2025
Briere, A. ; Vo, P. ; Yang, B. ; Adams, D. ; Amano, T. ; Amarie, O.V. ; Berberovic, Z. ; Bower, L. ; Brown, S.D.M. ; Burrill, S. ; Cho, S.Y. ; Clementson-Mobbs, S. ; D'Souza, A.R. ; Eskandarian, M. ; Flenniken, A.M. ; Fuchs, H. ; Gailus-Durner, V. ; Hérault, Y. ; Hrabě de Angelis, M. ; Jin, S. ; Joynson, R. ; Kang, Y.K. ; Kim, H. ; Masuya, H. ; Meziane, H. ; Nam, K.H. ; Noh, H. ; Nutter, L.M.J. ; Palkova, M. ; Prochazka, J. ; Raishbrook, M.J. ; Riet, F. ; Salazar, J. ; Sedlacek, R. ; Selloum, M. ; Seo, K.Y. ; Seong, J.K. ; Shin, H.S. ; Shiroishi, T. ; Stewart, M. ; Svenson, K.L. ; Tamura, M. ; Tolentino, H. ; Wells, S. ; Wurst, W. ; Yoshiki, A. ; Lanoue, L. ; Lloyd, K.C.K. ; Leonard, B.C. ; Roux, M.J. ; McKerlie, C. ; Moshiri, A.
Invest. Ophthalmol. Vis. Sci. 66:7 (2025)
PURPOSE: This study investigates genes contributing to late-adult corneal dystrophies (LACDs) in aged mice, with potential implications for late-onset corneal dystrophies (CDs) in humans. METHODS: The International Mouse Phenotyping Consortium (IMPC) database, containing data from 8901 knockout mouse lines, was filtered to include late-adult mice (49+ weeks) with significant (P < 0.0001) CD phenotypes. Candidate genes were mapped to human orthologs using the Mouse Genome Informatics group, with expression analyzed via PLAE and a literature review for prior CD associations. Comparative analyses of LACD genes from IMPC and established human CD genes from IC3D included protein interactions (STRING), biological processes (PANTHER), and molecular pathways (KEGG). RESULTS: Analysis identified 14 genes linked to late-adult abnormal corneal phenotypes. Of these, 2 genes were previously associated with CDs in humans, while 12 were novel. Seven of the 14 genes (50%) were expressed in the human cornea based on single-cell transcriptomics. Protein-protein interactions via STRING showed several significant interactions with known human CD genes. PANTHER analysis identified six biological processes shared with established human CD genes. Two genes (Rgs2 and Galnt9) were involved in pathways related to human corneal diseases, including cGMP-PKG signaling, mucin-type O-glycan biosynthesis, and oxytocin signaling. Other candidates were implicated in pathways such as pluripotency of stem cells, MAPK signaling, WNT signaling, actin cytoskeleton regulation, and cellular senescence. CONCLUSIONS: This study identified 14 genes linked to LACD in knockout mice, 12 of which are novel in corneal biology. These genes may serve as potential therapeutic targets for treating corneal diseases in aging human populations.
Wissenschaftlicher Artikel
Scientific Article
Eckstein, Y. ; Kessler, B. ; Hinrichs, A. ; Novak, I. ; von Thaden, A. ; Lorenzen, T. ; Rathkolb, B. ; Scholz, A. ; Blutke, A. ; Koopmans, S.J. ; Hrabě de Angelis, M. ; Christoffersen, B. ; Wolf, E. ; Renner, S.
STAR Protoc. 6:103774 (2025)
The pig is a valuable animal model in diabetes research; however, standardized protocols are essential for evaluating in vivo metabolism. Here, we present a protocol for in vivo assessment of glucose control and insulin secretion and sensitivity in the pig. We describe steps for catheter implantation, testing of intravenous glucose tolerance, performance of hyperinsulinemic-euglycemic clamps (HECs) and hyperglycemic clamps (HGCs), and blood processing. We then detail procedures for analysis of plasma glucose, insulin, glucagon, and C-peptide concentrations as well as data analysis. For complete details on the use and execution of this protocol, please refer to Renner et al.1 and Renner et al.2.
Wissenschaftlicher Artikel
Scientific Article
Krüger, P. ; Schroll, M. ; Fenzl, F. ; Hartinger, R. ; Lederer, E. ; Görlach, A. ; Gordon, L.B. ; Cavalcante, P. ; Iacomino, N. ; Rathkolb, B. ; Aguilar-Pimentel, J.A. ; Östereicher, M.A. ; Spielmann, N. ; Wolf, C.M. ; Hrabě de Angelis, M. ; Djabali, K.
