Pub Date : 2025-10-01DOI: 10.1038/s44161-025-00718-x
Konstantinos Lekkos, Zhilian Hu, Phong D. Nguyen, Hessel Honkoop, Esra Sengul, Rita Alonaizan, Jana Koth, Jun Ying, Madeleine E. Lemieux, Alisha Kenward, Sean Keeley, Bastiaan Spanjaard, Brett W. C. Kennedy, Xin Sun, Katherine Banecki, Helen G. Potts, Gennaro Ruggiero, James Montgomery, Daniela Panáková, Jan Philipp Junker, Lisa C. Heather, Xiaonan Wang, Juan Manuel Gonzalez-Rosa, Jeroen Bakkers, Mathilda T. M. Mommersteeg
In contrast to humans, fish can fully regenerate their hearts after cardiac injury. However, not all fish have the same regenerative potential, allowing comparative inter-species and intra-species analysis to identify the mechanisms controlling successful heart regeneration. Here we report a differential regenerative response to cardiac cryo-injury among different wild-type zebrafish strains. Correlating these data with single-cell and bulk RNA sequencing data, we identify oxidative phosphorylation (OXPHOS) as a positive regulator of long-term regenerative outcome. OXPHOS levels, driven by glycolysis through the malate-aspartate shuttle, increase as soon as cardiomyocyte proliferation decreases, and this increase is required for cardiomyocyte re-differentiation and successful long-term regeneration. Reduced upregulation of OXPHOS in Astyanax mexicanus cavefish results in the absence of a dynamic temporal sarcomere gene expression program during cardiomyocyte re-differentiation. These findings challenge the assumption that OXPHOS inhibits regeneration and reveal targetable pathways to enhance heart repair in humans after myocardial infarction. Lekkos et al. show that a metabolic switch toward oxidative phosphorylation is required for cardiomyocyte re-differentiation and heart regeneration after injury in fish.
{"title":"Oxidative phosphorylation is required for cardiomyocyte re-differentiation and long-term fish heart regeneration","authors":"Konstantinos Lekkos, Zhilian Hu, Phong D. Nguyen, Hessel Honkoop, Esra Sengul, Rita Alonaizan, Jana Koth, Jun Ying, Madeleine E. Lemieux, Alisha Kenward, Sean Keeley, Bastiaan Spanjaard, Brett W. C. Kennedy, Xin Sun, Katherine Banecki, Helen G. Potts, Gennaro Ruggiero, James Montgomery, Daniela Panáková, Jan Philipp Junker, Lisa C. Heather, Xiaonan Wang, Juan Manuel Gonzalez-Rosa, Jeroen Bakkers, Mathilda T. M. Mommersteeg","doi":"10.1038/s44161-025-00718-x","DOIUrl":"10.1038/s44161-025-00718-x","url":null,"abstract":"In contrast to humans, fish can fully regenerate their hearts after cardiac injury. However, not all fish have the same regenerative potential, allowing comparative inter-species and intra-species analysis to identify the mechanisms controlling successful heart regeneration. Here we report a differential regenerative response to cardiac cryo-injury among different wild-type zebrafish strains. Correlating these data with single-cell and bulk RNA sequencing data, we identify oxidative phosphorylation (OXPHOS) as a positive regulator of long-term regenerative outcome. OXPHOS levels, driven by glycolysis through the malate-aspartate shuttle, increase as soon as cardiomyocyte proliferation decreases, and this increase is required for cardiomyocyte re-differentiation and successful long-term regeneration. Reduced upregulation of OXPHOS in Astyanax mexicanus cavefish results in the absence of a dynamic temporal sarcomere gene expression program during cardiomyocyte re-differentiation. These findings challenge the assumption that OXPHOS inhibits regeneration and reveal targetable pathways to enhance heart repair in humans after myocardial infarction. Lekkos et al. show that a metabolic switch toward oxidative phosphorylation is required for cardiomyocyte re-differentiation and heart regeneration after injury in fish.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 10","pages":"1363-1380"},"PeriodicalIF":10.8,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s44161-025-00718-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145208348","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-29DOI: 10.1038/s44161-025-00726-x
