Biology subjects

Mattson, M. P.

Publications and source records attributed to Mattson, M. P..

8 recordsLinked to original sources

bioRxiv2026

Integrated Multiomics Reveals Intergenerational Brain Sensory System Remodeling Induced by Parental Intermittent Fasting

Intermittent fasting (IF) is increasingly recognized as a potent modulator of metabolic health, but its effects on brain function across generations remain poorly understood. Here, we show that parental IF, administered to both mothers and fathers before mating, is associated with coordinated molecular remodeling in the cerebral cortex of fathers and their offspring, with shared molecular signatures identified between these generations and a pronounced enrichment of sensory-associated pathways. Using whole-genome bisulfite sequencing, transcriptomic profiling, and proteomic analysis, we found that IF elicited widespread cortical epigenetic remodeling in fathers, accompanied by transcriptional and protein-level changes enriched for olfactory, taste, synaptic, and neurometabolic pathways. Strikingly, related molecular signatures were detected in F1 offspring that had never been directly exposed to fasting, consistent with intergenerational transmission of IF-associated cortical remodeling. Offspring responses were sex dependent, with female and male progeny exhibiting distinct patterns of DNA methylation, gene expression, and protein abundance. Integrated multiomic analyses identified conserved candidate networks involved in sensory perception, glutamatergic signaling, synaptic organization, intracellular trafficking, cytoskeletal regulation, and stress-response pathways. Together, these findings identify sensory-associated cortical remodeling as a prominent molecular feature associated with parental IF and reveal persistent, sex-dependent molecular alterations in the offspring brain.

genomics↗

bioRxiv2025

Uncovering Shared and Tissue-Specific Molecular Adaptations to Intermittent Fasting in Liver, Brain, and Muscle

Intermittent fasting (IF) has emerged as a powerful dietary intervention with profound metabolic benefits, yet the tissue-specific molecular mechanisms underlying these effects remain poorly understood. In this study, we employed comprehensive proteomics and transcriptomics analysis to investigate the systemic and organ-specific adaptations to IF in male C57BL/6 mice. Following a 16-hour daily fasting regimen (IF16) over four months, IF reduced blood glucose, HbA1c, and cholesterol levels while increasing ketone bodies, indicative of enhanced metabolic flexibility. Proteomic profiling of the liver, skeletal muscle, and cerebral cortex revealed tissue-specific responses, with the liver exhibiting the most pronounced changes, including upregulation of pathways involved in fatty acid oxidation, ketogenesis, and glycan degradation, and downregulation of steroid hormone and cholesterol metabolism. In muscle, IF enhanced pyruvate metabolism, fatty acid biosynthesis, and AMPK signaling, while suppressing oxidative phosphorylation and thermogenesis. The cerebral cortex displayed unique adaptations, with upregulation of autophagy, PPAR signaling, and metabolic pathways, and downregulation of TGF-beta and p53 signaling, suggesting a shift toward energy conservation and stress resilience. Notably, Serpin A1c emerged as the only protein commonly upregulated across all three tissues, highlighting its potential role in systemic adaptation to IF. Integrative transcriptomic and proteomic analyses revealed partial concordance between mRNA and protein expression, underscoring the complexity of post-transcriptional regulation. Shared biological signaling processes were identified across tissues, suggesting unifying mechanisms linking metabolic changes to cellular communication. Our findings reveal both conserved and tissue-specific responses by which IF may optimize energy utilization, enhance metabolic flexibility, and promote cellular resilience.

molecular biology↗

bioRxiv2025

Intermittent Fasting Reprograms Chromatin Accessibility to Modulate Gene Expression in Brain and Muscle

