Kariya, Yusuke Adachi, Hiroyuki Tokiwa, Masayuki Toyoda, Ryo Mafune, Yoshihiro Saito, Shun Nakamura, Kazutaka Ueda, Yuichi Ikeda, Issei Komuro
Summary: HFpEF is a global health issue with a lack of stable methods for detecting diastolic dysfunction in mouse models. The authors developed a pacing-controlled protocol to evaluate diastolic function at different heart rates in mice and successfully detected diastolic dysfunction specific to an HFpEF model.
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Antje Schauer, Volker Adams, Antje Augstein, Anett Jannasch, Runa Draskowski, Virginia Kirchhoff, Keita Goto, Jeniffer Mittag, Roberta Galli, Anita Maennel, Peggy Barthel, Axel Linke, Ephraim B. Winzer
Summary: The study revealed significant effects of Sac/Val on myocardial structure and function in a rat model of HFpEF, including reducing myocardial fibrosis and heart weight. However, the drug slightly improved endothelial function in the carotid artery but had no impact on skeletal muscle function.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Cell Biology
Michael H. Radke, Victor Badillo-Lisakowski, Thiago Britto-Borges, Dieter A. Kubli, Rene Juettner, Pragati Parakkat, Jacobo Lopez Carballo, Judith Huettemeister, Martin Liss, Arne Hansen, Christoph Dieterich, Adam E. Mullick, Michael Gotthardt
Summary: HFpEF is a prevalent and deadly heart disease for which no targeted therapy has been established. Research has shown that ASOs targeting the cardiac splice factor RBM20 can improve cardiac function and alleviate symptoms of heart failure. Experimental evidence demonstrates that this approach can promote the expression of compliant titin isoforms over a period of 2 months and has been validated in human heart tissue.
SCIENCE TRANSLATIONAL MEDICINE
(2021)
Article
Geriatrics & Gerontology
Volker Adams, Antje Schauer, Antje Augstein, Virginia Kirchhoff, Runa Draskowski, Anett Jannasch, Keita Goto, Gemma Lyall, Anita Maennel, Peggy Barthel, Norman Mangner, Ephraim B. Winzer, Axel Linke, Siegfried Labeit
Summary: MyoMed-205 improved myocardial diastolic function and prevented SKM atrophy/function in the HFpEF animal model. Mechanistically, SKM benefited from attenuation of the ubiquitin proteasome system and increased synthesis/activity of proteins of the mitochondrial respiratory chain, while the myocardium benefited from reduced titin modifications and fibrosis.
JOURNAL OF CACHEXIA SARCOPENIA AND MUSCLE
(2022)
Article
Cell Biology
Wen-Ye Song, Han Ding, Tiffany Dunn, Jun-Ling Gao, JavierAllende Labastida, Caitlin Schlagal, Guang-Zhi Ning, Shi-Qing Feng, Ping Wu
Summary: Research suggests that low-dose metformin treatment for subacute spinal cord injury can significantly improve functional recovery, possibly through anti-inflammatory and neuroprotective mechanisms.
NEURAL REGENERATION RESEARCH
(2021)
Article
Biochemistry & Molecular Biology
Maya Dia, Christelle Leon, Stephanie Chanon, Nadia Bendridi, Ludovic Gomez, Jennifer Rieusset, Helene Thibault, Melanie Paillard
Summary: Despite its cardioprotective role, metformin is not sufficient to delay the progression to early DCM.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Medicine, Research & Experimental
Ying-Hsi Lin, Jennifer L. Major, Tim Liebner, Zaynab Hourani, Joshua G. Travers, Sara A. Wennersten, Korey R. Haefner, Maria A. Cavasin, Cortney E. Wilson, Mark Y. Jeong, Yu Han, Michael Gotthardt, Scott K. Ferguson, Amrut Ambardekar, Maggie P. Y. Lam, Chunaram Choudhary, Henk L. Granzier, Kathleen C. Woulfe, Timothy A. McKinsey
Summary: This study demonstrates the role of histone deacetylase 6 (HDAC6) in controlling myofibril function and passive stiffness of the heart. Lack of HDAC6 increases myofibril stiffness, while overexpression of HDAC6 decreases myofibril stiffness. The modulation of myofibril stiffness by HDAC6 is dependent on a specific region of the titin protein.