K. M. Mellor, U. Varma, P. Koutsifeli, C. L. Curl, J. V. Janssens, L. J. Daniels, G. B. Bernasochi, A. J. A. Raaijmakers, M. Annandale, X. Li, S. L. James, D. J. Taylor, K. Raedschelders, K. L. Weeks, R. J. Mills, R. G. Parton, X. Hu, J. R. Bell, T. J. O’Brien, R. Katare, E. R. Porrello, J. E. Hudson, R. P. Xiao, J. E. Van Eyk, R. A. Gottlieb, L. M. D. Delbridge
Diabetic heart disease is highly prevalent and is associated with the early development of impaired diastolic relaxation. The mechanisms of diabetic heart disease are poorly understood, and it is a condition for which there are no targeted therapies. Recently, disrupted glycogen autophagy (glycophagy) and glycogen accumulation have been identified in the diabetic heart. Glycophagy involves glycogen receptor binding and linking with an ATG8 protein to locate and degrade glycogen within an intracellular phagolysosome. Here we show that glycogen receptor protein starch binding domain protein 1 (STBD1) is mobilized early in the cardiac glycogen response to metabolic challenge in vivo, and that deficiency of a specific ATG8 family protein, γ-aminobutyric acid type A receptor-associated protein-like 1 (GABARAPL1), is associated with diastolic dysfunction in diabetes. Gabarapl1 gene delivery treatment remediated cardiomyocyte and cardiac diastolic dysfunction in type 2 diabetic mice and the diastolic performance of ‘diabetic’ human induced pluripotent stem cell-derived cardiac organoids. We identify glycophagy dysregulation as a mechanism and potential treatment target for diabetic heart disease. Mellor et al. report that deficiency of GABARAPL1, an ATG8-specific linking protein, impairs diastolic function in diabetic mice. This effect can be reversed by gene delivery of the gene encoding GABARAPL1 in diabetic mice and a human organoid model of type 2 diabetes.
{"title":"Targeted glycophagy ATG8 therapy reverses diabetic heart disease in mice and in human engineered cardiac tissues","authors":"K. M. Mellor, U. Varma, P. Koutsifeli, C. L. Curl, J. V. Janssens, L. J. Daniels, G. B. Bernasochi, A. J. A. Raaijmakers, M. Annandale, X. Li, S. L. James, D. J. Taylor, K. Raedschelders, K. L. Weeks, R. J. Mills, R. G. Parton, X. Hu, J. R. Bell, T. J. O’Brien, R. Katare, E. R. Porrello, J. E. Hudson, R. P. Xiao, J. E. Van Eyk, R. A. Gottlieb, L. M. D. Delbridge","doi":"10.1038/s44161-025-00726-x","DOIUrl":"10.1038/s44161-025-00726-x","url":null,"abstract":"Diabetic heart disease is highly prevalent and is associated with the early development of impaired diastolic relaxation. The mechanisms of diabetic heart disease are poorly understood, and it is a condition for which there are no targeted therapies. Recently, disrupted glycogen autophagy (glycophagy) and glycogen accumulation have been identified in the diabetic heart. Glycophagy involves glycogen receptor binding and linking with an ATG8 protein to locate and degrade glycogen within an intracellular phagolysosome. Here we show that glycogen receptor protein starch binding domain protein 1 (STBD1) is mobilized early in the cardiac glycogen response to metabolic challenge in vivo, and that deficiency of a specific ATG8 family protein, γ-aminobutyric acid type A receptor-associated protein-like 1 (GABARAPL1), is associated with diastolic dysfunction in diabetes. Gabarapl1 gene delivery treatment remediated cardiomyocyte and cardiac diastolic dysfunction in type 2 diabetic mice and the diastolic performance of ‘diabetic’ human induced pluripotent stem cell-derived cardiac organoids. We identify glycophagy dysregulation as a mechanism and potential treatment target for diabetic heart disease. Mellor et al. report that deficiency of GABARAPL1, an ATG8-specific linking protein, impairs diastolic function in diabetic mice. This effect can be reversed by gene delivery of the gene encoding GABARAPL1 in diabetic mice and a human organoid model of type 2 diabetes.