Biology subjects

Tian, Y.

Publications and source records attributed to Tian, Y..

At least 163 records · Page 9Linked to original sources

bioRxiv2023

A muscle hypertrophy-derived myokine reprograms the stromal vascular fractions differentiation towards thermogenic adipocytes in subcutaneous adipose tissue

Skeletal muscle plays a significant role in both local and systemic energy metabolism; however, the cross-talk between skeletal muscle and adipose tissue remains largely unexplored. In this study, we identify the HIF2-Bambi-Thbs4 axis as a critical driver of muscle hypertrophy and metabolic improvement. Deletion of Bambi induces muscle hypertrophy and oxidative switching, thereby enhancing local and systemic metabolism under conditions of rodent chow and high-fat diets (HFD). Other than the metabolic regulation of skeletal muscle hypertrophy, we hypothesize that a portion of this improvement may be attributed to the metabolic reprogramming of the stromal vascular fraction (SVFs) of iWAT, promoting the development of beige adipocytes. Leveraging multi-omics approaches, we establish Thbs4 as a newly identified, muscle hypertrophy-derived myokine that serves as an essential regulator of this metabolic reprogramming. Thbs4 is upregulated in skeletal muscle during hypertrophy and aerobic exercise, localizes to the iWAT membrane, and facilitates the transformation of white adipocytes into beige adipocytes under conditions such as cold exposure, muscle hypertrophy, or aerobic exercise. Moreover, overexpression of Thbs4 elevates its plasma levels and leads to the transformation of white to beige adipocytes, therefore offering long-term protection against HFD-induced metabolic disorders. Conversely, Thbs4 knockout (Thbs4-KO) disrupts the metabolic reprogramming of SVFs and exacerbates metabolic syndromes induced by an HFD, mirroring the observed decline in Thbs4 levels in aged mice. Therefore, our findings underscore Thbs4s potential as both a long-term metabolic protective factor and a therapeutic target for the treatment of metabolic disorders. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=197 HEIGHT=200 SRC="FIGDIR/small/558627v1_ufig1.gif" ALT="Figure 1"> View larger version (63K): org.highwire.dtl.DTLVardef@1178e6org.highwire.dtl.DTLVardef@1184d4eorg.highwire.dtl.DTLVardef@7b592aorg.highwire.dtl.DTLVardef@1b0b03_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIBambi, a direct target gene of HIF2 in skeletal muscle, when deleted, triggers muscle hypertrophy and the transformation of white into beige adipocytes, improving systemic energy metabolism. C_LIO_LIThe metabolic reprogramming of stromal vascular fractions (SVFs) contributes to the observed improvements in energy metabolism and adipocyte hyperplasia. C_LIO_LIThbs4, a novel myokine produced in skeletal muscle during hypertrophy and aerobic exercise, plays a key role in the transformation of white into beige adipocytes. C_LIO_LIOverexpression of Thbs4 provides enduring protection against high-fat diet (HFD)-induced metabolic disorders, demonstrating its potential as a therapeutic target. C_LIO_LIThbs4 deletion abrogates the beneficial metabolic reprogramming of SVFs and exacerbates HFD-induced metabolic syndromes, further underlining its crucial role in metabolic regulation. C_LI

physiology↗

bioRxiv2023

The Neural Correlates of Ambiguity and Risk in Human Decision-Making under an Active Inference Framework

Active inference integrates perception, decision-making, and learning into a united theoretical frame-work, providing an efficient way to trade off exploration and exploitation by minimizing (expected) free energy. In this study, we asked how the brain represents values and uncertainties (novelty and variability), and resolves these uncertainties under the active inference framework in the exploration-exploitation trade-off. 25 participants performed a contextual two-armed bandit task, with electroen-cephalogram (EEG) recordings. By comparing the model evidence for active inference and rein-forcement learning models of choice behavior, we show that active inference better explains human decision-making under novelty and variability, which entails exploration or information seeking. The EEG sensor-level results show that the activity in the frontal, central, and parietal regions is associated with novelty, while activity in the frontal and central brain regions is associated with variability. The EEG source-level results indicate that the expected free energy is encoded in the frontal pole and middle frontal gyrus and uncertainties are encoded in different brain regions but with overlap. Our study dissociates the expected free energy and uncertainties in active inference theory and their neural correlates, speaking to the construct validity of active inference in characterizing cognitive processes of human decisions. It provides behavioral and neural evidence of active inference in decision processes and insights into the neural mechanism of human decisions under uncertainties.