Intermittent fasting (IF), a dietary regimen that mimics the natural feeding patterns observed across diverse organisms--from single-celled life to mammals--is thought to activate systemic survival responses and confer health benefits. However, the molecular mechanisms underlying these effects remain poorly understood. In this study, we utilized ATAC-Seq and RNA-Seq to investigate how IF influences chromatin accessibility and gene expression in brain and muscle tissues of mice, compared to ad libitum feeding. Our results reveal that IF induces significant changes in chromatin accessibility, modulating pathways related to metabolism, ribosome function, HIF-1 signaling, and glycolysis. Motif analysis identified tissue-specific transcription factors enriched in IF-regulated regions, including Sp1, Mef2a, NeuroD2, Banp, and NFIA in the brain, and SMAD4, TCF4, STAT5B, NKX3-1, and ZEB2 in muscle. Integrative analysis of ATAC-Seq and RNA-Seq data demonstrated that IF upregulates 50 genes and downregulates 15 in the cortex, while upregulating 31 genes and downregulating 10 in muscle. These gene expression changes are linked to pathways associated with neuroprotection and enhanced muscle function, offering mechanistic insights into the health benefits of IF. Our findings underscore the role of IF-induced chromatin remodeling in driving adaptive gene regulation.

bioinformatics↗

bioRxiv2024

Impact of Parental Time-Restricted Feeding on Offspring Metabolic Phenotypic Traits

A substantial body of research elucidates the mechanisms and health advantages associated with intermittent fasting (IF). However, the impact of parental IF on offspring remains unclear. Through an investigation involving four IF and ad libitum combinations of parental mating groups, we demonstrate that parental IF (daily time-restricted feeding) influences offsprings metabolic health indicators in male and female offspring in distinct ways. We found that when both parents are on IF their offspring exhibit protection against the adverse effects of a high-fat, high-sugar, and high-salt diet in a sex-specific manner. This study underscores the potential significance of parental lifestyle modifications involving dietary restriction for the metabolic status of their children and their risk for obesity and diabetes.

genetics↗

bioRxiv2021

TREM2 interacts with TDP-43 and mediates microglial neuroprotection against TDP-43-related neurodegeneration

Triggering receptor expressed on myeloid cell 2 (TREM2) is a surface receptor that, in the central nervous system, is exclusively expressed on microglia. TREM2 variants have been linked to increased risk for neurodegenerative diseases, but the functional effects of microglial TREM2 remain largely unknown. To this end, we investigated TAR-DNA binding protein 43 kDa (TDP-43)-related neurodegenerative disease via viral-mediated expression of human TDP-43 protein (hTDP-43) in neonatal and adult mice or inducible expression of hTDP43 with defective nuclear localization signals in transgenic mice. We found that TREM2 deficiency impaired microglia phagocytic clearance of pathological TDP-43, and enhanced neuronal damage and motor function impairments. Mass cytometry analysis revealed that hTDP-43 induced a TREM2-dependent subpopulation of microglia with high CD11c expression and higher phagocytic ability. Using mass spectrometry and surface plasmon resonance analysis, we further demonstrated an interaction between TDP-43 and TREM2, in vitro and in vivo, in hTDP-43-expressing transgenic mouse brains. We computationally identified the region within hTDP-43 that interacts with TREM2 and observed the potential interaction in ALS patient tissues. Our data reveal the novel interaction between TREM2 and TDP-43, highlighting that TDP-43 is a possible ligand for microglial TREM2 and the interaction mediates neuroprotection of microglial TREM2 in TDP-43-related neurodegeneration.

neuroscience↗

bioRxiv2021

Multiomics Analyses Reveal Dynamic Bioenergetic Pathways and Functional Remodeling of the Heart During Intermittent Fasting

