Grupos de investigación

Permanent URI for this collectionhttps://hdl.handle.net/20.500.12105/19587

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Immune mitochondrial complex I mediates vascular damage in toll-like receptor 7 (TLR7)-induced lupus.
(ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD, 2025-10) Miñano, Sofía; Moleón, Javier; González-Correa, Cristina; Robles-Vera, Iñaki; Gómez-Guzmán, Manuel; Sánchez, Manuel; Bayraktar, Semih; Visitación, Néstor de la; Martín-Morales, Natividad; O'Valle, Francisco; Romero, Miguel; Sancho, David; Toral, Marta; Duarte, Juan
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by immune dysregulation and high cardiovascular risk, including hypertension and endothelial dysfunction. Metabolic reprogramming of immune cells, particularly CD4 + T cells, contributes to SLE pathogenesis. We investigated the role of mitochondrial metabolism, specifically the NDUFS4 subunit of complex I, in immune cells during lupus induced by toll-like receptor (TLR)7 activation with imiquimod (IMQ). We analyzed transcriptomic data from peripheral blood mononuclear cells obtained from SLE patients and their matched healthy controls showing that dendritic cells and undetermined cells exhibited the highest mean expression levels of NDUFS4. Using bone marrow chimeric mice, we demonstrate that NDUFS4 deficiency in hematopoietic cells prevents IMQ-induced hypertension, reduces autoantibody production, and limits vascular oxidative stress, inflammation, and kidney injury. These effects are associated with a shift in CD4 + T cell polarization toward regulatory T cells and a reduction in Th1 and Th17 subsets in the spleen and blood. Pharmacological dual inhibition of glycolysis with 2-deoxy-D-glucose and mitochondrial metabolism with metformin further supports the therapeutic potential of metabolic targeting, improving vascular function and preventing aortic remodeling, characterized by proteoglycan and collagen accumulation, increased aortic stiffness, and secretory and profibrotic phenotypes. These interventions reduce oxidative stress and immune cell infiltration in the vascular wall, mitigating endothelial dysfunction and the shift to a synthetic phenotype. Our findings highlight mitochondrial complex I as a critical modulator of immune-mediated vascular damage in lupus induced by TLR7 activation and propose metabolic reprogramming as a promising therapeutic strategy for lupus-associated cardiovascular complications.
A sweet spot in myeloid cell pro-tumoral functions.
(Cell Press, 2025-06-10) Dunphy, Gillian; Sancho, David
The regulation of myeloid cell responses can determine tumor outcomes. In this issue of Immunity, Blidner et al. report that galectin-1 triggers both immunoregulatory and pro-angiogenic circuits in myeloid cells, promoting tumor growth via a VEGF-dependent mechanism.
Metabolic support of trained immune responses in myeloid cells.
(eLIFE SCIENCES PUBL LTD, 2026-06-19) Jarit-Cabanillas, Aitor; Dunphy, Gillian; Virga, Federico; Van den Bossche, Jan; Sancho, David
Trained immunity (TI) is defined as a form of innate immune memory characterised by a long-lasting ability to develop enhanced responses to a secondary challenge, whether of the same or a different nature than the initial stimulus. This process is mediated by several established hallmarks, most prominently the existence of activating epigenetic marks and metabolic adaptations. The activating epigenetic marks prime the expression of immune-related genes and are a direct driving force behind the increased cytokine production after secondary stimulation of trained monocytes and macrophages. Training stimuli also induce specific metabolic adaptations, such as the upregulation of glycolysis and lactate production or the activation of glutaminolysis leading to fumarate accumulation, which in turn promotes epigenetic changes. However, the mechanisms linking these epigenetic and metabolic changes to a TI phenotype are varied, and not all stimuli that increase glycolysis promote training, whereas some stimuli such as lipopolysaccharide (LPS) display a non-monotonic induction of TI. In addition to metabolism directly driving epigenetic changes, early gene expression changes can also reshape cell metabolism to promote a trained phenotype. In this review we aim to separate two main types of metabolic rewiring that have not been previously uncoupled. Firstly, those primary metabolic changes occurring during the initial stimulation, which precede TI induction by altering the epigenomic landscape around inflammatory genes. Secondly, those metabolic adaptations arising later as a consequence of the first wave of epigenetic regulation, which support an enhanced functional state of macrophages.