JOURNAL OF CLINICAL INVESTIGATION
(2022)
Article
Pharmacology & Pharmacy
Silke Duesener, Frederik Flenner, Christoph Maack, Michael Kohlhaas, Johannes Bay, Lucie Carrier, Felix W. Friedrich
Summary: Diastolic dysfunction is a major feature of hypertrophic cardiomyopathy (HCM). This study found that ouabain has acute effects on ventricular myocytes of an HCM mouse model, particularly worsening diastolic phenotype in KI cardiomyocytes. Lower amounts of Na+/K+ ATPase (NKA) in KI may amplify the impact of ouabain-induced elevation of intracellular Ca2+.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2021)
Article
Cell Biology
Xingzhu Du, Jun Li, Qingrui Zhuan, Luyao Zhang, Lin Meng, Panyu Ren, Xiaohan Huang, Jiachen Bai, Pengcheng Wan, Wenquan Sun, Yunpeng Hou, Shien Zhu, Xiangwei Fu
Summary: Oocyte cryopreservation has significant benefits in conserving animal germplasm resources and assisting reproductive technology. However, this technique can cause damage to oocytes, leading to a decrease in oocyte quality and post-fertilization embryonic development. This study examined oocyte cortical tension and found that vitrified oocytes had decreased cortical tension. Increasing cortical tension improved oocyte polar body extrusion, embryo development, spindle positioning, KT-MT attachment, SAC activity, and reduced aneuploidy in vitrified oocytes.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Article
Cell Biology
Xiaoyan Xu, Yaqin Sun, Xufeng Cen, Bing Shan, Qingwei Zhao, Tingxue Xie, Zhe Wang, Tingjun Hou, Yu Xue, Mengmeng Zhang, Di Peng, Qiming Sun, Cong Yi, Ayaz Najafov, Hongguang Xia
Summary: The study reveals that Metformin can induce CMA through activating the TAK1-IKKα/β signaling pathway to improve the pathogenesis of neurodegenerative diseases. Additionally, Metformin can reduce amyloid-beta plaques in the brain and reverse the molecular and behavioral phenotypes of Alzheimer's disease.
Article
Cardiac & Cardiovascular Systems
Sandor Batkai, Celina Genschel, Janika Viereck, Steffen Rump, Christian Baer, Tobias Borchert, Denise Traxler, Martin Riesenhuber, Andreas Spannbauer, Dominika Lukovic, Katrin Zlabinger, Ena Hasimbegovic, Johannes Winkler, Rita Garamvolgyi, Sonja Neitzel, Mariann Gyoengyoesi, Thomas Thum
Summary: In a chronic model of post-myocardial infarction heart failure, monthly administration of CDR132L improved cardiac function, reversed cardiac remodelling, and ameliorated diastolic function, indicating its safety and therapeutic efficacy for chronic heart failure treatment.
EUROPEAN HEART JOURNAL
(2021)
Article
Cardiac & Cardiovascular Systems
Sandor Batkai, Celina Genschel, Janika Viereck, Steffen Rump, Christian Bar, Tobias Borchert, Denise Traxler, Martin Riesenhuber, Andreas Spannbauer, Dominika Lukovic, Katrin Zlabinger, Ena Hasimbegovic, Johannes Winkler, Rita Garamvoelgyi, Sonja Neitzel, Mariann Gyoengyoesi, Thomas Thum
Summary: The study aimed to evaluate the safety and efficacy of CDR132L in a clinically relevant large animal model of chronic heart failure after myocardial infarction. Results showed that CDR132L treatment significantly improved cardiac function and reversed cardiac remodeling, indicating its potential as a treatment for chronic heart failure.