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 11","pages":"1487-1500"},"PeriodicalIF":10.8,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194142","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Thoracic aortic aneurysm and dissection (TAAD) represent a serious health threat, yet the role of air pollution exposure on its development has been underexplored. Here we investigate the relationships between air pollutants and TAAD incidence. In a Cox’s proportional hazards model, hazard ratios (95% confidence intervals) of TAAD for an interquartile range increase in air pollutants were 2.15 (1.96, 2.35) for particulate matter with an aerodynamic diameter ≤2.5 μm (PM2.5; per 2.15 μg m−3 increase), 1.76 (1.61, 1.92) for PM10 (per 2.99 μg m−3 increase), 1.45 (1.34, 1.58) for NO2 (per 6.97 μg m−3 increase) and 1.40 (1.29, 1.51) for NOx (per 11.58 μg m−3 increase). These estimates remained consistent when using inverse probability weighting and generalized propensity score methods. Furthermore, this study revealed potential joint effects and interactions between air pollutants and genetic susceptibility on TAAD risk, especially the multiplicative and additive interactions between PM2.5 and genetic susceptibility. Air pollution exposure is associated with an increased TAAD risk and genetic susceptibility modifies this association. Ma et al. demonstrate that air pollution is associated with an increased risk of thoracic aortic aneurysm and dissection (TAAD), and that genetic susceptibility to TAAD amplifies this risk through multiplicative and additive interactions.
{"title":"Association of air pollution exposure and genetic susceptibility with increased risk of thoracic aortic aneurysm and dissection","authors":"Yudiyang Ma, Jianing Wang, Linxi Tang, Feipeng Cui, Lei Zheng, Meiqi Xing, Yaohua Tian","doi":"10.1038/s44161-025-00719-w","DOIUrl":"10.1038/s44161-025-00719-w","url":null,"abstract":"Thoracic aortic aneurysm and dissection (TAAD) represent a serious health threat, yet the role of air pollution exposure on its development has been underexplored. Here we investigate the relationships between air pollutants and TAAD incidence. In a Cox’s proportional hazards model, hazard ratios (95% confidence intervals) of TAAD for an interquartile range increase in air pollutants were 2.15 (1.96, 2.35) for particulate matter with an aerodynamic diameter ≤2.5 μm (PM2.5; per 2.15 μg m−3 increase), 1.76 (1.61, 1.92) for PM10 (per 2.99 μg m−3 increase), 1.45 (1.34, 1.58) for NO2 (per 6.97 μg m−3 increase) and 1.40 (1.29, 1.51) for NOx (per 11.58 μg m−3 increase). These estimates remained consistent when using inverse probability weighting and generalized propensity score methods. Furthermore, this study revealed potential joint effects and interactions between air pollutants and genetic susceptibility on TAAD risk, especially the multiplicative and additive interactions between PM2.5 and genetic susceptibility. Air pollution exposure is associated with an increased TAAD risk and genetic susceptibility modifies this association. Ma et al. demonstrate that air pollution is associated with an increased risk of thoracic aortic aneurysm and dissection (TAAD), and that genetic susceptibility to TAAD amplifies this risk through multiplicative and additive interactions.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 10","pages":"1397-1408"},"PeriodicalIF":10.8,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145180705","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-26DOI: 10.1038/s44161-025-00729-8
Rong Tian
Upregulation of PGC-1α in the mouse heart during exercise training maintains mitochondrial homeostasis and promotes physiological hypertrophy by suppressing the stress-induced production of GDF15 in cardiomyocytes independently of its circulating levels. Identification of this cell-autonomous signaling circuit provides novel insights into the functional role of GDF15 in health and diseases. Future studies are warranted to investigate the interaction of PGC-1α and GDF15 in other stress conditions and in human subjects.