Int. J. Mol. Sci. 26, 4849 - 4849 (2025)
Hutchinson–Gilford progeria syndrome (HGPS) is a rare, fatal, and premature aging disorder caused by progerin, a truncated form of lamin A that disrupts nuclear architecture, induces systemic inflammation, and accelerates senescence. While the farnesyltransferase inhibitor lonafarnib extends the lifespan by limiting progerin farnesylation, it does not address the chronic inflammation or the senescence-associated secretory phenotype (SASP), which worsens disease progression. In this study, we investigated the combined effects of baricitinib (BAR), a JAK1/2 inhibitor, and lonafarnib (FTI) in a LmnaG609G/G609G mouse model of HGPS. BAR + FTI therapy synergistically extended the lifespan by 25%, surpassing the effects of either monotherapy. Treated mice showed improved health, as evidenced by reduced kyphosis, better fur quality, decreased incidence of cataracts, and less severe dysgnathia. Histological analyses indicated reduced fibrosis in the dermal, hepatic, and muscular tissues, restored cellularity and thickness in the aortic media, and improved muscle fiber integrity. Mechanistically, BAR decreased the SASP and inflammatory markers (e.g., IL-6 and PAI-1), complementing the progerin-targeting effects of FTI. This preclinical study demonstrates the synergistic potential of BAR + FTI therapy in addressing HGPS systemic and tissue-specific pathologies, offering a promising strategy for enhancing both lifespan and health.
Wissenschaftlicher Artikel
Scientific Article
Lechner, S. ; Sha, S. ; Sethiya, J.P. ; Szczupak, P. ; Dolot, R. ; Lomada, S. ; Sakhteman, A. ; Tüshaus, J. ; Prokofeva, P. ; Krauss, M. ; Breu, F. ; Voegerl, K. ; Morgenstern, M. ; German Mouse Clinic Consortium (Hrabě de Angelis, M. ; Amarie, O.V. ; Becker, L. ; Calzada-Wack, J. ; Dámek, F. ; Dragano, N.R.V. ; Garrett, L. ; Hölter, S. ; Kraiger, M. ; Leuchtenberger, S. ; Marschall, S. ; Östereicher, M.A. ; Rathkolb, B. ; Sanz-Moreno, A. ; Seisenberger, C. ; Spielmann, N. ; Stoeger, C. ; Wurst, W. ; Zimprich, A. ; Fuchs, H. ; Gailus-Durner, V.) ; Haucke, V. ; Wieland, T. ; Wagner, C. ; Médard, G. ; Bracher, F. ; Kuster, B. ; German Mouse Clinic Consortium (da Silva Buttkus, P.)
ACS Chem. Biol., DOI: 10.1021/acschembio.5c00108 (2025)
Metalloenzyme inhibitors often incorporate a hydroxamic acid moiety to bind the bivalent metal ion cofactor within the enzyme's active site. Recently, inhibitors of Zn2+-dependent histone deacetylases (HDACs), including clinically advanced drugs, have been identified as potent inhibitors of the metalloenzyme MBLAC2. However, selective chemical probes for MBLAC2, which are essential for studying its inhibitory effects, have not yet been reported. To discover highly selective MBLAC2 inhibitors, we conducted chemoproteomic target deconvolution and selectivity profiling of a library of hydroxamic acid-type molecules and other metal-chelating compounds. This screen revealed MBLAC2 as a frequent off-target of supposedly selective HDAC inhibitors, including the HDAC6 inhibitor SW-100. Profiling a focused library of SW-100-related phenylhydroxamic acids led to identifying two compounds, KV-65 and KV-79, which exhibit nanomolar binding affinity for MBLAC2 and over 60-fold selectivity compared to HDACs. Interestingly, some phenylhydroxamic acids were found to bind additional off-targets. We identified KV-30 as the first drug-like inhibitor of the histidine triad nucleotide-binding protein HINT1 and confirmed its mode of inhibition through a cocrystal structure analysis. Furthermore, we report the discovery of the first inhibitors for the undrugged nucleoside diphosphate kinases NME1, NME2, NME3, and NME4. Overall, this study maps the target and off-target landscape of 53 metalloenzyme inhibitors, providing the first selective MBLAC2 inhibitors. Additionally, the discovery of pharmacophores for NME1-4 and HINT1 establishes a foundation for the future design of potent and selective inhibitors for these targets.
Wissenschaftlicher Artikel
Scientific Article
Luo, S. ; Gailus-Durner, V. ; McGivern, B. ; Li, Q. ; Kottmeier, J. ; Ho, M.L. ; Mor-Shaked, H. ; Elpeleg, O. ; Aref-Eshghi, E. ; Brodeur, A.C. ; Schmitz-Abe, K. ; Genetti, C.A. ; Picker, J. ; Shi, J. ; Bux, R.I. ; Ben-Omran, T. ; Fuchs, H. ; Harel, T. ; Hrabě de Angelis, M. ; German Mouse Clinic Consortium (Garrett, L. ; Amarie, O.V. ; Spielmann, N. ; Sanz-Moreno, A. ; da Silva Buttkus, P. ; Becker, L. ; Hölter, S. ; Seisenberger, C. ; Marschall, S.) ; German Mouse Clinic Consortium (Dragano, N.R.V.) ; German Mouse Clinic Consortium (Aguilar-Pimentel, J.A.)