Reaching for the cure as progeria research comes of age at the 12th international scientific workshop.
(SPRINGERNATURE, 2026-07) Eriksson, Maria; Andrés, Vicente; Kieran, Mark W; Gordon, Leslie B
Vascular cell types in progeria: victims or villains?
(2026-01) Benedicto, Ignacio; Hamczyk, Magda R; Dorado, Beatriz; Andrés, Vicente
Hutchinson-Gilford progeria syndrome (HGPS) is an ultrarare genetic disease caused by progerin, a broadly expressed mutant variant of lamin A protein that accelerates aging and leads to premature death typically in adolescence. Progerin affects many organs and reproduces many characteristics of physiological aging, with the main cause of death in HGPS being atherosclerotic cardiovascular disease (CVD). Due to the rarity of HGPS, advances in understanding the disease and progress toward new therapeutic approaches are crucially dependent on preclinical models. We discuss recent research developments from a variety of HGPS experimental systems, with a special focus on in vivo studies of the role of vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) that are key players in atherosclerosis.
Low-dose Empagliflozin Does Not Modify Myocardial Energetics and Function in a Large-animal Model of Hibernating Myocardium.
(SPRINGER, 2026-06-18) Medina-Hernández, Danielle; Galán-Arriola, Carlos; Cepas, Pedro Luis; Pérez-Camargo, Daniel; Cádiz, Laura; Pereda, Daniel; Sánchez-González, Javier; García-Alvarez, Ana; Ibáñez, Borja
Adaptive motility enables neutrophils to rapidly navigate confined capillaries.
(AMER ASSOC ADVANCEMENT SCIENCE, 2026-09-04) Deygas, Mathieu; Bernard, Mathilde; Nivoit, Pierre; De Belly, Henry; Deslys, Alexandre; Jakuszeit, Theresa; Cuvelier, Damien; Garcia-Gomez, Moira; Barbier, Lucie; Wang, Li; Maurin, Mathieu; Tejerina, Emmanuel; Baaziz, Oumaima; Terriac, Emmanuel; Attia, Rafaele; Kniazeva, Anna; Garbay, Serge; Ortega-Zapero, Marina; Saez, Angela; Gomez-Bris, Raquel; Gonzalo, Pilar; Gonzalez-Granado, Jose M; Andrés, Vicente; Weiner, Orion D; Lennon-Duménil, Ana-Maria; Duménil, Guillaume; Piel, Matthieu; Vargas, Pablo
To reach inflamed tissues, neutrophils must traverse capillaries as narrow as 2 micrometers. However, how they do so without compromising blood flow or capillary function has remained unclear. By combining intravital live-cell imaging with biomimetic microdevices, we show that neutrophils maintain migration speed in capillaries across increasing levels of confinement. This behavior was not shared by other leukocytes and was independent of nuclear properties. Instead, confinement rapidly engaged Rho-dependent actomyosin contractility at the cell rear, thereby offsetting the increased mechanical resistance imposed by confinement. Disrupting this adaptive response caused neutrophil jamming and eventual occlusion of confined capillary-like networks. These findings identify a neutrophil-intrinsic mechanism that couples capillary confinement to rapid migratory adaptation, helping preserve vascular patency and potentially limiting tissue dysfunction during inflammation.
Ten quick tips for causal analysis of biomedical omics data.
(2026-08) Svinin, Gleb; Loo, Rebecca Ting Jiin; Kumar, Nikhilesh Vasantha; Murthy, Varsha Venkatesha; Odongo, Dilara Uzuner; Díaz-Uriarte, Ramón; Conesa, Ana; Bontempi, Gianluca; Vinga, Susana; Granata, Ilaria; Domingo-Fernández, Daniel; Lecca, Paola; Kuijjer, Marieke L; Krijthe, Jesse H; Koch, Ina; Calzone, Laurence; Rombo, Simona Ester; Sánchez-Cabo, Fátima; Glaab, Enrico
Haptoglobin and Immunoglobulin A2 Predict Cardiovascular Risk in Asymptomatic Subjects: The BioImage Study.