{"title":"Interaction of PGC-1α and GDF15 in the stressed heart","authors":"Rong Tian","doi":"10.1038/s44161-025-00729-8","DOIUrl":"10.1038/s44161-025-00729-8","url":null,"abstract":"Upregulation of PGC-1α in the mouse heart during exercise training maintains mitochondrial homeostasis and promotes physiological hypertrophy by suppressing the stress-induced production of GDF15 in cardiomyocytes independently of its circulating levels. Identification of this cell-autonomous signaling circuit provides novel insights into the functional role of GDF15 in health and diseases. Future studies are warranted to investigate the interaction of PGC-1α and GDF15 in other stress conditions and in human subjects.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 10","pages":"1216-1218"},"PeriodicalIF":10.8,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145180765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-26DOI: 10.1038/s44161-025-00721-2
Jonathan S. Achter, Thomas H. L. Jensen, Paola Pisano, Johan S. Bundgaard, Daniel Raaschou-Oddershede, Kasper Rossing, Michael Wierer, Alicia Lundby
Proteomic technologies have advanced our understanding of disease mechanisms, patient stratification and targeted therapies. However, applying cardiac proteomics in translational research requires overcoming the barrier of tissue accessibility. Formalin-fixed, paraffin-embedded (FFPE) heart tissue, widely preserved in pathology collections, remains a largely untapped resource. Here we demonstrate that proteomic profiles are well preserved in FFPE human heart specimens and compatible with high-resolution, quantitative analysis. Quantifying approximately 4,000 proteins per sample, we show this approach effectively distinguishes disease states and subanatomical regions, revealing distinct underlying protein signatures. Specifically, the human sinoatrial node exhibited enrichment of collagen VI and G protein-coupled receptor signaling. Myocardial biopsies from patients with arrhythmogenic cardiomyopathy were characterized by fibrosis and metabolic/cytoskeletal derangements, clearly separating them from donor heart biopsies. This study establishes FFPE heart tissue as a robust resource for cardiac proteomics, enabling retrospective molecular profiling at scale and unlocking archived specimens for disease discovery and precision cardiology. Achter et al. established a protocol for quantitative proteomic profiling of formalin-fixed, paraffin-embedded human cardiac tissues, benchmarked against fresh-frozen samples. They applied it to stratify patients with arrhythmogenic cardiomyopathy and performed deep proteomic analysis of the human sinoatrial node.
{"title":"Quantitative proteomics of formalin-fixed, paraffin-embedded cardiac specimens uncovers protein signatures of specialized regions and patient groups","authors":"Jonathan S. Achter, Thomas H. L. Jensen, Paola Pisano, Johan S. Bundgaard, Daniel Raaschou-Oddershede, Kasper Rossing, Michael Wierer, Alicia Lundby","doi":"10.1038/s44161-025-00721-2","DOIUrl":"10.1038/s44161-025-00721-2","url":null,"abstract":"Proteomic technologies have advanced our understanding of disease mechanisms, patient stratification and targeted therapies. However, applying cardiac proteomics in translational research requires overcoming the barrier of tissue accessibility. Formalin-fixed, paraffin-embedded (FFPE) heart tissue, widely preserved in pathology collections, remains a largely untapped resource. Here we demonstrate that proteomic profiles are well preserved in FFPE human heart specimens and compatible with high-resolution, quantitative analysis. Quantifying approximately 4,000 proteins per sample, we show this approach effectively distinguishes disease states and subanatomical regions, revealing distinct underlying protein signatures. Specifically, the human sinoatrial node exhibited enrichment of collagen VI and G protein-coupled receptor signaling. Myocardial biopsies from patients with arrhythmogenic cardiomyopathy were characterized by fibrosis and metabolic/cytoskeletal derangements, clearly separating them from donor heart biopsies. This study establishes FFPE heart tissue as a robust resource for cardiac proteomics, enabling retrospective molecular profiling at scale and unlocking archived specimens for disease discovery and precision cardiology. Achter et al. established a protocol for quantitative proteomic profiling of formalin-fixed, paraffin-embedded human cardiac tissues, benchmarked against fresh-frozen samples. They applied it to stratify patients with arrhythmogenic cardiomyopathy and performed deep proteomic analysis of the human sinoatrial node.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 10","pages":"1409-1423"},"PeriodicalIF":10.8,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s44161-025-00721-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145180745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-25DOI: 10.1038/s44161-025-00722-1