neuroscience↗

bioRxiv2023

Stabilization of RRBP1 mRNA via an m6A-dependent manner in prostate cancer constitutes a therapeutic vulnerability amenable to small-peptide inhibition of METTL3

Mounting evidence has implicated the RNA m6A methylation catalyzed by METTL3 in a wide range of physiological and pathological processes, including tumorigenesis. The detailed m6A landscape and molecular mechanism of METTL3 in prostate cancer (PCa) remains ill-defined. We find that METTL3 is overexpressed in PCa and correlates with worse patient survival. Functional studies establish METTL3 as an oncoprotein dependent on its m6A enzymatic activity in both AR+ and AR- PCa cells. To dissect the regulatory network of m6A pathway in PCa, we map the m6A landscape in clinical tumor samples using m6A-seq and identify genome-wide METTL3-binding transcripts via RIP-seq. Mechanistically, we discover RRBP1 as a direct METTL3 target in which METTL3 stabilizes RRBP1 mRNA in an m6A-dependent manner. RRBP1 positively correlates with METTL3 expression in PCa cohorts and exerts an oncogenic role in aggressive PCa cells. Leveraging the 3D structural protein-protein interaction between METTL3 and METTL14, we successfully develop two potential METTL3 peptide inhibitors (RM3 and RSM3) that effectively suppress cancer cell proliferation in vitro and tumor growth in vivo. Collectively, our study reveals a novel METTL3/m6A/RRBP1 axis in enhancing aggressive traits of PCa, which can be therapeutically targeted by small-peptide METTL3 antagonists.

cancer biology↗

bioRxiv2023

High-throughput Extracellular Matrix Proteomics of Human Lungs Enabled by Photocleavable Surfactant and diaPASEF

The extracellular matrix (ECM) is a complex assembly of proteins that provide interstitial scaffolding and elastic recoil to human lungs. The pulmonary extracellular matrix (ECM) is increasingly recognized as an independent bioactive entity by creating biochemical and mechanical signals that influence disease pathogenesis, making it an attractive therapeutic target. However, the pulmonary ECM proteome ("matrisome") remains challenging to analyze by mass spectrometry due to its inherent biophysical properties and relatively low abundance. Here, we introduce a strategy designed for rapid and efficient characterization of the human pulmonary ECM using the photocleavable surfactant Azo. We coupled this approach with trapped ion mobility MS with diaPASEF to maximize depth of matrisome coverage. Using this strategy, we identify nearly 400 unique matrisome proteins with excellent reproducibility that are known to be important in lung biology, including key insoluble ECM proteins.

systems biology↗

bioRxiv2023

Wiskott-Aldrich Syndrome Protein Regulates Nucleolar Organization and Function in Innate Immune Response

Wiskott-Aldrich syndrome (WAS) is a primary immunodeficiency disorder caused by the dysfunction of the WAS protein (WASP). Using an isogenic macrophage model derived from genome edited induced pluripotent stem cells we demonstrated that WASP functions in the nucleolus, which plays important roles in immune regulation. The absence of WASP resulted in smaller and misshapen nucleoli, decreased fibrillar center territory, and impaired ribosomal RNA (rRNA) transcription. The nucleolar and rRNA phenotypes were confirmed in WAS patient samples. Furthermore, WASP interacts with nucleolar proteins, including nucleophosmin 1 (NPM1) and fibrillarin (FBL). NPM1 deficiency is known to cause elevated cytokine expression following lipopolysaccharide (LPS) stimulation. Consistently, WASP deficient cells displayed lower levels of NPM1 and a heightened inflammatory cytokine response to LPS, which was rescued by overexpressing NPM1. Together, our research provides novel insights into the critical role of WASP in nucleolar function and the modulation of inflammatory cytokine production.

cell biology↗

bioRxiv2023

Forward genetic screening in engineered colorectal cancer organoids identifies novel regulators of metastasis