Eur. J. Hum. Genet., DOI: 10.1038/s41431-025-01863-4 (2025)
WD40 and SOCS box protein-2 (WSB2), a member of the large family of suppressor of cytokine signaling (SOCS)-box proteins, has recently been identified as a substrate receptor of cullin 5 E3 ligase that plays an important role in proteomic regulation through substrate ubiquitination and proteasomal degradation. Here we report five patients from four unrelated families presenting with neurodevelopmental delay, dysmorphic features, brain structural abnormalities with or without growth restriction, hypotonia, and microcephaly, all of whom are homozygous for extremely rare and predicted loss-of-function (pLoF) or missense variants in WSB2, inherited from consanguineous parents. The Wsb2-mutant mice exhibited several neurological findings that included hyperactivity, altered exploration, and hyper alertness. They also weighed less, had a lower heart rate, and presented an abnormal retinal blood vessel morphology and vasculature pattern along with decreased total thickness of the retina. Our findings suggest that homozygous LoF WSB2 variants cause a novel neurodevelopmental disorder in humans with similar neurologic and developmental findings seen in Wsb2-mutant mouse models.
Wissenschaftlicher Artikel
Scientific Article
Pini, T. ; Nixon, B. ; Timothy L, K. ; Teperino, R. ; Sanz-Moreno, A. ; da Silva Buttkus, P. ; Tüttelmann, F. ; Kliesch, S. ; Gailus-Durner, V. ; Fuchs, H. ; Marschall, S. ; Hrabě de Angelis, M. ; Skerrett-Byrne, D.A.
Reproduction, DOI: 10.1530/REP-25-0105 (2025)
Reproductive biology is often considered in three siloed research areas; humans, agriculture and wildlife. Yet, each demand solutions for treatment of subfertility, fertility biomarkers, development of assisted reproductive technologies and effective contraception. To efficiently develop solutions applicable to all species, we must improve our understanding of the common biology underpinning reproductive processes. Accordingly, we integrate proteomic data from 29 publicly available datasets (>2 TB of data) to characterize mature sperm proteomes spanning 12 vertebrate species, identifying 13,853 proteins. Although human and mouse have relatively wellannotated sperm proteomes, many non-model species rely heavily on predicted or homologyinferred identifications. Despite variation in proteome size, composition and reproductive strategies, comparative analyses revealed that vertebrates share a fundamental molecular framework essential for sperm function. A core set of 45 species-level and 135 order-level conserved proteins mapped to critical processes, including energy generation, acrosome function, as well as novel signalling pathways (BAG2 and FAT10). Knockout mouse models further validate the significance of these conserved proteins, demonstrating that their disruption impairs sperm motility and fertilization capacity. Moreover, we discovered loss-of-function variants of two additional core sperm proteins in clinical samples, linking them to severe sperm defects. Intriguingly, in-silico analysis reveals function-driven, context-dependent diversity surpassing evolutionary patterns. Collectively, these results highlight the value of integrating publicly available datasets and underscore the need for improved genome/proteome annotation in nonmodel species in mammals. This work provides a foundation for developing cross-species strategies to enhance fertility treatments, assisted reproductive technologies, and conservation efforts.
Wissenschaftlicher Artikel
Scientific Article
Sanz-Moreno, A. ; Becker, L. ; Xie, K. ; da Silva Buttkus, P. ; Dragano, N.R.V. ; Aguilar-Pimentel, J.A. ; Amarie, O.V. ; Calzada-Wack, J. ; Kraiger, M. ; Leuchtenberger, S. ; Seisenberger, C. ; Marschall, S. ; Rathkolb, B. ; Scifo, E. ; Liu, T. ; Thanabalasingam, A. ; Sanchez-Vazquez, R. ; Martinez, P. ; Blasco, M.A. ; Savage, S.A. ; Fuchs, H. ; Ehninger, D. ; Gailus-Durner, V. ; Hrabě de Angelis, M.
Sci. Adv. 11:eadp8093 (2025)
Telomere length regulation is essential for genome stability as short telomeres can trigger cellular senescence and apoptosis constituting an integral aspect of biological aging. Telomere biology disorders (TBDs) such as dyskeratosis congenita (DC) are rare, inherited diseases with known mutations in at least 16 different genes encoding components of the telomere maintenance complexes. The precise role of TEN1, part of the CST complex (CTC1, STN1, and TEN1), and the consequences of its loss of function in vivo are not yet known. We investigated the first viable murine model of Ten1 deficiency created by CRISPR-Cas9-mediated exon 3 deletion. Ten1 homozygous knockout mice present with telomere attrition, short life span, skin hyperpigmentation, aplastic anemia, and cerebellar hypoplasia. Molecular analyses revealed a reduction of proliferating cells, increased apoptosis, and stem cell depletion with activation of the p53/p21 signaling pathway. Our data demonstrate that Ten1 deficiency causes telomere shortening and associates with accelerated aging.
