Biology subjects

Keshishian, H.

Publications and source records attributed to Keshishian, H..

At least 19 recordsLinked to original sources

bioRxiv2026

Ether glycerophospholipid control of peroxisome degradation confers protection from ischemia

Ether glycerophospholipids (ether lipids) are a subclass of glycerophospholipids that are synthesized at the peroxisome and constitute nearly 20% of the total phospholipid content in metazoans. Biochemically, ether lipids have an alkyl chain attached by an ether bond at the sn-1 position of the glycerol backbone (alkyl-ether) primarily containing choline or ethanolamine head groups. Some ether lipids contain a cis bond adjacent to the ether linkage (alkenyl-ether) and are commonly referred to as plasmalogens. While the importance of ether lipids in humans is clear, highlighted by the severity of inherited peroxisomal disorders caused by ether lipid deficiency, the molecular roles of these lipids remain poorly understood. Here, we identify a link between ether lipid metabolism, peroxisome degradation, and oxygen availability. We find Fatty acyl-CoA-reductase 1 (FAR1), the rate-limiting enzyme in peroxisomal ether lipid metabolism, acts as a peroxisome receptor necessary for peroxisome degradation when oxygen is limiting. Hypoxia increases choline ether lipid abundance, promotes autophagy activation, and peroxisome degradation. Mechanistically, FAR1 binds ATG8-family protein LC3B and is necessary and sufficient to control peroxisome degradation under hypoxia. FAR1s enzymatic function as well as its capacity to bind LC3B is necessary to degrade peroxisomes under hypoxia. Similarly, loss of multiple components of peroxisomal ether lipid metabolism blocks peroxisome degradation under hypoxia in cells and in vivo. In mouse models of chronic HIF activation, Far1 is a direct HIF target gene and is necessary for peroxisome degradation in this setting. Increasing ether lipids using ether lipid precursors activates autophagy and promotes autophagy-dependent cardioprotection against ischemic injury. This work reveals FAR1 as a critical regulator of peroxisome homeostasis in the setting of oxygen limitation.

cell biology↗

bioRxiv2026

Multi-omic responses to acute exercise in abdominal subcutaneous adipose tissue of sedentary adults: findings from MoTrPAC

Exercise induces widespread health benefits across multiple tissues, yet the acute molecular responses in human adipose tissue remain poorly defined. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) profiled temporal molecular changes in abdominal subcutaneous adipose tissue (ASAT) following a single bout of exercise. Healthy sedentary adults were randomized to endurance (EE), resistance (RE), or control (CON) groups. ASAT biopsies were collected pre-exercise and at 45min, 4hr, and 24hr post-exercise, followed by transcriptomic, proteomic, phosphoproteomic, and metabolomic analyses. EE and RE elicited distinct, time-resolved molecular programs involving angiogenesis, extracellular matrix remodeling, mitochondrial metabolism, substrate utilization, and circadian regulation. Phosphoproteomics revealed acute changes in cytoskeletal and branched-chain amino acid metabolism proteins associated with glycemic control. Temporal metabolomic shifts were cell-type-specific. Finally, we identified candidate adipose-derived exerkines with predicted endocrine actions. This multi-omic map of acute ASAT responses offers insight into adipose-specific mechanisms by which exercise promotes metabolic health.

systems biology↗

bioRxiv2026

Integrative Multi-omics Analysis of the Human Skeletal Muscle Response to Endurance or Resistance Exercise: Findings from the Molecular Transducers of Physical Activity Consortium (MoTrPAC)

The Molecular Transducers of Physical Activity Consortium (MoTrPAC) was established to systematically characterize the molecular basis of the health benefits of exercise. Here, we present the integrative, multi-omics response of human skeletal muscle to acute endurance (EE) and resistance (RE) exercise. Distinct temporal responses were observed, with changes in ATAC-seq, phosphoproteome, and metabolome occurring before changes in the transcriptome and proteome. These distinct temporal multi-omic dynamics were used to identify transcriptional regulatory hubs converging around MEF2A and NFIC regulation of autophagy, angiogenesis and metabolism. Further, early RE-specific phosphoproteome signatures counteracted epigenetic modifications and downregulated transcripts involved in protein turnover. Additional findings include suppression of HIPK2/3 kinase signatures linked to the acute exercise regulation of sarcomeric proteins TTN, NEB, ANKRD2 and LMOD2. Our data demonstrate distinct temporal regulation across the multi-omic landscape of human skeletal muscle, with EE and RE eliciting common and unique molecular signatures.