(WILEY, 2026-09-09) García-Álvarez, Ana; Fuster, Valentín; Nuñez, Estefanía; Owen, Ruth; Ortega-Villanueva, Lucia; Mass, Virginia; García-Lunar, Inés; Quesada, Antonio; Fuster, Jose Javier; Devesa, Ana; Pérez-García, Carlos Nicolás; Sánchez-Gonzalez, Javier; Muntendam, Pieter; Andrés, Vicente; Blanco-Colio, Luis Miguel; Vázquez, Jesús; Ibañez, Borja; Martin-Ventura, Jose Luis
Plasma levels of haptoglobin and IgA2 (immunoglobulin A2) have recently been associated with subclinical atherosclerosis in European cohorts. We sought to validate these findings in an American population and to determine whether these biomarkers predict all-cause mortality or major cardiovascular adverse events beyond traditional risk scales (Framingham Risk Score) or vascular imaging. We analyzed 5328 asymptomatic US adults (mean age 69 years, 56.9% women) from the BioImage study (A Clinical Study of Burden of Atherosclerotic Disease in an At-Risk Population; NCT00738725). Subjects underwent carotid plaque burden assessment by ultrasound, coronary artery calcium by computed tomography, and baseline plasma haptoglobin and IgA2 levels measurement by immunoturbidimetry. The end point was a composite of major cardiovascular adverse events and all-cause death during follow-up. Haptoglobin and IgA2 correlated significantly with carotid plaque burden and coronary artery calcium, independent of Framingham Risk Score. After a median follow-up of 4.6 years, 466 participants (8.8%) experienced the composite outcome. Haptoglobin and IgA2 independently predicted the outcome, and associations remained significant after further adjustment for carotid plaque burden or coronary artery calcium. Similar results were observed for predictive capacity of high-sensitivity C-reactive protein. Individuals with high levels of all biomarkers (above the median) had a 2-fold higher event rate compared with those with low levels. Combined biomarker assessment, albeit modestly, significantly improved risk prediction beyond Framingham Risk Score and imaging. Haptoglobin and IgA2 predict the composite outcome of major cardiovascular adverse events and all-cause death, independently to Framingham Risk Score, in asymptomatic American adults. Their measurement, alone or in combination with imaging, may enhance cardiovascular risk stratification in primary prevention.
Tissue mitochondrial activity dictates the macrophage pool size.
(AMER ASSOC ADVANCEMENT SCIENCE, 2026-09-04) Pena-Couso, Laura; Sicilia, Jon; Vieto, Sofía; Silva-Rojas, Roberto; Sánchez-Díaz, María; Calvo, Enrique; Romero-Becerra, Rafael; Folgueira, Cintia; Herrera-Melle, Leticia; Justo-Méndez, Raquel; Hong, Xiaotong; Campanario, Silvia; López, Juan A; Crainiciuc, Georgiana; Gil, María; Martín-Salamanca, Sandra; Lukesova, Vera; Segalés, Jessica; Serrano, Antonio L; Ballesteros, Iván; León, Marta; de Andrés-Laguillo, Macarena; Stifter, Sebastian A; Esteban-Martínez, Lorena; Isern, Joan; Alegre-Cebollada, Jorge; Torres, Miguel; Greter, Melanie; Vázquez, Jesús; Enríquez, José A; Sabio-Buzo, Guadalupe; Muñoz-Cánoves, Pura; Hidalgo, Andrés; Nicolás-Ávila, José A
Removal of cellular waste from the extracellular space is fundamental for tissue health. Because the rate of material ejected by parenchymal cells varies across tissues, we searched for mechanisms that couple waste production and removal. Here, we show that the uptake of parenchyma-released mitochondria by macrophages is prominent across organs that rely on oxidative respiration-including heart, skeletal muscle, and brown adipose tissue-and that macrophage numbers closely align with the mitochondrial activity of each of these organs. We found that the mitochondrial activity of myofibers dictates the abundance of macrophages by modulating colony-stimulating factor 1 (CSF1) availability and the number of CSF1-producing fibroblasts in the tissue. Consequently, inhibition of CSF1-CSF1 receptor (CSF1R) signaling depleted macrophages and collapsed the mitochondrial activity of skeletal muscles. We propose that, by coupling macrophage abundance to the mitochondrial activity of their parenchyma, tissues ensure efficient waste disposal and fitness.
Loss of SHP-1 in CD11c cells impairs anti-tumor immunity.