Wissenschaftlicher Artikel
Scientific Article
Vo, P. ; Imai-Leonard, D.M. ; Yang, B. ; Briere, A. ; Shao, A. ; Casanova, M.I. ; Adams, D. ; Amano, T. ; Amarie, O.V. ; Berberovic, Z. ; Bower, L. ; Braun, R. ; Brown, S. ; Burrill, S. ; Cho, S.Y. ; Clementson-Mobbs, S. ; D'Souza, A.R. ; Dickinson, M. ; Eskandarian, M. ; Flenniken, A.M. ; Fuchs, H. ; Gailus-Durner, V. ; Heaney, J.D. ; Herault, Y. ; Hrabě de Angelis, M. ; Hsu, C.W. ; Jin, S. ; Joynson, R. ; Kang, Y.K. ; Kim, H. ; Masuya, H. ; Meziane, H. ; Murray, S.A. ; Nam, K.H. ; Noh, H. ; Nutter, L.M.J. ; Palkova, M. ; Prochazka, J. ; Raishbrook, M.J. ; Riet, F. ; Ryan, J. ; Salazar, J. ; Seavey, Z. ; Seavitt, J.R. ; Sedlacek, R. ; Selloum, M. ; Seo, K.Y. ; Seong, J.K. ; Shin, H.S. ; Shiroishi, T. ; Stewart, M. ; Svenson, K.L. ; Tamura, M. ; Tolentino, H. ; Udensi, U. ; Wells, S. ; White, J. ; Willett, A.M. ; Wotton, J.M. ; Wurst, W. ; Yoshiki, A. ; Lanoue, L. ; Lloyd, K.C.K. ; Leonard, B.C. ; Roux, M.J. ; McKerlie, C. ; Moshiri, A.
BMC Genomics 26:48 (2025)
PURPOSE: Corneal dysmorphologies (CDs) are typically classified as either regressive degenerative corneal dystrophies (CDtrs) or defective growth and differentiation-driven corneal dysplasias (CDyps). Both eye disorders have multifactorial etiologies. While previous work has elucidated many aspects of CDs, such as presenting symptoms, epidemiology, and pathophysiology, the genetic mechanisms remain incompletely understood. The purpose of this study was to analyze phenotype data from 8,707 knockout mouse lines to identify new genes associated with the development of CDs in humans. METHODS: 8,707 knockout mouse lines phenotyped by the International Mouse Phenotyping Consortium were queried for genes associated with statistically significant (P < 0.0001) abnormal cornea morphology to identify candidate CD genes. Corneal abnormalities were investigated by histopathology. A literature search was used to determine the proportion of candidate genes previously associated with CDs in mice and humans. Phenotypes of human orthologues of mouse candidate genes were compared with known human CD genes to identify protein-protein interactions and molecular pathways using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), Protein Analysis Through Evolutionary Relationships (PANTHER), and Kyoto Encyclopedia of Genes and Genomes. RESULTS: Analysis of data from 8,707 knockout mouse lines identified 213 candidate CD genes. Of these, 37 (17%) genes were previously known to be associated with CD, including 14 in the mouse, 16 in humans, and 7 in both. The remaining 176 (83%) genes have not been previously implicated in CD. We also searched publicly available RNAseq data and found that 131 of the total 213 (61.5%) were expressed in adult human corneal tissue. STRING analysis showed several interactions within and between candidate and established CD proteins. All cellular pathways of the established genes were found in the PANTHER analysis of the candidate genes. Several of the candidate genes were implicated in corneal disease, such as TGF-ß signaling. We also identified other possible underappreciated mechanisms relevant to the human cornea. CONCLUSIONS: We identified 213 mouse genes that resulted in statistically significant abnormal corneal phenotypes in knockout mice, many of which have not previously been implicated in corneal pathology. Bioinformatic analyses implicated candidate genes in several signaling pathways which are potential therapeutic targets.
Wissenschaftlicher Artikel
Scientific Article
2024
Ahola, S. ; Pazurek, L.A. ; Mayer, F. ; Lampe, P. ; Hermans, S. ; Becker, L. ; Amarie, O.V. ; Fuchs, H. ; Gailus-Durner, V. ; Hrabě de Angelis, M. ; Riedel, D. ; Nolte, H. ; Langer, T.
Sci. Adv. 10:eadp0443 (2024)
Mitochondrial fusion and fission accompany adaptive responses to stress and altered metabolic demands. Inner membrane fusion and cristae morphogenesis depends on optic atrophy 1 (Opa1), which is expressed in different isoforms and is cleaved from a membrane-bound, long to a soluble, short form. Here, we have analyzed the physiological role of Opa1 isoforms and Opa1 processing by generating mouse lines expressing only one cleavable Opa1 isoform or a non-cleavable variant thereof. Our results show that expression of a single cleavable or non-cleavable Opa1 isoform preserves embryonic development and the health of adult mice. Opa1 processing is dispensable under metabolic and thermal stress but prolongs life span and protects against mitochondrial cardiomyopathy in OXPHOS-deficient Cox10-/- mice. Mechanistically, loss of Opa1 processing disturbs the balance between mitochondrial biogenesis and mitophagy, suppressing cardiac hypertrophic growth in Cox10-/- hearts. Our results highlight the critical regulatory role of Opa1 processing, mitochondrial dynamics, and metabolism for cardiac hypertrophy.
Wissenschaftlicher Artikel
Scientific Article
Daryadel, A. ; Küng, C.J. ; Haykir, B. ; Sabrautzki, S. ; Hrabě de Angelis, M. ; Hernando, N. ; Rubio-Aliaga, I. ; Wagner, C.A.