Fanhua Guo, Chenyang Zhao, Qinyang Shou, Ning Jin, Kay Jann, Xingfeng Shao, Danny JJ Wang
Arterial pulsation is crucial for promoting neurofluid circulation. Most previous studies quantified pulsatility via blood velocity-based indices in large arteries. Here we propose an innovative method to quantify the microvascular volumetric pulsatility index (mvPI) across cortical layers and white matter (WM) using high-resolution four-dimensional (4D) vascular space occupancy (VASO) and arterial spin labeling (ASL) magnetic resonance imaging (MRI) at 7 T with simultaneous pulse recording. We assessed aging-related changes in mvPI in 11 young (28.4 ± 5.8 years) and 12 older (60.2 ± 6.8 years) participants and compared mvPI with large artery pulsatility assessed by 4D-flow MRI. mvPI peaked in the pial surface (0.18 ± 0.04). Deep WM mvPI was significantly higher in older participants (P = 0.006) than young ones. Deep WM mvPI correlated with large artery velocity PI (r = 0.56, P = 0.0099). We performed test–retest scans, non-parametric reliability test and simulations to demonstrate the reproducibility and accuracy of the method. In conclusion, our non-invasive method enables in vivo fine-grained measurement of mvPI, with implications for glymphatic function, aging and neurodegenerative diseases. Guo, Zhao and colleagues use high-resolution 7 T MRI to measure the pulsatility of cerebral small vessels and uncover age-related differences in vascular dynamics, which offer new insights into mechanisms of brain aging and vascular risks.
{"title":"Assessing cerebral microvascular volumetric with high-resolution 4D cerebral blood volume MRI at 7 T","authors":"Fanhua Guo, Chenyang Zhao, Qinyang Shou, Ning Jin, Kay Jann, Xingfeng Shao, Danny JJ Wang","doi":"10.1038/s44161-025-00722-1","DOIUrl":"10.1038/s44161-025-00722-1","url":null,"abstract":"Arterial pulsation is crucial for promoting neurofluid circulation. Most previous studies quantified pulsatility via blood velocity-based indices in large arteries. Here we propose an innovative method to quantify the microvascular volumetric pulsatility index (mvPI) across cortical layers and white matter (WM) using high-resolution four-dimensional (4D) vascular space occupancy (VASO) and arterial spin labeling (ASL) magnetic resonance imaging (MRI) at 7 T with simultaneous pulse recording. We assessed aging-related changes in mvPI in 11 young (28.4 ± 5.8 years) and 12 older (60.2 ± 6.8 years) participants and compared mvPI with large artery pulsatility assessed by 4D-flow MRI. mvPI peaked in the pial surface (0.18 ± 0.04). Deep WM mvPI was significantly higher in older participants (P = 0.006) than young ones. Deep WM mvPI correlated with large artery velocity PI (r = 0.56, P = 0.0099). We performed test–retest scans, non-parametric reliability test and simulations to demonstrate the reproducibility and accuracy of the method. In conclusion, our non-invasive method enables in vivo fine-grained measurement of mvPI, with implications for glymphatic function, aging and neurodegenerative diseases. Guo, Zhao and colleagues use high-resolution 7 T MRI to measure the pulsatility of cerebral small vessels and uncover age-related differences in vascular dynamics, which offer new insights into mechanisms of brain aging and vascular risks.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 10","pages":"1424-1438"},"PeriodicalIF":10.8,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s44161-025-00722-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145152332","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-24DOI: 10.1038/s44161-025-00712-3