Cancer is the second leading cause of death globally, due primarily to metastatic dissemination and colonization of distal sites. Recurrent genetic drivers of metastasis are elusive, suggesting that, unlike the stereotyped mutations promoting primary tumor development, drivers of metastasis may be variable. Here, we interrogate pathways governing metastasis through CRISPR/Cas9-based forward genetic screening in a genetically defined colorectal adenocarcinoma tumor organoid (tumoroid) model using ex vivo invasion screens and orthotopic, in vivo screens for gain of metastatic potential. We identify Ctnna1 and Bcl2l13 as bona fide metastasis suppressors. CTNNA1 loss promotes carcinoma cell invasion and migration through an atypical EMT-like mechanism, whereas BCL2L13 loss promotes cell survival after extracellular matrix detachment and non-cell-autonomous macrophage polarization. Ultimately, this study provides a proof-of-principle that high-content forward genetic screening can be performed in tumor-organoid models in vivo and identifies novel regulators of colon cancer metastasis.

cancer biology↗

bioRxiv2023

Genome editing induces the transfer of mitochondrial DNA into the nuclear genome

Mitochondria serve as the cellular powerhouse, and their distinct DNA makes them a prospective target for gene editing to treat genetic disorders. However, the impact of genome editing on mitochondrial DNA (mtDNA) stability remains a mystery. Our study reveals previously unknown risks of genome editing that both nuclear and mitochondrial editing cause broad transfer of mitochondrial DNA segments into the nuclear genome in various cell types including human cell lines, primary T cells, retinal cells, and mouse embryos. Furthermore, drug-induced mitochondrial stresses and mtDNA breaks exacerbate this transfer of mtDNA into the nuclear genome. Notably, we observe that the newly developed mitochondrial base editor DdCBE can also cause widespread mtDNA integrations. However, we provide a practical solution to suppress the transfer of mtDNA by co-expressing TREX1 or TREX2 exonucleases during DdCBE editing. These findings also shed light on the origins of mitochondrial-nuclear DNA segments.

genomics↗

bioRxiv2023

Interchromosomal Colocalization with Parental Genes Is Linked to the Function and Evolution of Mammalian Retrocopies

Retrocopies are gene duplicates arising from reverse transcription of mature mRNA transcripts and their insertion back into the genome. While long being regarded as processed pseudogenes, more and more functional retrocopies have been discovered. How the stripped- down retrocopies recover expression capability and become functional paralogs continually intrigues evolutionary biologists. Here, we investigated the function and evolution of retrocopies in the context of three-dimensional (3D) genome organization. By mapping retrocopy-parent pairs onto sequencing-based and imaging-based chromatin contact maps in human and mouse cell lines and onto Hi-C interaction maps in five other mammals, we found that retrocopies and their parental genes show a higher-than-expected interchromosomal colocalization frequency. The spatial interactions between retrocopies and parental genes occur frequently at loci in active subcompartments and near nuclear speckles. Accordingly, colocalized retrocopies are more actively transcribed and translated, and are more evolutionarily conserved than noncolocalized ones. The active transcription of colocalized retrocopies may result from their permissive epigenetic environment and shared regulatory elements with parental genes. Population genetic analysis of retroposed gene copy number variants (retroCNVs) in human populations revealed that retrocopy insertions are not entirely random in regard to interchromosomal interactions and that colocalized retroCNVs are more likely to reach high frequencies, suggesting that both insertion bias and natural selection contribute to the colocalization of retrocopy-parent pairs. Further dissection implies that reduced selection efficacy, rather than positive selection, contributes to the elevated allele frequency of colocalized retroCNVs. Overall, our results hint a role of interchromosomal colocalization in the "resurrection" of initially neutral retrocopies.

evolutionary biology↗

bioRxiv2023

Transcriptome brings variations of gene expression, alternative splicing, and structural variations into gene-scale trait dissection in soybean

Genome-wide association study (GWAS) identifies trait-associated loci, but due in part to slow decay of linkage disequilibrium (LD), identifying the causal genes can be a bottleneck. Transcriptome-wide association study (TWAS) addresses this by identifying gene expression-phenotype associations or integrating gene expression quantitative trait loci (eQTLs) with GWAS results. Here, we used self-pollinated soybean as a model to evaluate the application of TWAS in the genetic dissection of traits in plant species that exhibit slow LD decay. The first RNA-Seq analysis of a soybean diversity panel was conducted, which identified the genetic regulation of 29,286 genes. Different TWAS solutions were less affected by LD and robust with source of expression that identified known genes related to traits from different development stages and tissues. A novel gene named pod color L2 was identified via TWAS and functionally validated by genome editing. Our introduction of the new exon proportion feature significantly improves the capture of expression variations resulting from structural variations and alternative splicing. As a result, the genes identified by our TWAS approach exhibited a diverse range of causal variations, including SNP, insertion/deletion, gene fusion, copy number variation, and alternative splicing. Using our TWAS approach, we identified genes associated with flowering time, including both previously known candidates and novel genes that had not been linked to this trait before, providing complementary insights with GWAS. In summary, this study supports the application of TWAS for candidate gene identification in species with low rates of LD decay.