Am. J. Physiol.-Renal Physiol. 326, F792-F801 (2024)
The kidney controls systemic inorganic phosphate (Pi) levels by adapting reabsorption to Pi intake. Renal Pi reabsorption is mostly mediated by sodium-phosphate cotransporters NaPi-IIa (SLC34A1) and NaPi-IIc (SLC34A3) which are tightly controlled by various hormones including parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23). PTH and FGF23 rise in response to Pi intake and decrease NaPi-IIa and NaPi-IIc brush border membrane abundance enhancing phosphaturia. Phosphaturia and transporter regulation occur even in the absence of PTH and FGF23 signalling. The calcium-sensing receptor (CaSR) regulates PTH and FGF23 secretion, and may also directly affect renal Pi handling. Here, we combined pharmacological and genetic approaches to examine the role of the CaSR in the acute phosphaturic response to Pi-loading. Animals pretreated with the calcimimetic cinacalcet were hyperphosphatemic, had blunted PTH levels upon Pi administration, a reduced Pi-induced phosphaturia and no Pi-induced NaPi-IIa downregulation. The calcilytic NPS-2143 exaggerated the PTH response to Pi-loading but did not abolish Pi-induced downregulation of NaPi-IIa. In mice with a dominant inactivating mutation in the Casr (CasrBCH002), baseline NaPi-IIa expression was higher, whereas downregulation of transporter expression was blunted in double CasrBCH002/PTH KO transgenic animals. Thus, in response to an acute Pi load, acute modulation of the CaSR affects the endocrine and renal response, while chronic genetic inactivation, displays only subtle differences in the downregulation of NaPi-IIa and NaPi-IIc renal expression. We did not find evidence that the CaSR impacts on the acute renal response to oral Pi-loading beyond its role in regulating PTH secretion.
Wissenschaftlicher Artikel
Scientific Article
Galter, I. ; Schneltzer, E. ; Marr, C. ; Spielmann, N. ; Hrabě de Angelis, M.
In: (Medical Image Understanding and Analysis). Gewerbestrasse 11, Cham, Ch-6330, Switzerland: Springer International Publishing Ag, 2024. 366-381 (Lect. Notes Comput. Sc. ; 14860 LNCS)
Echocardiography is a fast and cost-effective imaging technique for assessing cardiac function and structure. However, image-derived phenotypic evaluation is challenging. Current AI-approaches designed for automatic interpretation of echocardiography data are progressing, but algorithms for animal models frequently used in pre-clinical studies are rare. Here, we propose a deep active learning approach, called EchoVisuAL, that uses large-scale, multi-center data of the International Mouse Phenotyping Consortium (IMPC). This heterogeneous IMPC data set includes 96 392 echocardiograms with 3 831 290 frames from 17 991 mice. Heterogeneity is characterized by differences in age, sex, background strains, anesthesia, imaging frequency and focus depth. EchoVisuAL is founded on a Bayesian U-Net that produces inner trace segmentations alongside with two confidence metrics, an uncertainty measure and a BALD score. This architecture, embedded in an active learning framework, enables a substantial reduction of the annotation efforts by an intelligent selection of the next frames that should be annotated. In total, 15 models were trained on step-wise increasing training data sets based on the model’s confidence. For model evaluation, 25 echocardiograms with 1062 frames were annotated by four highly experienced, independent experts. Inter-rater-agreement across all frames was high with a mean Randolph’s kappa score of 0.91±0.10. Across models, high Dice scores were observed on these expert annotations, currently considered as the gold standard, with model M15 achieving a mean Dice score of 0.98±0.02. EchoVisuAL is a new deep active learning application robust to automatically analyze heterogeneous mouse echocardiograms, including uncertainty scores for user guidance.
Garrett, L. ; Trümbach, D. ; Lee, D. ; Mandillo, S. ; Samaco, R.C. ; Flenniken, A.M. ; Stewart, M. ; White, J.K. ; McKerlie, C. ; Nutter, L.M.J. ; Vukobradovic, I. ; Veeraragavan, S. ; Yuva, L. ; Heaney, J.D. ; Dickinson, M.E. ; Meziane, H. ; Hérault, Y. ; Wells, S. ; Lloyd, K.C.K. ; Bower, L. ; Lanoue, L. ; Clary, D. ; Zimprich, A. ; Gailus-Durner, V. ; Fuchs, H. ; Brown, S.D.M. ; Chesler, E.J. ; Wurst, W. ; Hrabě de Angelis, M. ; Hölter, S.M.
Neurosci. App. 3:104075 (2024)
Wissenschaftlicher Artikel
Scientific Article
Geist, D. ; Hönes, G.S. ; Grund, S.C. ; Pape, J. ; Siemes, D. ; Spangenberg, P. ; Tolstik, E. ; Dörr, S. ; Spielmann, N. ; Fuchs, H. ; Gailus-Durner, V. ; Hrabě de Angelis, M. ; Mittag, J. ; Engel, D.R. ; Führer, D. ; Lorenz, K. ; Moeller, L.C.