(FRONTIERS MEDIA, 2026) Galán, Miguel; Hernández-García, Elena; Munné, Pablo; Redondo-Urzainqui, Ana; Cueto, Francisco J; Sicilia, Jon; Alejano, Sergio Callejas; Rey-Martín, M Ascensión; Dopazo, Ana; Sancho, David; Iborra, Salvador
Tyrosine kinases and phosphatases regulate protein phosphorylation and maintain cellular homeostasis. The phosphoprotein tyrosine phosphatase SHP-1 (encoded by the gene) has been proposed as an immune checkpoint in CD8 T cells in preclinical models, yet its pharmacological inhibition has shown no efficacy against tumor growth in clinical trials. This suggests that SHP-1 may play opposing roles in different cell types within the tumor microenvironment. Here, we investigated the effect of depleting SHP-1 in CD11c cells on the anti-tumoral response. To dissect the specific role of SHP1 in CD11c antigen-presenting cells, or specifically in conventional type 1 dendritic cells (cDC1s) or macrophages, we subcutaneously inoculated different tumors in , Δ and Δ mice, respectively. Tumor growth and survival were monitored, and immune infiltrates were analyzed using flow cytometry or scRNA-seq. Tumor rejection was impaired when SHP-1 was depleted in CD11c cells, as well as in XCR1 or Lyz2 cells. scRNA-seq analysis revealed that both tumor-associated macrophages and cDC1s exhibited downregulation of interferon response pathways in tumor-bearing mice compared with controls. Reduced MHC-II expression in tumor-associated macrophages was validated by flow cytometry, supporting impaired antigen presentation in these cells, whereas cDC subsets displayed heterogeneous alterations in co-stimulatory marker expression rather than a defect. Consistent with these findings, flow cytometry analysis showed that mice injected with MC38 tumor and treated with anti-PD1 displayed a reduction in CD8 IFN-γ cells in comparison with littermates. These results show that SHP-1 depletion in CD11c cells impairs anti-tumor immunity and suggest that both cDC1s and macrophages contribute to this effect.
Mitochondrial metabolism regulates the immunogenic responsiveness of dendritic cells.
(CELL PRESS, 2026-06-02) Heras-Murillo, Ignacio; Mañanes, Diego; Calafell-Segura, Josep; Belinchón García, Adrián; Borràs-Eroles, Clara; Munné, Pablo; Mastrangelo, Annalaura; Martínez-Cano, Sarai; Hernansanz-Agustín, Pablo; Zuriaga, María A; Fuster, José J; Szibor, Marten; Melero, Ignacio; Enríquez, José Antonio; Chandel, Navdeep S; Ballestar, Esteban; Wculek, Stefanie K; Sancho, David
Activation of conventional dendritic cells (cDCs) favors increased glycolysis-driven lactic fermentation, while oxidative phosphorylation (OXPHOS) links to tolerance. Here, selective targeting of the mitochondrial electron transport chain (ETC) in cDCs uncovers a critical role for OXPHOS in regulating their immunogenicity. Disruption of ETC complex III dampens adjuvant-triggered primary human and mouse cDC1 activation and their capability to prime T cells for anti-cancer immunity, while it has a milder effect on cDC2s. Mechanistically, complex III impairment in cDC1s leads to a dysregulated redox and metabolite balance, altering DNA methylation of PU.1 and activator-protein-1 (AP-1) binding regions. These epigenetic changes hinder the rapid induction of immediate-early stimulus-induced genes in cDC1s upon stimulation. The reduced immunogenic responsiveness of ETC-impaired cDC1s can be rescued by ectopic expression of alternative oxidase and phenocopied by Tet2 deficiency. Our findings reveal that electron flow through the ETC maintains a poised activation state in cDC1s, essential for effective anti-tumor immunity.
NOD1 is a key mediator of atrial myopathy in heart failure.