systems biology↗

bioRxiv2026

Molecular Transducers of Physical Activity Consortium (MoTrPAC): Initial Insights into the Dynamic Human Responses to Exercise

The goal of the Molecular Transducers of Physical Activity Consortium (MoTrPAC) is to examine the physiological and molecular basis for health benefits in response to acute and chronic exercise. Prior to COVID-19 suspension, healthy, sedentary participants (N=206, 18-74y) were randomized to endurance exercise (N=80), resistance exercise (N=81), or non-exercise control (N=45) interventions. The prescribed vigorous acute endurance and resistance exercise bouts induced physiological and metabolic perturbations relative to resting homeostasis. The supervised chronic (3d/wk, 12wk) endurance or resistance training programs robustly improved several physiological parameters (i.e., VO2peak, muscular strength). Temporal biospecimen (blood, muscle, and adipose) collections and processing coupled to the acute exercise bouts were highly successful. In most cases, over 90% success was achieved for blood, muscle, and adipose samples. Endurance and resistance exercise induced distinct acute and chronic physiological responses, which provide a framework to interrogate the molecular basis for health adaptations to these two popular exercise modalities. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/705347v1_ufig1.gif" ALT="Figure 1"> View larger version (65K): org.highwire.dtl.DTLVardef@554ee9org.highwire.dtl.DTLVardef@afb28dorg.highwire.dtl.DTLVardef@f381cdorg.highwire.dtl.DTLVardef@cef19c_HPS_FORMAT_FIGEXP M_FIG C_FIG

systems biology↗

bioRxiv2026

Exercise modulation of the alternative splicing landscape in human tissues

The diverse health benefits of exercise are associated with multi-organ molecular responses. Alternative RNA splicing (AS) is an important determinant of transcriptome and proteome diversity. We profiled the temporal effects of acute endurance and resistance exercise on the AS landscape of human skeletal muscle, adipose tissue, and blood, and studied regulatory mechanisms through integrated multi-omic analyses. We identified 5102 distinct differential AS (DAS) events, with the majority modifying protein-coding sequence (89%) and being independent of altered RNA expression (67%). Endurance and resistance exercise induced differing patterns of AS alterations with divergent temporal trajectories. We inferred the DAS-associated RNA-binding and DNA-binding proteins. In skeletal muscle, where DAS events were the most abundant, DAS genes were enriched for muscle structure- and RNA splicing-related processes, and splicing machinery components were regulated at the protein phosphorylation, RNA, and AS levels. These findings implicate AS regulation as a major mediator of the responses to exercise.

systems biology↗

bioRxiv2026

Multi-Omic, Multi-Tissue Responses to Acute Exercise in Sedentary Adults: Findings from the Molecular Transducers of Physical Activity Consortium

Regular physical activity represents one of the greatest mechanisms for maintaining human health, yet the underlying molecular transducers of these benefits remain incompletely understood. Multi-omic assays now provide new opportunities to study the coordinated molecular responses of body tissues to different exercise modalities. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) was established to address this need by creating a molecular map of the response to physical activity. Described here is the first human cohort of MoTrPAC: sedentary adults enrolled prior to study suspension during the COVID-19 pandemic (N=175) randomized to either endurance or resistance exercise, or non-exercise control. From these participants, we detail their global acute molecular response in skeletal muscle, adipose tissue, and blood, integrated at multiple levels: tissue, exercise modality, timepoint, and omic category. These analyses characterize key molecular pathways, identify central regulators, and implicate novel candidate exerkines in mediating multi-organ exercise effects.

systems biology↗

bioRxiv2025

Spatially resolved translational dysregulation in Grin2a+/- mouse model of schizophrenia