Thyroid 34, 785-795 (2024)
BACKGROUND: Stimulation of ventricular hypertrophy and heart rate are two major cardiac effects of thyroid hormone (TH). Aim of this study was to determine in vivo which TH receptor (TR), α or β, and which mode of TR action, canonical gene expression or DNA binding independent noncanonical action, mediate these effects. MATERIAL AND METHODS: We compared global TRα and TRβ knockout mice (TRαKO; TRβKO) with wild-type (WT) mice to determine the TR isoform responsible for T3 effects. The relevance of TR DNA binding was studied in mice with a mutation in the DNA-binding domain that selectively abrogates DNA binding and canonical TR action (TRαGS; TRβGS). Hearts were studied with echocardiography at baseline and after seven weeks T3 treatment. Gene expression was measured with real-time PCR. Heart rate was recorded with radiotelemetry transmitters for seven weeks in untreated, hypothyroid and T3-treated mice. RESULTS: T3 induced ventricular hypertrophy in WT and TRβKO mice, but not in TRαKO mice. Hypertrophy was also induced in TRαGS mice. Thus, hypertrophy is mostly mediated by noncanonical TRα action. Similarly, repression of Mhy7 occurred in WT and TRαGS mice. Basal heart rate was largely dependent on canonical TRα action. But responsiveness to hypothyroidism and T3 treatment as well as expression of pacemaker gene Hcn2 were still preserved in TRαKO mice, demonstrating that TRβ could compensate for absence of TRα. CONCLUSION: T3-induced cardiac hypertrophy could be attributed to noncanonical TRα action, whereas heart rate regulation was mediated by canonical TRα action. TRβ could substitute for canonical, but not noncanonical TRα action.
Wissenschaftlicher Artikel
Scientific Article
Giusti, S.A. ; Pino, N.S. ; Pannunzio, C. ; Ogando, M.B. ; Armando, N.G. ; Garrett, L. ; Zimprich, A. ; Becker, L. ; Gimeno, M.L. ; Lukin, J. ; Merino, F.L. ; Pardi, M.B. ; Pedroncini, O. ; Di Mauro, G.C. ; Gailus-Durner, V. ; Fuchs, H. ; Hrabě de Angelis, M. ; Patop, I.L. ; Turck, C.W. ; Deussing, J.M. ; Vogt Weisenhorn, D.M. ; Jahn, O. ; Kadener, S. ; Hölter, S.M. ; Brose, N. ; Giesert, F. ; Wurst, W. ; Marin-Burgin, A. ; Refojo, D.
Sci. Adv. 10:eadj8769 (2024)
Circular RNAs (circRNAs) are a large class of noncoding RNAs. Despite the identification of thousands of circular transcripts, the biological significance of most of them remains unexplored, partly because of the lack of effective methods for generating loss-of-function animal models. In this study, we focused on circTulp4, an abundant circRNA derived from the Tulp4 gene that is enriched in the brain and synaptic compartments. By creating a circTulp4-deficient mouse model, in which we mutated the splice acceptor site responsible for generating circTulp4 without affecting the linear mRNA or protein levels, we were able to conduct a comprehensive phenotypic analysis. Our results demonstrate that circTulp4 is critical in regulating neuronal and brain physiology, modulating the strength of excitatory neurotransmission and sensitivity to aversive stimuli. This study provides evidence that circRNAs can regulate biologically relevant functions in neurons, with modulatory effects at multiple levels of the phenotype, establishing a proof of principle for the regulatory role of circRNAs in neural processes.
Wissenschaftlicher Artikel
Scientific Article
Harada, M. ; Han, S. ; Shi, M. ; Ge, J. ; Yu, S. ; Adam, J. ; Adamski, J. ; Scheerer, M.F. ; Neschen, S. ; Hrabě de Angelis, M. ; Wang-Sattler, R.
Int. J. Biol. Macromol. 265:130962 (2024)
Combining a Sodium-Glucose-Cotransporter-2-inhibitor (SGLT2i) with metformin is recommended for managing hyperglycemia in patients with type 2 diabetes (T2D) who have cardio-renal complications. Our study aimed to investigate the metabolic effects of SGLT2i and metformin, both individually and synergistically. We treated leptin receptor-deficient (db/db) mice with these drugs for two weeks and conducted metabolite profiling, identifying 861 metabolites across kidney, liver, muscle, fat, and plasma. Using linear regression and mixed-effects models, we identified two SGLT2i-specific metabolites, X-12465 and 3-hydroxybutyric acid (3HBA), a ketone body, across all examined tissues. The levels of 3HBA were significantly higher under SGLT2i monotherapy compared to controls and were attenuated when combined with metformin. We observed similar modulatory effects on metabolites involved in protein catabolism (e.g., branched-chain amino acids) and gluconeogenesis. Moreover, combination therapy significantly raised pipecolate levels, which may enhance mTOR1 activity, while modulating GSK3, a common target of SGLT2i and 3HBA inhibition. The combination therapy also led to significant reductions in body weight and lactate levels, contrasted with monotherapies. Our findings advocate for the combined approach to better manage muscle loss, and the risks of DKA and lactic acidosis, presenting a more effective strategy for T2D treatment.