(IVYSPRING INT PUBL, 2026) Gil-Fernández, Marta; Val-Blasco, Almudena; Bueno-Sen, Andrea; Cantolla-Pablo, Paula; Galán-Arriola, Carlos; Ayaon, Ali; López-Fernández, Teresa; Aguilar-Sanchez, Yuriana; Lahiri, Satadru K; Navarro-García, José Alberto; Peinado, Rafael; Aroca, Angel; Rubio, Miguel Ángel; Blázquez, José Antonio; Tamayo, María; López-Collazo, Eduardo; Ruiz-Hurtado, Gema; Jorge, Inmaculada; Vázquez, Jesús; Prieto, Patricia; Smani, Tarik; Ordoñez, Antonio; Filgueiras-Dama, David; Moreno, Raúl; Rivero-Santana, Borja; Nuche, Jorge; Jalife, José; Ibáñez, Borja; Delgado, Carmen; Boscá, Lisardo; Wehrens, Xander H T; Fernández-Velasco, María
Heart failure (HF)-associated atrial myopathy is driven by complex and poorly understood mechanisms. Emerging evidence suggests that innate immune components contribute to atrial remodeling, yet the role of nucleotide-binding oligomerization domain-containing protein 1 (NOD1) receptors remains unclear. NOD1 expression was characterized in atrial myocardium of HF patients (n = 36) and non-failing controls (n = 45) undergoing valve surgery, and in two porcine models of atrial myopathy with divergent ventricular phenotypes: aortic banding (AoB; preserved LVEF) and left atrial infarction (LAI; reduced LVEF). The causal role of NOD1 in atrial remodeling was assessed using genetic ( and pharmacological (ML-130) loss-of-function approaches in a murine transverse aortic constriction (TAC) model, and through selective NOD1 activation with C12-iE-DAP in wild-type, , and -S2814A mice. Proteomic, phosphoproteomic, transcriptomic, and Ca²⁺ imaging analyses were performed across experimental systems. NOD1 was markedly upregulated in atrial myocardium of HF patients and in both porcine models, across divergent ventricular phenotypes and irrespective of documented rhythm status, correlating with structural and functional indices of atrial disease severity. Genetic NOD1 deficiency in TAC mice prevented atrial dysfunction, structural remodeling, activation of profibrotic molecular pathways and Ca²⁺ mishandling. Pharmacological NOD1 inhibition with ML-130 reproduced the protective effects on atrial structural and Ca²⁺ handling. Selective NOD1 activation with C12-iE-DAP induced atrial Ca²⁺ dysregulation through CaMKII-dependent RyR2-Ser2814 hyperphosphorylation, effects that were abrogated by CaMKII inhibition, and absent in -S2814A mice. Human atrial transcriptomic analysis confirmed enrichment of inflammatory, Ca²⁺-signaling, and extracellular matrix remodeling pathways in HF. Increased CaMKII phosphorylation in human atrial myocardium further corroborated the translational relevance of the NOD1-CaMKII-RyR2 axis. These findings identify the NOD1-CaMKII-RyR2 axis as a cardiomyocyte-centered mechanism linking innate immune activation to atrial Ca²⁺ dysregulation and structural remodeling in HF, establishing NOD1 as a molecular indicator of atrial myopathy burden and a mechanism-based therapeutic target.
Inverse correlation between plasma pyrophosphate hydrolysis and early growth of abdominal aortic aneurysm: a pilot study.
(SPRINGER, 2026-01-04) Villa-Bellosta, Ricardo; Lindholt, Jes S; Martin-Ventura, Jose Luis
Abdominal aortic aneurysm (AAA) is often associated with vascular calcification, the calcium-phosphate crystal deposition in the aortic wall, which could impact aneurysm progression and/or stability. Tissue-nonspecific alkaline phosphatase (TNAP) hydrolyzes pyrophosphate-a natural inhibitor of calcification-thereby promoting calcium deposition. This study analyzes phosphatase activity and pyrophosphate dynamics in the plasma of AAA patients, randomly selected from the whole VIVA cohort, including controls (n = 48, aortic diameter in < 30 mm) and small AAA patients (n = 96, aortic diameter 30-55 mm), which were stratified by growth rate (low < 2 mm/year or high > 2 mm/year, n = 48 in each group), initially adjusted by aortic diameter. The phosphatase activity was assessed at physiological (7.4) and optimal (10.5) pH levels. Phosphatase activity was significantly higher in AAA patients at physiological pH, a pattern absent at optimal pH, suggesting disease-specific alterations. Small AAA patients showed notably higher phosphatase activity and pyrophosphate hydrolysis than controls at physiological pH. An inverse correlation was also observed between phosphatase activity and aortic growth rate. KEY MESSAGES: Increased alkaline phosphatase activity was detected in heparin-plasma samples from patients with abdominal aortic aneurysm at physiological pH (7.4), but not under optimal experimental conditions (pH 10.5), suggesting a disease-related effect that may reflect processes occurring in vivo. Concentrations of tissue-nonspecific alkaline phosphatase in heparin-plasma samples remained unchanged, despite increased hydrolysis of pyrophosphate, a key inhibitor of vascular calcification. Pyrophosphate hydrolysis in heparin-plasma samples correlated inversely with aortic growth rate in abdominal aortic aneurysm patients.
