Biology subjects

Cortes, C. J.

Publications and source records attributed to Cortes, C. J..

6 recordsLinked to original sources

bioRxiv2026

Long-term voluntary exercise reveals limited translation of hippocampal molecular responses into neuroprotection in 5xFAD mice

Physical exercise promotes systemic and neural adaptations that support healthy brain aging and may mitigate Alzheimers disease (AD) progression. However, the capacity of the AD-afflicted brain to mount and translate exercise-responsive molecular adaptations into neuroprotection remains unclear. Here, we examined the effects of long-term voluntary wheel running (VWR) on molecular, neuropathological, and behavioral outcomes in independently studied male and female 5xFAD mice. VWR elicited expected metabolic and transcriptional remodeling of inguinal white adipose tissue, confirming engagement of exercise-responsive peripheral biology. In contrast, hippocampal transcriptional responses were modest, with few differentially expressed genes and coordinated changes emerging primarily at the pathway level. These responses involved synaptic, neuroimmune, mitochondrial, neurotrophic, and monoaminergic processes and differed qualitatively between the two groups. Several components of the canonical hippocampal exercise response also failed to converge into coordinated cellular adaptations: synaptic protein abundance changed without altering synapse density, while neurotrophic, neurogenic, and vascular responses showed little correspondence across molecular and cellular measures. VWR also produced little change in hippocampal amyloid pathology or behavioral function despite sustained exercise engagement. Together, these findings demonstrate that the 5xFAD brain retains modest molecular responsiveness to prolonged voluntary exercise but may be unable to mount a sufficiently robust or coordinated response to produce broad neuroprotective effects. These findings highlight disease context as an important determinant of the efficacy of exercise-based interventions in neurodegenerative disease.

neuroscience↗

bioRxiv2026

Single-nuclei RNA-sequencing uncovers sexually divergent exercise signatures partially mimicked by TFEB overexpression in mouse skeletal muscle

Exercise induces extensive, cell-type-specific transcriptional remodeling in skeletal muscle to support metabolic flexibility and adaptation. However, the regulatory mechanisms underlying these transcriptional programs, and the extent to which they differ between sexes, remain poorly defined. We previously reported that lifelong, muscle-specific overexpression of human Transcription Factor E-B (cTFEB;HSACre transgenic mice) recapitulates many adaptive features of endurance training in both sexes, leading to profound geroprotective effects during aging even in the absence of exercise. Here, we profile transcriptional adaptations to voluntary wheel running (VWR) and TFEB-overexpression at single-nucleus resolution in young male and female mouse tibialis anterior muscle. This represents, to our knowledge, the first integrated analysis of exercise and TFEB signaling using sex as a biological variable. Using robust bioinformatic and single-nuclei RNA-sequencing approaches, we profiled six muscle-resident cell populations and uncover previously unrecognized, sex-dependent signaling nodes governing exercise-associated metabolic plasticity. TFEB activation and endurance training by VWR elicit strongly correlated transcriptional programs enriched for lipid metabolism, mitochondrial remodeling, and immune modulation, establishing TFEB-overexpression as a partial exercise mimetic. In general, female muscle exhibited enhanced extracellular matrix and lipid-associated responses to endurance training and TFEB overexpression, whereas males preferentially engaged in angiogenic and oxidative networks, revealing distinct sex-specific, sex-dimorphic, or sex-agnostic regulatory routes to metabolic flexibility. Integration with independent multi-omics datasets from endurance-trained rats (MoTrPAC) confirms the conservation of TFEB-exercise transcriptional convergence in skeletal muscle across species and potentially muscle types. Together, these findings define TFEB as a regulator of exercise transcriptional programs and reveal sex-specific molecular frameworks that drive metabolic adaptation in skeletal muscle. Furthermore, the resulting sex-resolved, single-nucleus transcriptional atlas provides a unique resource for the field, enabling comparative, mechanistic, and hypothesis-driven exploration of exercise-responsive skeletal muscle regulatory networks across sexes.

physiology↗

bioRxiv2025

Convergent Skeletal Muscle Cytokine Responses to TFEB Overexpression and Voluntary Wheel Running Reflect Sex-Based Variability in Exercise Adaptations