genetics↗

bioRxiv2023

Crystal structures reveal nucleotide-induced conformational changes in G motifs and distal regions in guanylate-binding protein 2

Guanylate-binding proteins (GBPs) are interferon-inducible GTPases that confer protective immunity against a variety of intracellular pathogens including bacteria, viruses, and protozoan parasites. GBP2 is one of the two highly inducible GBPs, yet the precise mechanisms underlying the activation and regulation of GBP2, in particular the nucleotide-induced conformational changes in GBP2, remain poorly understood. In this study, we elucidate the structural dynamics of GBP2 upon nucleotide binding through crystallographic analysis. GBP2 dimerizes upon GTP hydrolysis and returns to monomer state once GTP is hydrolyzed to GDP. By determining the crystal structures of GBP2 G domain (GBP2GD) in complex with GDP and nucleotide-free full-length GBP2, we unveil distinct conformational states adopted by the nucleotide-binding pocket and distal regions of the protein. Our findings demonstrate that the binding of GDP induces a distinct closed conformation both in the G motifs and the distal regions in the G domain. The conformational changes in the G domain are further transmitted to the C-terminal helical domain, leading to large-scale conformational rearrangements. Through comparative analysis, we identify subtle but critical differences in the nucleotide-bound states of GBP2, providing insights into the molecular basis of its dimer-monomer transition and enzymatic activity. Overall, our study expands the understanding of the nucleotide-induced conformational changes in GBP2, shedding light on the structural dynamics governing its functional versatility. These findings pave the way for future investigations aimed at elucidating the precise molecular mechanisms underlying GBP2s role in the immune response and may facilitate the development of targeted therapeutic strategies against intracellular pathogens.

biochemistry↗

bioRxiv2023

Cynipid wasps systematically reprogram host metabolism and restructure cell walls in developing galls

Many insects have evolved the ability to manipulate plant growth to generate extraordinary structures called galls in which insect larva can develop while being sheltered within and feeding on the plant. In particular, Cynipid (Hymenoptera: Cynipidae) wasps have evolved to form some of the most morphologically complex galls known and generate an astonishing array of gall shapes, colors, and sizes. However, the biochemical basis underlying these remarkable cellular and developmental transformations remains poorly understood. A key determinant in plant cellular development is the deposition of the cell wall to dictate the physical form and physiological function of newly developing cells, tissues, and organs. However, it is unclear to what degree cell walls are restructured to initiate and support the formation of new gall tissue. Here, we characterize the molecular alterations underlying gall development using a combination of metabolomic, histological, and biochemical techniques to elucidate how leaf cells are reprogrammed to form galls. Strikingly, gall development involves an exceptionally coordinated spatial deposition of lignin and xylan to form de novo gall vasculature. Our results highlight how Cynipid wasps can radically change the metabolite profile and restructure the cell wall to enable the formation of galls, providing new insights into the mechanism of gall induction and the extent to which plants can be entirely reprogrammed to form novel structures and organs.

plant biology↗

bioRxiv2023

A rapid workflow for neuron counting in combined light sheet microscopy and magnetic resonance histology

Information on regional variation in cell numbers and densities in the CNS provides critical insight into structure, function, and the progression of CNS diseases. However, variability can be real or can be a consequence of methods that do not account for technical biases, including morphologic deformations, errors in the application of cell type labels and boundaries of regions, errors of counting rules and sampling sites. We address these issues of by introducing a workflow that consists of the following steps: 1. Magnetic resonance histology (MRH) to establish the size, shape, and regional morphology of the mouse brain in situ. 2. Light-sheet microscopy (LSM) to selectively label all neurons or other cells in the entire brain without sectioning artifacts. 3. Register LSM volumes to MRH volumes to correct for dissection errors and morphological deformations. 4. Implement novel protocol for automated sampling and counting of cells in 3D LSM volumes. This workflow can analyze the cells density of one brain region in less than 1 min and is highly replicable to cortical and subcortical gray matter regions and structures throughout the brain. We report deformation-corrected neuron (NeuN) counts and neuronal density in 13 representative regions in 5 C57B6/6J and 2 BXD strains. The data represent the variability among cases for the same brain region and across regions within case. Our data are consistent with previous studies. We demonstrate the application of our workflow to a mouse model of aging. This workflow improves the accuracy of neuron counting and the assessment of neuronal density on a region-by-region basis, with broad applications in how genetics, environment, and development across the lifespan impact brain structure.