Anthracycline cardiotoxicity: role of metabolic vulnerability induced by cardiac pressure overload.
(OXFORD UNIV PRESS, 2026-01-13) Galán-Arriola, Carlos; Pérez-Camargo, Daniel; Jorge, Inmaculada; Bautista, Víctor; Ayaon-Albarrán, Ali; Pérez-Martínez, Claudia; de Molina-Iracheta, Antonio; Cádiz, Laura; Medina-Hernández, Danielle; Caballero-Henares, Carlos; Lopez-Martín, Gonzalo J; Vázquez, Jesús; Ochala, Julien; Fuster, Valentin; Sánchez-González, Javier; Ibáñez, Borja
Hypertension and valvular heart disease, both associated with left ventricular (LV) pressure overload, increase the risk of anthracycline cardiotoxicity. While epidemiologically established, the underlying mechanisms remain unclear, precluding identification of therapeutic targets. Two-month-old Yucatan pigs (males and females) underwent aortic banding to induce LV pressure overload or no operation. After 4 months, animals received a low-risk cumulative dose of doxorubicin (5 weekly 1 mg/kg intravenous injections) or vehicle, generating four groups: (i) healthy controls (no LV overload, no doxorubicin), (ii) Dox (doxorubicin, no LV overload), (iii) Banding (B: LV overload, no doxorubicin), and (iv) B + Dox (LV overload plus doxorubicin). Cardiac function, structure, and metabolism were assessed over 8 months by cardiac magnetic resonance, magnetic resonance spectroscopy, and hybrid positron emission tomography/computed tomography. At study end, proteomics and mitochondrial structure and function were analysed. Complementary in vivo and ex vivo studies examined the mechanistic role of energetic imbalance. LV overload increased LV mass (P < .0001) and ejection fraction (P = .0081), with compensatory metabolic changes (drop in phosphocreatine (P = .022)). Low-risk Dox alone altered myocardial metabolism (increased glucose uptake, P = .014) but preserved cardiac function. In pigs with pre-existing LV pressure overload, doxorubicin increased mortality (P < .0001 vs all other groups), reduced left ventricular ejection fraction (LVEF) (P < .0001), increased fibrosis, and impaired mitochondrial respiration (P = .032). In HL-1 cardiomyocytes, reducing energy demand with mavacamten rescued cell viability under combined doxorubicin and hypertrophic stress. LV pressure overload increases myocardial susceptibility to anthracycline cardiotoxicity by inducing a high-energy-demand state. Anthracycline treatment, even at a low-risk dose, disrupts compensatory mechanisms in the pressure-overloaded heart, rapidly leading to cardiac dysfunction and heart failure. Preventive strategies targeting this metabolic vulnerability are urgently needed for patients with extant LV pressure overload (e.g. hypertension or valvular heart disease) who are undergoing anthracycline therapy.
Administration of Single or Repeated Doses of CDCs in a Swine Model of Reperfused Myocardial Infarction: Magnetic Resonance and Proteomics Evaluation.
(MDPI, 2025-11-22) de Pedro, María Ángeles; Báez-Díaz, Claudia; Jorge, Inmaculada; Vázquez-Lopez, Fátima; Torrescusa-Bermejo, Axiel; Martinez-Fernandez, Beatriz; Pulido, María; López, Esther; Vázquez, Jesús; Sánchez-Margallo, Francisco M; Crisostomo, Veronica
Some studies report better outcomes in cell therapy for myocardial infarction (MI) with repeated administrations. We aimed to elucidate the potential differences in terms of cardiac function and protein expression after one or three doses of cardiosphere-derived cells (CDCs) in a porcine MI model. CDCs were isolated from swine cardiac explants, cultured in cardiomyocyte growth medium (CGM), and prepared for administration. Pigs surviving a 90 min balloon occlusion of the mid-left anterior descending coronary artery (LAD) were randomly allocated to receive vehicle (CON), one (D1), or three (D3) doses of 30 × 10 CDCs via the infarct-related coronary artery. Cardiac function was assessed with magnetic resonance at baseline and 10 weeks. Programmed electrical stimulation to study arrhythmogenicity was performed at 10 weeks. High-throughput quantitative proteomic analysis of infarcted tissue was performed to identify biological processes based on protein abundance changes between groups. No significant differences were found between the three groups for any cardiac function parameter at 10 weeks. No increase in ventricular tachycardia inducibility was seen in treated groups. However, gene ontology and topological analyses revealed potentially beneficial molecular adaptations. Upregulation of GYS1, AGL, and GBE1 indicated an increase in glycogen biosynthesis and energy availability, while an increase in ANK2, along with hub proteins ALB and TRAP1, suggested cardioprotective effects. Furthermore, the increase in remodeling-related proteins, including EPHA4, PODN, and ALPK3, pointed to favorable structural adaptation following infarction. In conclusion, the intracoronary administration of single or repeated doses of 30 × 10 CDCs to a porcine reperfused MI model shows only slight differential improvement in both cardiac function and protein profile in this experimental setting, thus presenting limited translational potential.