Endurance exercise (running) promotes skeletal muscle remodeling through metabolic and inflammatory signaling cascades. However, the extent to which these responses are sex-dependent remains unclear. Here, we profiled cytokine responses in quadriceps muscle lysates from sedentary, voluntary wheel-running (VWR; 5 weeks), and muscle-specific TFEB-overexpressing (cTFEB;HSACre) male and female mice. Cytokine analysis revealed 40 differentially expressed factors associated with exercise and/or TFEB overexpression, many displaying sex-dimorphic expression patterns. In males, VWR induced significant increases in interleukins (e.g., IL-1, IL-1{beta}, IL-2, IL-5, IL-17) and chemokines (e.g., MCP-1, CCL5, CXCL9), as well as cytokines involved in TNF signaling (e.g., TNF, sTNFR1/2, Fas ligand). TFEB overexpression in sedentary males recapitulated many of these cytokine elevations. In contrast, female runner muscle showed limited cytokine activation, with significant changes restricted to IL-3, IL-3Rb, IL-13, and CXCL16. Both sexes exhibited a reduction in IL-4 and an increase in IGFBP-5 with running. Several additional male-specific cytokine profiling responses, including increases in IFN{gamma}, SCF, TPO, VCAM1A, and leptin, further underscored the sex-specificity of exercise-related inflammatory adaptations. These findings demonstrate that skeletal muscle cytokine responses to endurance-like stimuli are profoundly influenced by sex and suggest that male muscle exhibits a broader and/or later remodeling profile than female muscle. Our data also implicate skeletal muscle TFEB-overexpression as a partial molecular mediator of the cytokine shifts observed with exercise, particularly in males, and highlights their potential use as a new prioritization platform for exercise-associated phenotypes.

physiology↗

bioRxiv2024

Activation of the muscle-to-brain axis ameliorates neurocognitive deficits in an Alzheimer disease mouse model via enhancing neurotrophic and synaptic signaling

INTRODUCTIONSkeletal muscle regulates central nervous system (CNS) function and health, activating the muscle-to-brain axis through the secretion of skeletal muscle originating factors ( myokines) with neuroprotective properties. However, the precise mechanisms underlying these benefits in the context of Alzheimers disease (AD) remain poorly understood. METHODSTo investigate muscle-to-brain axis signaling in response to amyloid {beta} (A{beta})- induced toxicity, we generated 5xFAD transgenic female mice with enhanced skeletal muscle function (5xFAD;cTFEB;HSACre) at prodromal (4-months old) and late (8-months old) symptomatic stages. RESULTSSkeletal muscle TFEB overexpression reduced A{beta} plaque accumulation in the cortex and hippocampus at both ages and rescued behavioral neurocognitive deficits in 8- months-old 5xFAD mice. These changes were associated with transcriptional and protein remodeling of neurotrophic signaling and synaptic integrity, partially due to the CNS-targeting myokine prosaposin (PSAP). DISCUSSIONOur findings implicate the muscle-to-brain axis as a novel neuroprotective pathway against amyloid pathogenesis in AD.

neuroscience↗

bioRxiv2024

Evaluation of altered cell-cell communication between glia and neurons in the hippocampus of 3xTg-AD mice at two time points

Alzheimers disease (AD) is the most common form of dementia and is characterized by progressive memory loss and cognitive decline, affecting behavior, speech, and motor abilities. The neuropathology of AD includes the formation of extracellular amyloid-{beta} plaque and intracellular neurofibrillary tangles of phosphorylated tau, along with neuronal loss. While neuronal loss is an AD hallmark, cell-cell communication between neuronal and non-neuronal cell populations maintains neuronal health and brain homeostasis. To study changes in cellcell communication during disease progression, we performed snRNA-sequencing of the hippocampus from female 3xTg-AD and wild-type littermates at 6 and 12 months. We inferred differential cell-cell communication between 3xTg-AD and wild-type mice across time points and between senders (astrocytes, microglia, oligodendrocytes, and OPCs) and receivers (excitatory and inhibitory neurons) of interest. We also assessed the downstream effects of altered glia-neuron communication using pseudobulk differential gene expression, functional enrichment, and gene regulatory analyses. We found that glia-neuron communication is increasingly dysregulated in 12-month 3xTg-AD mice. We also identified 23 AD-associated ligand-receptor pairs that are upregulated in the 12-month-old 3xTg-AD hippocampus. Our results suggest increased AD association of interactions originating from microglia. Signaling mediators were not significantly differentially expressed but showed altered gene regulation and TF activity. Our findings indicate that altered glia-neuron communication is increasingly dysregulated and affects the gene regulatory mechanisms in neurons of 12-month-old 3xTg-AD mice.

genomics↗

bioRxiv2022

Skeletal Muscle Proteostasis Promotes Central Nervous System Rejuvenation and Reduces Neuroinflammation during Aging and Neurodegenerative Disease

Skeletal muscle has recently arisen as a novel regulator of Central Nervous System (CNS) function and aging, secreting bioactive molecules known as myokines with metabolism-modifying functions in targeted tissues, including the CNS. Here we report the generation of a novel transgenic mouse with enhanced skeletal muscle lysosomal and mitochondrial function via targeted overexpression of Transcription Factor E-B (TFEB). We have discovered that the resulting geroprotective effects in skeletal muscle reduce neuroinflammation and the accumulation of tau-associated pathological hallmarks in a mouse model of tau pathology. Muscle-specific TFEB overexpression also significantly ameliorates proteotoxicity, reduces neuroinflammation and promotes transcriptional remodeling of the aged CNS, preserving cognition and memory in aged mice. Our results implicate the maintenance of skeletal muscle function throughout aging to direct regulation of CNS health and disease, and suggest that skeletal-muscle originating factors may act as novel therapeutic targets against age-associated neurodegenerative disorders.

neuroscience↗