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Harada, M. ; Adam, J. ; Covic, M. ; Ge, J. ; Brandmaier, S. ; Muschet, C. ; Huang, J. ; Han, S. ; Rommel, M. ; Rotter, M. ; Heier, M. ; Mohney, R.P. ; Krumsiek, J. ; Kastenmüller, G. ; Rathmann, W. ; Zou, Z. ; Zukunft, S. ; Scheerer, M.F. ; Neschen, S. ; Adamski, J. ; Gieger, C. ; Peters, A. ; Ankerst, D.P. ; Meitinger, T. ; Alderete, T.L. ; Hrabě de Angelis, M. ; Suhre, K. ; Wang-Sattler, R.
Cardiovasc. Diabetol. 23:199 (2024)
BACKGROUND: Metformin and sodium-glucose-cotransporter-2 inhibitors (SGLT2i) are cornerstone therapies for managing hyperglycemia in diabetes. However, their detailed impacts on metabolic processes, particularly within the citric acid (TCA) cycle and its anaplerotic pathways, remain unclear. This study investigates the tissue-specific metabolic effects of metformin, both as a monotherapy and in combination with SGLT2i, on the TCA cycle and associated anaplerotic reactions in both mice and humans. METHODS: Metformin-specific metabolic changes were initially identified by comparing metformin-treated diabetic mice (MET) with vehicle-treated db/db mice (VG). These findings were then assessed in two human cohorts (KORA and QBB) and a longitudinal KORA study of metformin-naïve patients with Type 2 Diabetes (T2D). We also compared MET with db/db mice on combination therapy (SGLT2i + MET). Metabolic profiling analyzed 716 metabolites from plasma, liver, and kidney tissues post-treatment, using linear regression and Bonferroni correction for statistical analysis, complemented by pathway analyses to explore the pathophysiological implications. RESULTS: Metformin monotherapy significantly upregulated TCA cycle intermediates such as malate, fumarate, and α-ketoglutarate (α-KG) in plasma, and anaplerotic substrates including hepatic glutamate and renal 2-hydroxyglutarate (2-HG) in diabetic mice. Downregulated hepatic taurine was also observed. The addition of SGLT2i, however, reversed these effects, such as downregulating circulating malate and α-KG, and hepatic glutamate and renal 2-HG, but upregulated hepatic taurine. In human T2D patients on metformin therapy, significant systemic alterations in metabolites were observed, including increased malate but decreased citrulline. The bidirectional modulation of TCA cycle intermediates in mice influenced key anaplerotic pathways linked to glutaminolysis, tumorigenesis, immune regulation, and antioxidative responses. CONCLUSION: This study elucidates the specific metabolic consequences of metformin and SGLT2i on the TCA cycle, reflecting potential impacts on the immune system. Metformin shows promise for its anti-inflammatory properties, while the addition of SGLT2i may provide liver protection in conditions like metabolic dysfunction-associated steatotic liver disease (MASLD). These observations underscore the importance of personalized treatment strategies.
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Hasenbein, T.P. ; Hoelzl, S. ; Smith, Z.D. ; Gerhardinger, C. ; Gonner, M.O.C. ; Aguilar-Pimentel, J.A. ; Amarie, O.V. ; Becker, L. ; Calzada-Wack, J. ; Dragano, N.R.V. ; da Silva Buttkus, P. ; Garrett, L. ; Hölter, S.M. ; Kraiger, M. ; Östereicher, M.A. ; Rathkolb, B. ; Sanz-Moreno, A. ; Spielmann, N. ; Wurst, W. ; Gailus-Durner, V. ; Fuchs, H. ; Hrabě de Angelis, M. ; Meissner, A. ; Engelhardt, S. ; Rinn, J.L. ; Andergassen, D.
Nat. Commun. 15:10631 (2024)
The lncRNA Crossfirre was identified as an imprinted X-linked gene, and is transcribed antisense to the trans-acting lncRNA Firre. The Firre locus forms an inactive-X-specific interaction with Dxz4, both loci providing the platform for the largest conserved chromatin structures. Here, we characterize the epigenetic profile of these loci, revealing them as the most female-specific accessible regions genome-wide. To address their in vivo role, we perform one of the largest X-linked knockout studies by deleting Crossfirre, Firre, and Dxz4 individually and in combination. Despite their distinct epigenetic features observed on the X chromosome, our allele-specific analysis uncovers these loci as dispensable for imprinted and random X chromosome inactivation. However, we provide evidence that Crossfirre affects autosomal gene regulation but only in combination with Firre. To shed light on the functional role of these sex-specific loci, we perform an extensive standardized phenotyping pipeline and uncover diverse knockout and sex-specific phenotypes. Collectively, our study provides the foundation for exploring the intricate interplay of conserved X-linked loci in vivo.