Sumeet A. Khetarpal, Haobo Li, Tevis Vitale, James Rhee, Saketh Challa, Claire Castro, Steffen Pabel, Yizhi Sun, Jing Liu, Dina Bogoslavski, Ariana Vargas-Castillo, Amanda L. Smythers, Katherine A. Blackmore, Louisa Grauvogel, Melanie J. Mittenbühler, Melin J. Khandekar, Casie Curtin, Jose Max Narvaez-Paliza, Chunyan Wang, Nicholas E. Houstis, Hans-Georg Sprenger, Sean J. Jurgens, Kiran J. Biddinger, Alexandra Kuznetsov, Rebecca Freeman, Patrick T. Ellinor, Matthias Nahrendorf, Joao A. Paulo, Steven P. Gygi, Phillip A. Dumesic, Aarti Asnani, Krishna G. Aragam, Pere Puigserver, Jason D. Roh, Bruce M. Spiegelman, Anthony Rosenzweig
Endurance exercise promotes adaptive growth and improved function of myocytes, which is supported by increased mitochondrial activity. In skeletal muscle, these benefits are in part transcriptionally coordinated by peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). The importance of PGC-1α to exercise-induced adaptations in the heart has been unclear. Here we show that deleting PGC-1α specifically in cardiomyocytes prevents the expected benefits from exercise training and instead leads to heart failure after just 6 weeks of training. Consistent with this, in humans, rare genetic variants in PPARGC1A, which encodes PGC-1α, are associated with increased risk of heart failure. In this model, we identify growth differentiation factor 15 (GDF15) as a key heart-secreted mediator that contributes to this dysfunction. Blocking cardiac Gdf15 expression improves cardiac performance and exercise capacity in these mice. Finally, in human heart tissue, lower cardiomyocyte PPARGC1A expression is associated with higher GDF15 expression and reduced cardiomyocyte density. These findings uncover a crucial role for cardiomyocyte PGC-1α in enabling healthy cardiac adaptation to exercise in part through suppression of GDF15. Khetarpal et al. show that the metabolic regulator PGC-1α is essential in heart muscle cells for exercise-driven cardiac growth, and that suppression of the stress-induced myokine GDF15 is required to enable cardiomyocyte adaptations to training.
{"title":"Cardiac adaptation to endurance exercise training requires suppression of GDF15 via PGC-1α","authors":"Sumeet A. Khetarpal, Haobo Li, Tevis Vitale, James Rhee, Saketh Challa, Claire Castro, Steffen Pabel, Yizhi Sun, Jing Liu, Dina Bogoslavski, Ariana Vargas-Castillo, Amanda L. Smythers, Katherine A. Blackmore, Louisa Grauvogel, Melanie J. Mittenbühler, Melin J. Khandekar, Casie Curtin, Jose Max Narvaez-Paliza, Chunyan Wang, Nicholas E. Houstis, Hans-Georg Sprenger, Sean J. Jurgens, Kiran J. Biddinger, Alexandra Kuznetsov, Rebecca Freeman, Patrick T. Ellinor, Matthias Nahrendorf, Joao A. Paulo, Steven P. Gygi, Phillip A. Dumesic, Aarti Asnani, Krishna G. Aragam, Pere Puigserver, Jason D. Roh, Bruce M. Spiegelman, Anthony Rosenzweig","doi":"10.1038/s44161-025-00712-3","DOIUrl":"10.1038/s44161-025-00712-3","url":null,"abstract":"Endurance exercise promotes adaptive growth and improved function of myocytes, which is supported by increased mitochondrial activity. In skeletal muscle, these benefits are in part transcriptionally coordinated by peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). The importance of PGC-1α to exercise-induced adaptations in the heart has been unclear. Here we show that deleting PGC-1α specifically in cardiomyocytes prevents the expected benefits from exercise training and instead leads to heart failure after just 6 weeks of training. Consistent with this, in humans, rare genetic variants in PPARGC1A, which encodes PGC-1α, are associated with increased risk of heart failure. In this model, we identify growth differentiation factor 15 (GDF15) as a key heart-secreted mediator that contributes to this dysfunction. Blocking cardiac Gdf15 expression improves cardiac performance and exercise capacity in these mice. Finally, in human heart tissue, lower cardiomyocyte PPARGC1A expression is associated with higher GDF15 expression and reduced cardiomyocyte density. These findings uncover a crucial role for cardiomyocyte PGC-1α in enabling healthy cardiac adaptation to exercise in part through suppression of GDF15. Khetarpal et al. show that the metabolic regulator PGC-1α is essential in heart muscle cells for exercise-driven cardiac growth, and that suppression of the stress-induced myokine GDF15 is required to enable cardiomyocyte adaptations to training.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 10","pages":"1277-1294"},"PeriodicalIF":10.8,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145139652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-17DOI: 10.1038/s44161-025-00711-4