EUROPEAN HEART JOURNAL
(2021)
Article
Endocrinology & Metabolism
Alexander J. Moody, Marjorie Molina-Wilkins, Geoffrey D. Clarke, Aurora Merovci, Carolina Solis-Herrera, Eugenio Cersosimo, Robert J. Chilton, Patricia Iozzo, Amalia Gastaldelli, Muhammad Abdul-Ghani, Ralph A. DeFronzo
Summary: This study aimed to investigate the effects of pioglitazone on epicardial and paracardial adipose tissue, as well as diastolic function and insulin sensitivity in patients with type 2 diabetes mellitus. The results showed that pioglitazone reduced the areas of epicardial and paracardial adipose tissue, improved left ventricular diastolic function, and increased insulin sensitivity.
DIABETES OBESITY & METABOLISM
(2023)
Article
Genetics & Heredity
Jes-Niels Boeckel, Maximilian Moebius-Winkler, Marion Mueller, Sabine Rebs, Nicole Eger, Laura Schoppe, Rewati Tappu, Karoline E. Kokot, Jasmin M. Kneuer, Susanne Gaul, Diana M. Bordalo, Alan Lai, Jan Haas, Mahsa Ghanbari, Philipp Drewe-Boss, Martin Liss, Hugo A. Katus, Uwe Ohler, Michael Gotthardt, Ulrich Laufs, Katrin Streckfuss-Boemeke, Benjamin Meder
Summary: Alternative mRNA splicing is a fundamental process in increasing the versatility of the genome. In this study, SLM2 is identified as a novel cardiac splicing regulator that plays an essential role in maintaining cardiomyocyte integrity.
GENOMICS PROTEOMICS & BIOINFORMATICS
(2022)
Article
Biochemistry & Molecular Biology
Yanghai Zhang, Chunyan Wang, Mingming Sun, Yutong Jin, Camila Urbano Braz, Hasan Khatib, Timothy A. Hacker, Martin Liss, Michael Gotthardt, Henk Granzier, Ying Ge, Wei Guo
Summary: Arginine-serine (RS) domains play critical roles in protein-protein interaction, splicing control, and nucleocytoplasmic transport. By using mass spectrometry, we identified 16 phosphorylation sites on RS domains, including two sites located in the RSRSP stretch. Mutations on these sites affected splicing, nucleocytoplasmic transport, and protein-RNA condensates. Our study also revealed that RBM20 mutations led to cardiac pathogenesis.
Article
Cardiac & Cardiovascular Systems
Chunyan Wang, Yanghai Zhang, Mei Methawasin, Camila Urbano Braz, Jeffrey Gao-Hu, Betty Yang, Joshua Strom, Jochen Gohlke, Timothy Hacker, Hasan Khatib, Henk Granzier, Wei Guo
Summary: A study found that the RBM20 S639G mutation is associated with dilated cardiomyopathy and early death. By using a knock-in mouse model, researchers showed that this mutation promotes the formation of RBM20 granules in the sarcoplasm and leads to differential expression and splicing of genes related to arrhythmia, cardiomyopathy, and sudden death. Additionally, the knock-in mice exhibited impaired cardiac function.
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
(2022)
Article
Cardiac & Cardiovascular Systems
Mei Methawasin, Gerrie P. Farman, Shawtaroh Granzier-Nakajima, Joshua Strom, Balazs Kiss, John E. Smith, Henk Granzier
Summary: This study reveals the importance of titin's C-zone in regulating cardiac function, as it affects the contraction and relaxation of cardiomyocytes by regulating the length of the thick filament.
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Carlos Henrique Vieira-Vieira, Vita Dauksaite, Anje Sporbert, Michael Gotthardt, Matthias Selbach
Summary: Researchers have developed a quantitative RNA-interactome capture method to assess the function of phosphorylation sites in RNA-binding proteins.