Loss-of-function (LoF) mutations of GRIN2A, encoding the GluN2A subunit of N-methyl-D-aspartate receptor (NMDAR), confer a high risk for schizophrenia (SCZ)1-3, yet how they affect diverse brain cell types remains poorly understood. Here, we combined subcellular-resolution spatial omics technologies, STARmap4 and RIBOmap5, to jointly resolve single-cell transcriptomes and translatomes for 3,447 genes in the brains of Grin2a+/- mice and their wild-type littermates across 538,188 cells. Translational dysregulation was markedly more prominent than transcriptional changes in neurons. Across neuronal subtypes, a set of genes including Camk2a, Arc, Egr1, Egr3, Chmp2b, and Pja2 exhibited translational reduction in a Grin2a gene dose-dependent fashion, suggesting a connection between NMDAR hypofunction and reduced protein synthesis of downstream synaptic plasticity effectors. In interneurons (particularly parvalbumin interneurons), a strong reduction of Gad2 translation implies loss of inhibitory function in cortical microcircuits, which has long been hypothesized for SCZ pathophysiology. Non-neuronal cell types including astrocytes, oligodendrocytes, and vascular cells also exhibited region-specific translational changes in neurotransmitter transport, lipid synthesis, myelination, and stress response pathways, some of which co-varied with regional neuron state. Together, our study reveals brain-wide translation dysregulation as a critical mechanism underlying SCZ pathophysiology.

neuroscience↗

bioRxiv2025

GPR34 regulation of disease-associated microglial states and responses to physiological stimuli

Expression of the G protein coupled receptor GPR34 is highly enriched in microglia and has been reported to be downregulated in several brain disease contexts, including Alzheimers disease (AD) and multiple sclerosis (MS). GPR34 function is poorly understood, as is its role in regulation of microglial states. Using RNA-sequencing, we find that microglia from Gpr34 knockout (KO) mouse brains exhibited a transcriptomic shift toward disease-associated microglia (DAM) and inflammatory profiles, partially resembling the microglial phenotype seen in 5xFAD AD model mice. Moreover, when Gpr34 KO mice were crossed with 5xFAD mice, the DAM transcriptional profile of microglia and glial pathology were further enhanced beyond the already robust DAM signature driven by 5xFAD alone. This occurred without affecting amyloid plaque burden. Human stem cell-derived microglia (iMGLs) lacking GPR34 showed reduced calcium (Ca{superscript 2}) and phosphorylated ERK (pERK) signaling in response to stimulation with known GPR34 agonists (lyso-phosphatidylserine (lysoPS) and myelin), as well as transcriptomic changes in immune regulation and cell proliferation related pathways. Interestingly, GPR34 KO iMGLs were selectively impaired in phagocytosis of myelin but not amyloid-{beta} (A{beta}) or E. coli, and showed a diminished transcriptional response elicited by myelin. Together, these findings suggest that GPR34 is important for maintaining microglia in a homeostatic state, promotes phagocytosis of and transcriptional response to myelin, and limits microglial activation in neurodegenerative disease conditions.

neuroscience↗

bioRxiv2025

A genetically engineered vertebrate animal model of NAA15-related heart disease uncovers myocardial growth, contractility, and mitochondrial defects

Delineating the genetic and environmental instigators of congenital heart disease (CHD), affecting up to 1% of newborns, will improve preventative, diagnostic, and therapeutic efforts to mitigate disease outcomes. Although mutations in NAA15, which encodes the auxiliary subunit of N-alpha-acetyltransferase A (NatA), are associated with CHD in humans, vertebrate animal models of NAA15-related heart disease have yet to be described. Therefore, we isolated zebrafish strains carrying null mutations in paralogs naa15a and naa15b, which we co-localized to the early larval myocardium. Double knockout (DKO) naa15-deficient larvae exhibited diminutive, lowly contractile, and bradycardic ventricles composed of fewer and smaller cardiomyocytes (CMs) incapable of proliferation. On a subcellular level, mutant CMs exhibited moderately disorganized myofibrils. CM-specific re-expression of naa15a partially rescued the contractility and growth deficits, revealing an indispensable myocardial function. Ubiquitous mis-expression of human NAA15 achieved complete rescue, enabling functional testing of human NAA15 variants. Animals with a reduced dosage (RD) of naa15 survived to adulthood and shared phenotypes with DKO larvae, including smaller ventricular chambers and CMs, which exhibited mosaic myofibril disarray. Deep quantitative proteomic profiling of WT and naa15RD adult hearts revealed differential expression of multiple protein classes, including several subunits of mitochondrial respiratory complex I, a component of the electron transport chain. Accordingly, we documented reduced mitochondrial content and function in the myocardium of naa15-deficient larvae. Taken together, our data reveal myocardial functional and structural abnormalities associated with mitochondrial dysfunction in a vertebrate animal model of NAA15-related heart disease.

developmental biology↗

bioRxiv2025

Abnormal Lipid Metabolism and Altered Neuronal Support by Astrocytes Lacking Akap11, a Risk Gene for Schizophrenia and Bipolar Disorder