Benjamin G. Chapman, Konstantinos Klaourakis, Carla de Villiers, Mala Gunadasa-Rohling, Maria-Alexa Cosma, Susanna T. E. Cooper, Kshitij Mohan, Michael Weinberger, Carolyn A. Carr, David R. Greaves, David G. Jackson, Daniela Pezzolla, Robin P. Choudhury, Joaquim M. Vieira, Paul R. Riley
In adult mice, myocardial infarction (MI) activates the cardiac lymphatics, which undergo sprouting angiogenesis (lymphangiogenesis), drain interstitial fluid and traffic macrophages to mediastinal lymph nodes (MLNs). This prevents edema and reduces inflammatory/fibrotic immune cell content to improve cardiac function. Here we investigated the role of cardiac lymphatics and macrophage clearance across the neonatal mouse regenerative window. The response to injury revealed limited lymphangiogenesis and clearance of macrophages from postnatal day 1 compared to postnatal day 7 infarcted hearts. This coincides with the maturation of lymphatic endothelial cell junctions from impermeable to permeable and with altered signaling between lymphatic endothelial cells and macrophages. Mice lacking the lymphatic endothelial receptor-1 (LYVE-1), where macrophage lymphatic trafficking is impaired in adults, experienced worse long-term outcomes after MI induced at postnatal day 1, suggesting an alternative role for LYVE-1 in macrophages. Macrophage-specific deletion of Lyve1 during neonatal heart injury impaired heart regeneration. This study demonstrates that immature cardiac lymphatics are impermeable to clearance in early neonates, ensuring retention of pro-regenerative LYVE-1-dependent macrophages. Chapman, Klaourakis and colleagues reveal that a lymphatic vasculature with poor clearance capacity in perinatal, regeneration-competent mouse hearts is required to retain pro-reparative macrophages and allow cardiac regeneration.
{"title":"Cardiac lymphatics retain LYVE-1-dependent macrophages during neonatal mouse heart regeneration","authors":"Benjamin G. Chapman, Konstantinos Klaourakis, Carla de Villiers, Mala Gunadasa-Rohling, Maria-Alexa Cosma, Susanna T. E. Cooper, Kshitij Mohan, Michael Weinberger, Carolyn A. Carr, David R. Greaves, David G. Jackson, Daniela Pezzolla, Robin P. Choudhury, Joaquim M. Vieira, Paul R. Riley","doi":"10.1038/s44161-025-00711-4","DOIUrl":"10.1038/s44161-025-00711-4","url":null,"abstract":"In adult mice, myocardial infarction (MI) activates the cardiac lymphatics, which undergo sprouting angiogenesis (lymphangiogenesis), drain interstitial fluid and traffic macrophages to mediastinal lymph nodes (MLNs). This prevents edema and reduces inflammatory/fibrotic immune cell content to improve cardiac function. Here we investigated the role of cardiac lymphatics and macrophage clearance across the neonatal mouse regenerative window. The response to injury revealed limited lymphangiogenesis and clearance of macrophages from postnatal day 1 compared to postnatal day 7 infarcted hearts. This coincides with the maturation of lymphatic endothelial cell junctions from impermeable to permeable and with altered signaling between lymphatic endothelial cells and macrophages. Mice lacking the lymphatic endothelial receptor-1 (LYVE-1), where macrophage lymphatic trafficking is impaired in adults, experienced worse long-term outcomes after MI induced at postnatal day 1, suggesting an alternative role for LYVE-1 in macrophages. Macrophage-specific deletion of Lyve1 during neonatal heart injury impaired heart regeneration. This study demonstrates that immature cardiac lymphatics are impermeable to clearance in early neonates, ensuring retention of pro-regenerative LYVE-1-dependent macrophages. Chapman, Klaourakis and colleagues reveal that a lymphatic vasculature with poor clearance capacity in perinatal, regeneration-competent mouse hearts is required to retain pro-reparative macrophages and allow cardiac regeneration.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 10","pages":"1258-1276"},"PeriodicalIF":10.8,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s44161-025-00711-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145081798","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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