Article
Multidisciplinary Sciences
Elena Ortiz-Zapater, Dustin C. Bagley, Virginia Llopis Hernandez, Luke B. Roberts, Thomas J. A. Maguire, Felizia Voss, Philipp Mertins, Marieluise Kirchner, Isabel Peset-Martin, Grzegorz Woszczek, Jody Rosenblatt, Michael Gotthardt, George Santis, Maddy Parsons
Summary: This study demonstrates the important role of epithelial protein CAR in regulating lung inflammation and remodelling. Deletion of CAR leads to reduced house dust mite-induced lung inflammation, decreased neutrophil accumulation and alterations in airway remodelling.
NATURE COMMUNICATIONS
(2022)
Article
Biochemistry & Molecular Biology
Anika Neuschulz, Olga Bakina, Victor Badillo-Lisakowski, Pedro Olivares-Chauvet, Thomas Conrad, Michael Gotthardt, Helmut Kettenmann, Jan Philipp Junker
Summary: Tissue dissociation during single-cell sample preparation can induce transcriptional changes due to cellular stress response. We developed a method to measure this response by labeling dissociation-induced transcripts for sequencing identification. Our study revealed general and cell-type-specific dissociation response programs in zebrafish larvae, and sample-to-sample variation in mouse cardiomyocyte dissociation response despite controlled conditions. Additionally, we demonstrated the artificial activation of microglia in the mouse hippocampus upon dissociation. Our approach enables experimental optimization and computational removal of transcriptional perturbation response.
MOLECULAR SYSTEMS BIOLOGY
(2023)
Review
Cardiac & Cardiovascular Systems
Michael Gotthardt, Victor Badillo-Lisakowski, Victoria Nicole Parikh, Euan Ashley, Marta Furtado, Maria Carmo-Fonseca, Sarah Schudy, Benjamin Meder, Markus Grosch, Lars Steinmetz, Claudia Crocini, Leslie Leinwand
Summary: Alternative splicing plays a crucial role in determining the diversity of RNA transcripts in the heart. This review discusses its regulation in cardiac development, adaptation, and disease, as well as the advancements in technology and potential applications in cardiovascular medicine. The analysis of cardiac isoform expression can lead to improved diagnosis and therapy.
NATURE REVIEWS CARDIOLOGY
(2023)
Article
Biology
Claudia Matthaeus, Rene Juettner, Michael Gotthardt, Fritz G. Rathjen
Summary: The IgCAM coxsackie-adenovirus receptor (CAR) plays a crucial role in heart development and electrical conduction. This study found that CAR knockout cardiomyocytes showed increased beating frequencies and calcium cycling. It was also discovered that CAR may influence electrical propagation between cardiomyocytes through modulating the localization and oligomerization of Cx43 at the plasma membrane.
Article
Biology
Sarah Nordmeyer, Milena Kraus, Matthias Ziehm, Marieluise Kirchner, Marie Schafstedde, Marcus Kelm, Sylvia Niquet, Mariet Mathew Stephen, Istvan Baczko, Christoph Knosalla, Matthieu-P Schapranow, Gunnar Dittmar, Michael Gotthardt, Martin Falcke, Vera Regitz-Zagrosek, Titus Kuehne, Philipp Mertins
Summary: Pressure overload and volume overload in heart valve diseases lead to specific forms of cardiac remodeling. Proteome profiling of human left ventricular myocardial biopsies revealed differences in protein composition compared to controls, particularly in the areas of extracellular matrix, cytoskeleton, energy metabolism, and proteostasis. Sex-specific differences were also observed. These findings provide insight into the molecular mechanisms of cardiac remodeling in patients with heart valve diseases, which could help in developing personalized treatment strategies.