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Hönes, G.S. ; Geist, D. ; Wenzek, C. ; Pfluger, P.T. ; Müller, T.D. ; Aguilar-Pimentel, J.A. ; Amarie, O.V. ; Becker, L. ; Dragano, N.R.V. ; Garrett, L. ; Hölter, S.M. ; Rathkolb, B. ; Rozman, J. ; Spielmann, N. ; Treise, I. ; Wolf, E. ; Wurst, W. ; Fuchs, H. ; Gailus-Durner, V. ; Hrabě de Angelis, M. ; Führer, D. ; Moeller, L.C.
Endocrinology 165:bqae067 (2024)
Thyroid hormone (TH) effects are mediated through TH receptors (TRs) TRα1, TRβ1, and TRβ2. The TRs bind to the DNA and regulate expression of TH target genes (canonical signaling). In addition, they mediate activation of signaling pathways (noncanonical signaling). Whether noncanonical TR action contributes to the spectrum of TH effects is largely unknown. Aim of this study was to attribute physiological effects to the TR isoforms and their canonical and noncanonical signaling. We conducted multi-parameter phenotyping in male and female TR knockout mice (TRαKO, TRβKO), mice with disrupted canonical signaling due to mutations in the TR DNA-binding domain (TRαGS, TRβGS) and their wild-type littermates. Perturbations in senses, especially hearing (mainly TRβ with a lesser impact of TRα), visual acuity, retinal thickness (TRα and TRβ) and in muscle metabolism (TRα) highlighted the role of canonical TR action. Strikingly, selective abrogation of canonical TR action often had little phenotypic consequence, suggesting that noncanonical TR action sufficed to maintain the wild-type phenotype for specific effects. For instance, macrocytic anemia, reduced retinal vascularization or increased anxiety related behavior were only observed in TRαKO, but not TRαGS mice. Noncanonical TRα action improved energy utilization and prevented hyperphagia observed in female TRαKO mice. In summary, by examining the phenotypes of TRα and TRβ knockout models alongside their DNA-binding-deficient mutants and wild-type counterparts, we could establish that the noncanonical actions of TRα and TRβ play a crucial role in modulating sensory, behavioral, and metabolic functions and, thus, contribute to the spectrum of physiological TH effects.
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Inau, E.T. ; Dedié, A. ; Anastasova, I. ; Schick, R. ; Zdravomyslov, Y. ; Fröhlich, B. ; Birkenfeld, A.L. ; Hrabě de Angelis, M. ; Roden, M. ; Zeleke, A.A. ; Preusse, M. ; Waltemath, D.
Sci. Data 11:1159 (2024)
The German Center for Diabetes Research (DZD) established a core data set (CDS) of clinical parameters relevant for diabetes research in 2021. The CDS is central to the design of current and future DZD studies. Here, we describe the process and outcomes of FAIRifying the initial version of the CDS. We first did a baseline evaluation of the FAIRness using the FAIR Data Maturity Model. The FAIRification process and the results of this assessment led us to convert the CDS into the recommended format for spreadsheets, annotating the parameters with standardized medical codes, licensing the data set, enriching the data set with metadata, and indexing the metadata. The FAIRified version of the CDS is more suitable for data sharing in diabetes research across DZD sites and beyond. It contributes to the reusability of health research studies.
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Jiang, S. ; Yuan, T. ; Rosenberger, F.A. ; Mourier, A. ; Dragano, N.R.V. ; Kremer, L. ; Rubalcava-Gracia, D. ; Hansen, F.M. ; Borg, M. ; Mennuni, M. ; Filograna, R. ; Alsina, D. ; Misic, J. ; Koolmeister, C. ; Papadea, P. ; Hrabě de Angelis, M. ; Ren, L. ; Andersson, O. ; Unger, A. ; Bergbrede, T. ; Di Lucrezia, R. ; Wibom, R. ; Zierath, J.R. ; Krook, A. ; Giavalisco, P. ; Mann, M. ; Larsson, N.G.
Nat. Metab. 6, 1024-1035 (2024)
The oxidative phosphorylation system1 in mammalian mitochondria plays a key role in transducing energy from ingested nutrients2. Mitochondrial metabolism is dynamic and can be reprogrammed to support both catabolic and anabolic reactions, depending on physiological demands or disease states. Rewiring of mitochondrial metabolism is intricately linked to metabolic diseases and promotes tumour growth3–5. Here, we demonstrate that oral treatment with an inhibitor of mitochondrial transcription (IMT)6 shifts whole-animal metabolism towards fatty acid oxidation, which, in turn, leads to rapid normalization of body weight, reversal of hepatosteatosis and restoration of normal glucose tolerance in male mice on a high-fat diet. Paradoxically, the IMT treatment causes a severe reduction of oxidative phosphorylation capacity concomitant with marked upregulation of fatty acid oxidation in the liver, as determined by proteomics and metabolomics analyses. The IMT treatment leads to a marked reduction of complex I, the main dehydrogenase feeding electrons into the ubiquinone (Q) pool, whereas the levels of electron transfer flavoprotein dehydrogenase and other dehydrogenases connected to the Q pool are increased. This rewiring of metabolism caused by reduced mtDNA expression in the liver provides a principle for drug treatment of obesity and obesity-related pathology.
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