Chaperone-mediated autophagy sustains muscle stem cell regenerative functions but declines with age.
(NATURE PORTFOLIO, 2025-12) Ramírez-Pardo, Ignacio; Campanario, Silvia; Chavda, Bhakti; Santiago-Fernández, Olaya; Flández, Marta; Grima-Terrén, Mercedes; Cisneros, Andrés; Calls-Cobos, Aina; Itzhak, Daniel N; Ngo, Bryan; Janaki-Raman, Sudha; Kantz, Edward D; Ortet, Laura; Diaz, Antonio; Lindenau, Kristen; Doménech-Fernández, Julio; Gómez-Cabrera, Mari Carmen; Camafeita, Emilio; Vázquez, Jesús; Martinez-Vicente, Marta; Serrano, Antonio L; Perdiguero, Eusebio; Isern, Joan; Cuervo, Ana Maria; Muñoz-Cánoves, Pura
Proteostasis supports stemness, and its loss correlates with the functional decline of diverse stem cell types. Chaperone-mediated autophagy (CMA) is a selective autophagy pathway implicated in proteostasis, but whether it plays a role in muscle stem cell (MuSC) function is unclear. Here we show that CMA is necessary for MuSC regenerative capacity throughout life. Genetic loss of CMA in young MuSCs, or failure of CMA in aged MuSCs, causes proliferative impairment resulting in defective skeletal muscle regeneration. Using comparative proteomics to identify CMA substrates, we find that actin cytoskeleton organization and glycolytic metabolism are key processes altered in aged murine and human MuSCs. CMA reactivation and glycolysis enhancement restore the proliferative capacity of aged mouse and human MuSCs, and improve their regenerative ability. Overall, our results show that CMA is a decisive stem cell-fate regulator, with implications in fostering muscle regeneration in old age.
Pro-regenerative fingerprints identified in a sub-population of adult mouse cardiomyocytes by integrative single-cell proteomics.
(BioMed Central, 2026-05-22) Marín-Vicente, Consuelo; Villa Del Campo, Cristina; Calvo, Enrique; Rodríguez, Jose Manuel; Sierra, Rocío; Martín-Salamanca, Sandra; Torroja, Carlos; Végvári, Akos; Zubarev, Roman A; Torres, Miguel; Vázquez, Jesús
Recent advances in instrument sensitivity and sample preparation techniques are significantly improving the ability to study the heterogeneity of cell populations at the single-cell level by mass spectrometry-based proteomics. Integrating multiple layers of cellular data offers additional and yet unexplored insights in single-cell proteomics. In regenerative research, cardiomyocyte proliferation driven by the overexpression of the Myc transcription factor has been described, however, it has not yet been investigated at single-cell resolution. By using an optimized adult cardiomyocytes isolation procedure from mouse models and taking advantage of the integrative capabilities of the iSanXoT application, we are able to minimize batch effects and cell size-related biases, obtain quantitative subcellular compartment information and detect protein alterations within subcellular compartments, as it had not yet been defined for this methodology. This approach enhances data quantification accuracy and facilitates biological interpretation. We show that the Myc transcription factor switches the expression profile of metabolic enzymes and expands a subpopulation of adult cardiomyocytes with a pro-regenerative signature. We demonstrate that different layers of information can properly pattern the proteomic phenotype of single-cells. The analysis of single-cardiomyocyte data with the integrative statistical framework of iSanXoT provided important clues to understand the impact of Myc transcription factor in provoking different immaturity and pro-regenerative signatures in adult mouse cardiomyocytes. The cellular heterogeneity exerted by mouse cardiomyocytes upon Myc overexpression demonstrates the relevance of conducting regenerative studies at the single-cell level for precisely defining the amplitude of this response in the heart.