AimsIntermittent fasting (IF) reduces cardiovascular risk factors in animals and humans, and can protect the heart against ischemic injury in models of myocardial infarction, but the underlying molecular mechanisms are unknown. To delineate molecular and cellular adaptations of the heart to IF, we carried out system-wide comprehensive analyses of proteome and phosphoproteome, complemented with transcriptome profiling, followed by functional analysis. Methods and resultsIn order to understand molecular and cellular remodeling of the heart during IF, we employed advanced mass spectrometry for system-wide profiling of the proteome and phosphoproteome of heart tissues obtained from mice maintained for 6 months on either daily 12- or 16-hour fasting, every-other-day fasting or ad libitum control feeding regimens. We also performed transcriptome analyses using RNA sequencing to evaluate whether the observed molecular responses to IF occur at the transcriptional or post-transcriptional levels. IF regimens significantly affected pathways that regulate cyclic GMP signaling, lipid and amino acid metabolism, cell adhesion, cell death, and inflammation. Comparison of differentially expressed proteome and transcriptome upon IF showed the higher correlation of pathway alternation in short IF regimen but the inverse correlation of metabolic processes such as fatty acid oxidation and immune processes in longer IF regimens. In addition, functional echocardiographic analyses demonstrated that IF enhances stress-induced cardiac performance. ConclusionOur systematic multi-omics study elucidates a molecular framework for understanding how IF impacts the hearts function and its vulnerability to injury and disease. Translational perspectiveIntermittent fasting is emerging as a desirable lifestyle adaptation to impact cardiovascular health through the modulation of molecular and cellular mechanisms, and by acting on disease risk factors. Evidence from numerous studies indicates that the fasting cycles are highly and consistently effective in protecting against cardiovascular diseases and improving cardiac health in animals and human. Using multi-omics, here we dissect distinct molecular adaptations of the heart to different intermittent fasting regimens. Our results unveil novel cardioprotective mechanisms and open up new avenues for innovative pharmacological approaches to prevent and treat cardiovascular diseases.

systems biology↗

bioRxiv2020

Astrocyte- and neuron-derived extracellular vesicles from Alzheimer's disease patients effect complement-mediated neurotoxicity

We have previously shown that blood astrocytic-origin extracellular vesicles (AEVs) from Alzheimers disease (AD) patients contain high complement levels. To test the hypothesis that circulating EVs from AD patients can induce complement-mediated neurodegeneration, we assessed the neurotoxicity of immunocaptured AEVs (with anti-GLAST antibody), neuronal-origin NEVs (with anti-L1CAM antibody), and multicellular-origin (with anti-CD81 antibody) EVs from the plasma of AD, frontotemporal lobar degeneration (FTLD) and control participants. AEVs (and, less effectively, NEVs) of AD participants induced Membrane Attack Complex (MAC) expression on recipient neurons, membrane disruption, reduced neurite density, and decreased cell viability in rat cortical neurons and human IPSC-derived neurons. Neurodegenerative effects were not produced by multicellular-origin EVs from AD participants or AEVs/NEVs from FTLD or control participants, and were suppressed by the MAC inhibitor CD59 and other complement inhibitors. Our results support the stated hypothesis and suggest that neuronal MAC deposition is necessary for AEV/NEV-mediated neurodegeneration in AD.

neuroscience↗

bioRxiv2020

Integrative Epigenomic and Transcriptomic Analysis Reveals Robust Metabolic Switching in the Brain During Intermittent Fasting

Intermittent fasting (IF) is a lifestyle intervention comprising a dietary regimen in which energy intake is restricted via alternating periods of fasting and ad libitum food consumption, without compromising nutritional composition. While epigenetic modifications can mediate effects of environmental factors on gene expression, no information is yet available on potential effects of IF on the epigenome. In this study, we found that IF causes modulation of histone H3 lysine 9 trimethylation (H3K9me3) epigenetic mark in the cerebellum of male C57/BL6 mice, which in turn orchestrates a plethora of transcriptomic changes involved in the robust metabolic switching processes commonly observed during IF. Interestingly, both epigenomic and transcriptomic modulation continued to be observed after refeeding, suggesting that memory of the IF-induced epigenetic change is maintained at the locus. Notably though, we found that termination of IF results in a loss of H3K9me3 regulation of the transcriptome. Collectively, our study characterizes a novel mechanism of IF in the epigenetic-transcriptomic axis, which controls myriad metabolic process changes. In addition to providing a valuable and innovative resource, our systemic analyses reveal molecular framework for understanding how IF impacts the metaboloepigenetics axis of the brain. Highlights{circ} Intermittent fasting (IF) and refeeding modifies epigenome in the cerebellum {circ}Integrative epigenomic and transcriptomic analyses revealed metabolic switching {circ}IF affects the metaboloepigenetics axis in regulating metabolic processes {circ}Integrative analyses revealed a loss of epigenetic reprogramme following refeeding

neuroscience↗