neuroscience↗

bioRxiv2023

Multiple sequence-alignment-based RNA language model and its application to structural inference

Compared to proteins, DNA and RNA are more difficult languages to interpret because 4-letter-coded DNA/RNA sequences have less information content than 20-letter-coded protein sequences. While BERT (Bidirectional Encoder Representations from Transformers)-like language models have been developed for RNA, they are ineffective at capturing the evolutionary information from homologous sequences because unlike proteins, RNA sequences are less conserved. Here, we have developed an unsupervised Multiple sequence-alignment-based RNA language model (RNA-MSM) by utilizing homologous sequences from an automatic pipeline, RNAcmap. The resulting unsupervised, two-dimensional attention maps and one-dimensional embeddings from RNA-MSM can be directly mapped with high accuracy to 2D base pairing probabilities and 1D solvent accessibilities, respectively. Further fine-tuning led to significantly improved performance on these two downstream tasks over existing state-of-the-art techniques. We anticipate that the pre-trained RNA-MSM model can be fine-tuned on many other tasks related to RNA structure and function.

bioinformatics↗

bioRxiv2023

Astroglial exosome HepaCAM signaling and ApoE antagonization coordinates early postnatal cortical pyramidal neuronal axon growth and dendritic spine formation

Developing astroglia play important roles in regulating synaptogenesis through secreted and contact signals. Whether they regulate postnatal axon growth is unknown. By selectively isolating exosomes using size-exclusion chromatography (SEC) and employing cell-type specific exosome reporter mice, our current results define a secreted astroglial exosome pathway that can spread long-range in vivo and stimulate axon growth of cortical pyramidal neurons. Subsequent biochemical and genetic studies found that surface expression of glial HepaCAM protein essentially and sufficiently mediates the axon-stimulating effect of astroglial exosomes. Interestingly, apolipoprotein E (ApoE), a major astroglia-secreted cholesterol carrier to promote synaptogenesis, strongly inhibits the stimulatory effect of astroglial exosomes on axon growth. Developmental ApoE deficiency also significantly reduces spine density of cortical pyramidal neurons. Together, our study suggests a surface contact mechanism of astroglial exosomes in regulating axon growth and its antagonization by ApoE, which collectively coordinates early postnatal pyramidal neuronal axon growth and dendritic spine formation.

neuroscience↗

bioRxiv2023

Duck pan-genome reveals two transposon-derived structural variations caused bodyweight enlarging and white plumage phenotype formation during evolution

Structural variations (SVs) are a major source of domestication and improvement traits, however SV profiles of duck and their phenotypic impacts largely hidden. We present the first duck pan-genome constructed using five genome assemblies capturing [~]40.98 Mb new sequences. This pan-genome together with high-depth sequencing data ([~]46.5X) identified 101,041 SVs, of which substantial proportions were derived from transposable element (TE) activity. Many TE-derived SVs anchoring in a gene body or regulatory region are linked to ducks domestication and improvement. By combining quantitative genetics with molecular experiments, we dissect how TE-derived SVs change gene expression of IGF2BP1 and generate a novel transcript of MITF, shaping bodyweight and white plumage. In the IGF2BP1 locus, the TE-derived SV explains the largest effect on bodyweight among avian species (27.61% of phenotypic variation). Our findings highlight the importance of using a pan-genome as a reference in genomics studies and explore the roles of TE-derived SVs in trait formation and in livestock breeding.

genetics↗

bioRxiv2023

Combined CRISPR and proteomics screening reveal a cohesin-CTCF-bound allele contributing to increased expression of RUVBL1 and prostate cancer progression