Mitochondrial remodeling in skeletal muscle underlies exercise-induced reversal of age-associated functional decline in mice and humans.
(NATL ACAD SCIENCES, 2026-04-07) García-Domínguez, Esther; García-Domínguez, Cristina; Cabrera-Alarcón, José Luis; Muñoz-Hernández, María Del Mar; Hernansanz-Agustín, Pablo; Curtabbi, Andrea; Domenech-Fernandez, Julio; Calvo, Enrique; Vázquez, Jesús; Serrano, Antonio L; Muñoz-Cánoves, Pura; Olaso-González, Gloria; Enríquez, José Antonio; Gómez-Cabrera, María Carmen
Loss of skeletal muscle mass and strength are common manifestations of frailty in older people and are linked to reduced quality of life. However, whether mitochondria are mechanistically linked to frailty and how physical activity, or lack thereof, is involved in age-related functional decline are still unknown. We report that exercise-induced improvements in functional capacity, including reduced frailty in old mice, are dependent on mitochondrial adaptations in skeletal muscle at structural, enzymatic, and functional levels. Our preclinical study included a healthy aging mouse line, a transgenic model of robustness, and a muscle-specific mitochondrial-deficient mutant mice, allowing us to assess both mitochondrial plasticity with aging and the necessity of intact mitochondrial function for exercise-induced adaptations. These findings were corroborated by a cross-sectional human study examining the relationship between skeletal muscle mitochondrial function, age, and physical capacity. We analyzed biopsies from 30 donors (men and women, aged 17 to 99 y) stratified into young and older adults with varying functional statuses. Our results indicate that mitochondrial dysfunction in skeletal muscle is associated with the decline in locomotor muscle function in the elderly, highlighting the potential role of exercise or habitual physical activity in mitigating this phenotype. Notably, we demonstrate that skeletal muscle mitochondria maintain plasticity during aging in mice and humans, and that this preserved adaptability can be leveraged to improve muscle performance and overall functional capacity.
Glycative Stress Disrupts the Mitochondrial-Lysosome Axis and Promotes Geroconversion in Aging Cardiomyocytes.
(WILEY, 2026-03) Bou-Teen, Diana; Valiuska, Simonas; Miro-Casas, Elisabet; Rubeo, Chiara; Bonzon-Kulichenko, Elena; Nichtova, Zuzana; Fernandez-Sanz, Celia; Inserte, Javier; Rodriguez-Sinovas, Antonio; Benito, Begoña; Ródenas-Alesina, Eduard; Vázquez, Jesús; Ferreira-González, Ignacio; Ruiz-Meana, Marisol
Aging is a major risk factor for heart failure, yet the molecular mechanisms linking cardiac aging to the inflammatory pathophysiology of heart failure remain elusive. Mitochondrial dysfunction and defective organelle quality control are emerging hallmarks of the aging heart, but their biochemical underpinnings are poorly defined. Using comprehensive glycomics, we found that cardiac mitochondria from physiologically aged mice (≥ 20 months) are the major intracellular reservoirs of advanced glycation end products (AGEs), derived primarily from the chemical attack of some α-oxoaldehydes on proteins. This was associated with mild mitochondrial dysfunction and structural remodeling. Lysosomes in aged hearts were enlarged, more abundant, less acidic, and frequently loaded with lipofuscin. Notably, ~7% of cardiomyocytes showed proinflammatory senescence traits. In vitro, glycative stress in H9c2 myoblasts reproduced mitochondrial AGE buildup, dysfunction, and activation of the mitochondria-lysosome axis. However, AGE-modified mitochondria impaired lysosomal acidification and proteolysis, hindering mitophagic clearance and contributing to lipofuscin accumulation. This sequence of events ultimately led to proinflammatory senescence in a subset of cells. These findings identify mitochondrial AGE accumulation as a novel mechanism of sublethal nonsolved aging-associated stress that eventually triggers geroconversion in cardiomyocytes. This mechanism could facilitate the transition of the aging heart towards a failing phenotype.

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