A-Kinase Anchoring Protein 11 (AKAP11) is a shared genetic risk factor for schizophrenia and bipolar disorder, yet its role in the brain remains poorly understood. Through multi-omic analysis of Akap11 mutant mouse brains and cultured astrocytes, we identified significant transcriptomic, proteomic, and metabolomic alterations. Key findings include the upregulation of cholesterol and fatty acid metabolic pathways, accumulation of lipid species such as cholesteryl esters, triacylglycerols, ceramides, and glycerophospholipids, and elevated levels of 3,5-cyclic AMP and protein kinase A (PKA) signaling. These metabolic perturbations manifested as increased lipid droplet accumulation in Akap11 mutant astrocytes, highlighting AKAP11s critical role in regulating intracellular lipid homeostasis. Mechanistically, AKAP11 functions as an autophagy receptor mediating PKA degradation and interacts with endoplasmic reticulum-resident proteins VAP-A and VAP-B through its FFAT motif, providing possible molecular insight into AKAP11s regulation of lipid metabolism. Co-culture experiments with mouse astrocytes and human induced pluripotent stem cell-derived neurons demonstrated that loss of Akap11 in astrocytes, relative to wild-type, increases excitatory neurotransmission and neuronal activity. Collectively, these findings link AKAP11-mediated lipid and synaptic dysregulation to psychiatric disease risk and highlight the potential role of astrocytes in these disorders.

cell biology↗

bioRxiv2025

Epigenetic changes, neuronal dysregulation and metabolomic abnormalities in Zmym2 mutant mice, a genetic model of schizophrenia and neurodevelopmental disorders

Loss-of-function mutations in ZMYM2 are associated with an increased risk of schizophrenia (SCZ) and neurodevelopmental disorders (NDD). ZMYM2 interacts with proteins involved in histone modification and gene regulation, including LSD1 and ADNP; however, its specific roles in the brain remain poorly understood. In this multi-omics study, we demonstrate that heterozygous knockout of Zmym2 in mice results in widespread disturbances in gene expression affecting diverse molecular pathways, including those related to histone modifications and neuronal activity. Proteomic analysis of synapses reveals dysregulation of lipid metabolism and neurofilament-associated pathways, while metabolomic profiling identifies alterations in sphingomyelin and ceramide levels. Furthermore, Zmym2 mutant mice exhibit abnormal brain oscillation patterns on EEG and locomotor hyperactivity in the open field test. Collectively, these findings underscore the critical role of ZMYM2 in brain development and function and highlight Zmym2 mutant mice as a genetic animal model for SCZ and NDD.

neuroscience↗

bioRxiv2024

Brain-region-specific changes and dysregulation of activity regulated genes in Gria3 mutant mice, a genetic animal model of schizophrenia

Protein-truncating variants in GRIA3 (encoding the GluA3/GluR3 subunit of -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors) are associated with substantially increased risk of schizophrenia (SCZ). Here we characterized Gria3 mutant mice carrying a protein-truncating mutation that mimics a SCZ-associated variant. Transcriptomic analysis revealed that activity-regulated genes are downregulated in cortical regions, while immune and glia-related pathways exhibit brain-region-specific changes. The transcriptomic changes in Gria3 mutant mice are remarkably different from those in Grin2a mutant mice, particularly in the prefrontal cortex, even though both encode glutamate receptors and are associated with SCZ risk. Proteomic analysis further demonstrated that loss-of-function of Gria3 profoundly alters the protein composition of synapses. These findings in a genetic mouse model provide potential insights into the pathophysiological mechanisms underlying SCZ.

neuroscience↗

bioRxiv2024

Reduction of SynGAP-γ, disrupted splicing of Agap3, and oligodendrocyte deficits in Srrm2 mice, a genetic model of schizophrenia and neurodevelopmental disorder