Genome-wide association studies along with expression quantitative trait loci (eQTL) mapping have identified hundreds of single nucleotide polymorphisms (SNPs) and their target genes in prostate cancer (PCa), yet functional characterization of these risk loci remains challenging. To screen for potential regulatory SNPs, we designed a CRISPRi library containing 9133 guide RNAs (gRNAs) to target 2,166 candidate SNP sites implicated in PCa and identified 117 SNPs that could regulate 90 genes for PCa cell growth advantage. Among these, rs60464856 was covered by multiple gRNAs significantly depleted in the screening (FDR<0.05). Pooled SNP association analysis in the PRACTICAL and FinnGen cohorts showed significantly higher PCa risk for the rs60464856 G allele (pvalue=1.2E-16 and 3.2E-7). Subsequent eQTL analysis revealed that the G allele is associated with increased RUVBL1 expression in multiple datasets. Further CRISPRi and xCas9 base editing proved the rs60464856 G allele leading to an elevated RUVBL1 expression. Furthermore, SILAC-based proteomic analysis demonstrated allelic binding of cohesin subunits at the rs60464856 region, where HiC dataset showed consistent chromatin interactions in prostate cell lines. RUVBL1 depletion inhibited PCa cell proliferation and tumor growth in xenograft mouse model. Gene set enrichment analysis suggested an association of RUVBL1 expression with cell-cycle-related pathways. An increased expression of RUVBL1 and activations of cell-cycle pathways were correlated with poor PCa survival in TCGA datasets. Together, our CRISPRi screening prioritized about one hundred regulatory SNPs essential for prostate cell proliferation. In combination with proteomics and functional studies, we characterized the mechanistic role of rs60464856 and RUVBL1 in PCa progression.

genetics↗

bioRxiv2023

Construction of Model Animals to Explore Intestinal Microbiome for Detection of Breast Cancer

Breast cancer ranks first among female cancers and has become a major public health problem in the current society. More studies indicated that these cancers are related to the change in the gut microbiome that can cause metabolic and immune system disorders in the body. However, there are few studies on the changes in gut microbiome caused by the onset of breast cancer, and the relationship between breast cancer and gut microbiome needs to be further clarified. In this study, we inoculated 4T1 breast cancer cells to induce breast cancer tumorigenesis in mice and collected their feces samples at different stages during this process. These intestinal florae were analyzed using 16S rRNA gene amplicon sequencing, and the results showed that at the phylum level, the ratio of Firmicutes/Bacteroidetes decreased with the development of the tumor; at the family level, the intestinal microbiome had obvious variations of Lachnospiraceae, Bacteroidaceae, Erysipelotrichaceae, etc. The Kyoto Encyclopedia of Genes and Genomes (KEGG) and COG annotation demonstrated that decreased abundance of cancer related signaling pathways. This study elucidated the relationship between breast cancer and intestinal microbiome, and the research results can be used as an important biomarker for the diagnosis of breast cancer.

cancer biology↗

bioRxiv2023

The SARS-CoV-2 Spike protein induces long-term transcriptional perturbations of mitochondrial metabolic genes, causes cardiac fibrosis, and reduces myocardial contractile in obese mice

BackgroundAs the pandemic evolves, post-acute sequelae of CoV-2 (PACS) including cardiovascular manifestations have emerged as a new health threat. This study aims to study whether the Spike protein plus obesity can exacerbate PACS-related cardiomyopathy. MethodsA Spike protein-pseudotyped (Spp) virus with the proper surface tropism of SARS-CoV-2 was developed for viral entry assay in vitro and administration into high fat diet (HFD)-fed mice. The systemic viral loads and cardiac transcriptomes were analyzed at 2 and 24 hrs, 3, 6, and 24 weeks post introducing (wpi) Spp using RNA-seq or real time RT-PCR. Echocardiography was used to monitor cardiac functions. ResultsLow-density lipoprotein cholesterol enhanced viral uptake in endothelial cells, macrophages, and cardiomyocyte-like H9C2 cells. Selective cardiac and adipose viral depositions were observed in HFD mice but not in normal-chow-fed mice. The cardiac transcriptional signatures in HFD mice at 3, 6, and 24 wpi showed systemic suppression of mitochondria respiratory chain genes including ATP synthases and nicotinamide adenine dinucleotide:ubiquinone oxidoreductase gene members, upregulation of stress pathway-related crucial factors such as nuclear factor-erythroid 2-related factor 1 and signal transducer and activator of transcription 5A, and increases in expression of glucose metabolism-associated genes. As compared with the age-matched HFD control mice, cardiac ejection fraction and fractional shortening were significantly decreased, while left ventricular end-systolic diameter and volume were significantly elevated, and cardiac fibrosis was increased in HFD mice at 24 wpi. ConclusionOur data demonstrated that the Spike protein could induce long-term transcriptional suppression of mitochondria metabolic genes and cause cardiac fibrosis and myocardial contractile impairment, providing mechanistic insights to PACS-related cardiomyopathy.

microbiology↗