LIFE SCIENCE ALLIANCE
(2023)
Article
Biochemistry & Molecular Biology
Clara-L. Sandmann, Jana F. Schulz, Jorge Ruiz-Orera, Marieluise Kirchner, Matthias Ziehm, Eleonora Adami, Maike Marczenke, Annabel Christ, Nina Liebe, Johannes Greiner, Aaron Schoenenberger, Michael B. Muecke, Ning Liang, Robert L. Moritz, Zhi Sun, Eric W. Deutsch, Michael Gotthardt, Jonathan M. Mudge, John R. Prensner, Thomas E. Willnow, Philipp Mertins, Sebastiaan van Heesch, Norbert Hubner
Summary: This study analyzes the evolutionary origins of 7,264 recently cataloged human short open reading frames (sORFs) and finds that most of them are evolutionarily young and emerged de novo. The researchers also identify 221 previously missed sORFs that potentially encode peptides smaller than the smallest annotated human microprotein. By conducting mass-spectrometry-based interactome screens and cellular assays, the study associates some of these sORFs with mRNA splicing, translational regulation, and endocytosis-related functions.
Article
Multidisciplinary Sciences
Markus Grosch, Laura Schraft, Adrian Chan, Leonie Kuechenhoff, Kleopatra Rapti, Anne-Maud Ferreira, Julia Kornienko, Shengdi Li, Michael H. Radke, Chiara Kraemer, Sandra Clauder-Muenster, Emerald Perlas, Johannes Backs, Michael Gotthardt, Christoph Dieterich, Maarten M. G. van den Hoogenhof, Dirk Grimm, Lars M. Steinmetz
Summary: Dilated cardiomyopathy can be repaired using CRISPR gene therapy, but challenges with delivery and off-target effects have limited its applicability. By combining AAVMYO viral vector with CRISPR base editors, we repaired patient mutations in the cardiac splice factor Rbm20. Treatment restored cardiac function and showed no evidence of off-target editing.
NATURE COMMUNICATIONS
(2023)
Article
Multidisciplinary Sciences
Julia Kornienko, Marta Rodriguez-Martinez, Kai Fenzl, Florian Hinze, Daniel Schraivogel, Markus Grosch, Brigit Tunaj, Dominik Lindenhofer, Laura Schraft, Moritz Kueblbeck, Eric Smith, Chad Mao, Emily Brown, Anjali Owens, Ardan M. M. Saguner, Benjamin Meder, Victoria Parikh, Michael Gotthardt, Lars M. M. Steinmetz
Summary: The authors demonstrate that loss of interaction with the nuclear importer TNPO3 leads to cytoplasmic mislocalization of RBM20 variants associated with severe dilated cardiomyopathy. Restoring their nuclear localization can alleviate the disease phenotype. These findings provide insight into the molecular mechanism of RBM20 mislocalization and its role in dilated cardiomyopathy.
NATURE COMMUNICATIONS
(2023)
Article
Biochemistry & Molecular Biology
Fabian Freiberg, Meghna Thakkar, Wiebke Hamann, Jacobo Lopez Carballo, Rene Juettner, Felizia K. Voss, Peter M. Becher, Dirk Westermann, Carsten Tschoepe, Arnd Heuser, Oliver Rocks, Robert Fischer, Michael Gotthardt
Summary: Heart attack leads to the death of heart muscle cells, causing lesions that turn into fibrotic tissue. Inhibiting the cell contact protein CAR can limit the damage and improve survival in patients with myocardial infarction, suggesting it as a potential therapeutic target.
EXPERIMENTAL AND MOLECULAR MEDICINE
(2023)
Article
Medicine, Research & Experimental
Ying-Hsi Lin, Jennifer L. Major, Tim Liebner, Zaynab Hourani, Joshua G. Travers, Sara A. Wennersten, Korey R. Haefner, Maria A. Cavasin, Cortney E. Wilson, Mark Y. Jeong, Yu Han, Michael Gotthardt, Scott K. Ferguson, Amrut Ambardekar, Maggie P. Y. Lam, Chunaram Choudhary, Henk L. Granzier, Kathleen C. Woulfe, Timothy A. McKinsey
Summary: This study demonstrates the role of histone deacetylase 6 (HDAC6) in controlling myofibril function and passive stiffness of the heart. Lack of HDAC6 increases myofibril stiffness, while overexpression of HDAC6 decreases myofibril stiffness. The modulation of myofibril stiffness by HDAC6 is dependent on a specific region of the titin protein.
JOURNAL OF CLINICAL INVESTIGATION
(2022)