Rare loss-of-function variants in SRRM2, which encodes a nuclear speckle scaffold and splicing factor, are associated with schizophrenia and neurodevelopmental disorders. How SRRM2 haploinsufficiency disrupts brain function is unknown. We find that Srrm2+/- mice exhibit (i) large-scale changes in gene expression in neuronal and glial cells, affecting DNA-binding-, synapse-, translation-, mitochondria-related pathways across multiple brain regions; (ii) alterations in splicing and/or abundance of multiple postsynaptic proteins, including reduction of the gamma isoform of SynGAP and elevation of its interactor, Agap3; and (iii) reduced oligodendrocyte proportions, particularly in striatum, accompanied by decreased expression of myelin-related mRNAs and proteins. Human iPSC-derived neurons deficient in SRRM2 display conserved AGAP3 splicing defects. Behaviorally, Srrm2+/- mice have reduced locomotor activity and impaired startle responses, and EEG recordings reveal reduced sleep spindles resembling humans with schizophrenia. Our findings identify specific synaptic changes, splicing dysregulation, and impaired myelination as mechanisms linking SRRM2 haploinsufficiency to neuropsychiatric disease.

neuroscience↗

bioRxiv2024

Muti-omics characterization reveals brain-wide disruption of synapses and region- and age-specific changes in neurons and glia in Sp4 mutant mice, a genetic model of schizophrenia and bipolar disorder

Schizophrenia and bipolar disorder are highly heritable mental illnesses with unclear pathophysiology. Heterozygous loss-of-function mutations of Sp4, a zinc-finger transcription factor, greatly increase risk of schizophrenia and bipolar disorder. To investigate the molecular functions of Sp4 in an unbiased manner in vivo, we performed multi-omics analyses of Sp4 mutant mice. Bulk and single nucleus RNA-seq data showed prominent gene expression changes in all brain regions and most cell types, including neuronal and non-neuronal cells. Gene set enrichment analysis of transcriptomic changes revealed alterations in many molecular pathways, including synapse, oxidative phosphorylation, and ribosome. Synapse proteomics of Sp4 mutants pointed to impaired glutamatergic signaling and altered presynaptic function. In Sp4 heterozygous mutant mice, prefrontal cortex and striatum exhibited downregulation of synapse pathways and neuronal hypoactivity at 1 month, associated with reduced sterol biosynthesis in astrocytes, whereas at 3 months, there was a shift to neuronal hyperactivity, concurrent with suppressed immune pathways in the striatal microglia. Furthermore, our study found that much of the transcriptomic changes might be accounted for by a set of transcription regulators (Nr3c1, Creb1, and Kdm5b) under the control of Sp4. Overall, this study provides cellular and molecular features resulting from Sp4 LoF that may explain the pathophysiology of SCZ-BD psychotic disorder spectrum.

neuroscience↗

bioRxiv2024

Elevated synaptic PKA activity and abnormal striatal dopamine signaling in Akap11 mutant mice, a genetic model of schizophrenia and bipolar disorder

AbstractLoss-of-function mutations in AKAP11 (a protein kinase A (PKA)-binding protein) greatly increase the risk of bipolar disorder and schizophrenia. To determine the neurobiological functions of AKAP11, we conduct multi-omic and neurobiological analyses of Akap11 mutant mouse brains. We find that AKAP11 is a key regulator of PKA proteostasis in the brain whose loss leads to dramatically increased levels of PKA subunits and phosphorylated PKA substrates, especially in synapses. Akap11 mutant mice show extensive transcriptomic changes throughout the brain, including prominent decreases in synapse-related genes sets. Gene expression is highly impacted in spiny projection neurons of the striatum, a brain region implicated in motivation, cognition and psychotic disorders. Real-time measurements of PKA activity reveal elevated basal PKA activity in the striatum of Akap11-/- mice, with exaggerated additional response to dopamine receptor antagonists. Behaviorally, Akap11 mutant mice show abnormally prolonged locomotor response to amphetamine, deficits in associative learning and contextual discrimination, as well as depression-like behaviors. Our study connects molecular changes to circuit dysfunction and behavioral disturbance in a genetically valid animal model of psychotic disorder.

neuroscience↗

bioRxiv2024

Identification of markers for the isolation of neuron-specific extracellular vesicles

Extracellular vesicles (EVs) are released by all cells and contain RNA and protein from their cell of origin. EVs in biofluids could be used as diagnostic biomarkers to non-invasively report the state of inaccessible cells, such as neurons in the brain. As biofluids such as cerebrospinal fluid (CSF) and plasma contain EVs originating from many different cells, isolating cell type-specific EVs and measuring their cargo could help determine the state of specific cell types. Here, we demonstrate an approach aiming to immuno-isolate EVs from neurons based on neuron-derived protein surface markers. We first developed a framework to select transmembrane proteins suitable as neuron-specific EV markers based on gene expression and EV proteomics data. Leveraging a novel, high-purity EV isolation method we developed, we further cataloged the proteins present on EVs in human CSF and plasma. Using ultrasensitive immunoassays against several of the predicted neuron-specific proteins, we confirmed one marker, NRXN3 as present on EVs in CSF and plasma by size exclusion chromatography (SEC) and density gradient centrifugation (DGC). Finally, we developed efficient EV immuno-isolation methods and applied them to isolate NRXN3+ EVs. Our study provides a general methodology for the isolation of cell-type specific EVs and paves the way for the use of neuron-derived EVs to study and diagnose neurological disease.

molecular biology↗

bioRxiv2022

Brain region-specific changes in neurons and glia and dysregulation of dopamine signaling in Grin2a mutant mice

Schizophrenia disease mechanisms remain poorly understood, in large part due to a lack of valid animal models. Rare heterozygous loss-of-function mutations in GRIN2A, encoding a subunit of the NMDA (N-methyl-d-aspartate) receptor, greatly increase the risk of schizophrenia. By transcriptomic, proteomic, electroencephalogram (EEG) recording and behavioral analysis, we report that heterozygous Grin2a mutant mice show: (i) large-scale gene expression changes across multiple brain regions and in neuronal (excitatory and inhibitory) and non-neuronal cells (astrocytes, oligodendrocytes); (ii) evidence of reduced activity in prefrontal cortex and increased activity in hippocampus and striatum; (iii) elevated dopamine signaling in striatum; (iv) altered cholesterol biosynthesis in astrocytes; (v) reduction of glutamatergic receptor signalin g proteins in the synapse; (iv) heightened gamma oscillation power in EEG; (vi) aberrant locomotor behavioral pattern opposite of that induced by antipsychotic drugs. These findings reveal potential pathophysiologic mechanisms, provide support for both the "hypo-glutamate" and "hyper-dopamine" hypotheses of schizophrenia, and underscore the utility of Grin2a-deficient mice as a new genetic model of schizophrenia.

neuroscience↗

bioRxiv2022

Temporal dynamics of the multi-omic response to endurance exercise training across tissues

Regular exercise promotes whole-body health and prevents disease, yet the underlying molecular mechanisms throughout a whole organism are incompletely understood. Here, the Molecular Transducers of Physical Activity Consortium (MoTrPAC) profiled the temporal transcriptome, proteome, metabolome, lipidome, phosphoproteome, acetylproteome, ubiquitylproteome, epigenome, and immunome in whole blood, plasma, and 18 solid tissues in Rattus norvegicus over 8 weeks of endurance exercise training. The resulting data compendium encompasses 9466 assays across 19 tissues, 25 molecular platforms, and 4 training time points in young adult male and female rats. We identified thousands of shared and tissue- and sex-specific molecular alterations. Temporal multi-omic and multi-tissue analyses demonstrated distinct patterns of tissue remodeling, with widespread regulation of immune, metabolism, heat shock stress response, and mitochondrial pathways. These patterns provide biological insights into the adaptive responses to endurance training over time. For example, exercise training induced heart remodeling via altered activity of the Mef2 family of transcription factors and tyrosine kinases. Translational analyses revealed changes that are consistent with human endurance training data and negatively correlated with disease, including increased phospholipids and decreased triacylglycerols in the liver. Sex differences in training adaptation were widespread, including those in the brain, adrenal gland, lung, and adipose tissue. Integrative analyses generated novel hypotheses of disease relevance, including candidate mechanisms that link training adaptation to non-alcoholic fatty liver disease, inflammatory bowel disease, cardiovascular health, and tissue injury and recovery. The data and analysis results presented in this study will serve as valuable resources for the broader community and are provided in an easily accessible public repository (https://motrpac-data.org/). HighlightsO_LIMulti-tissue resource identifies 35,439 analytes regulated by endurance exercise training at 5% FDR across 211 combinations of tissues and molecular platforms. C_LIO_LIInterpretation of systemic and tissue-specific molecular adaptations produced hypotheses to help describe the health benefits induced by exercise. C_LIO_LIRobust sex-specific responses to endurance exercise training are observed across multiple organs at the molecular level. C_LIO_LIDeep multi-omic profiling of six tissues defines regulatory signals for tissue adaptation to endurance exercise training. C_LIO_LIAll data are available in a public repository, and processed data, analysis results, and code to reproduce major analyses are additionally available in convenient R packages. C_LI

molecular biology↗