Single-Nucleus RNA Sequencing Reveals Sex-Dimorphic Molecular Remodeling by Running and TFEB-Overexpression in Skeletal Muscle

Sep 28, 2026

Endurance exercise triggers coordinated structural and functional remodeling in skeletal muscle, improving metabolic efficiency and supporting geroprotective effects, yet sex-specific differences remain unclear. To address this, single-nuclei RNA sequencing was performed on tibialis anterior muscle from male and female mice across sedentary controls, voluntary wheel running, and muscle-specific TFEB overexpression groups. Results show condition- and sex-dependent changes in myonuclei and non-myonuclear populations, including fiber-type switching, extracellular matrix remodeling, mitochondrial function, and immune signaling pathways. TFEB overexpression reproduces many endurance-exercise transcriptional features with convergent but distinct sex-dependent responses, enabling exercise-mimetic therapeutic discovery.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages1

Reading Time3 min

AccessFree to download

Abstract

Study Design and Groups

Key Findings Across Sex and Conditions

Role of TFEB Overexpression

Innovation in Aging, 2025, Vol. 9, No. S2 451 Abstract citation ID: igaf122.1534 SINGLE-NUCLEUS RNA-SEQUENCING REVEALS SEX-DIMORPHIC MOLECULAR REMODELING BY RUNNING AND TFEB-OVEREXPRESSION IN SKELETAL MUSCLE Constanza Cortes, University of Southern California, Los Angeles, California, United States Endurance exercise induces complex structural and functional remodeling in skeletal muscle, promoting metabolic efficiency and geroprotective effects. However, to date, our understanding of how these pathways may differ by sex remains poorly understood. We have previously shown that TFEB-overexpression in skeletal muscle (cTFEB;HSACre transgenic mice) recapitulates multiple aspects of running-activated metabolic remodeling across the lifespan. To determine the degree to which running and TFEB-overexpression transcriptionally remodels skeletal muscle, we performed single-nuclei RNA sequencing on tibialis anterior muscle from male and female mice across young sedentary, voluntary wheel running, and muscle-specific TFEB-overexpressing groups. Our results reveal significant sexand condition-specific changes in myonuclei subtypes and non-myonuclear populations, including fiber-type switching, extracellular matrix remodeling, mitochondrial function, and immune signaling pathways. Importantly, TFEB overexpression recapitulates many transcriptional features of endurance exercise, with convergent yet distinct transcriptional responses across sexes, highlighting shared molecular pathways involved in muscle adaptation. This study advances our understanding of the molecular mechanisms driving sex-specific skeletal muscle plasticity in response to endurance running and demonstrates that TFEB overexpression effectively mimics key aspects of exercise-induced transcriptional remodeling in a sex-dependent manner. Moreover, it positions cTFEB;HSACre transgenic mice as a valuable experimental system for the discovery and prioritization of novel exercise-mimetic therapeutics aimed at promoting geroprotective muscle adaptations.

FAQs

What is the main question this study investigates about endurance exercise?

How running and TFEB overexpression transcriptionally remodel skeletal muscle in a sex-dependent manner.

What experimental approach was used to measure molecular changes?

Single-nuclei RNA sequencing on tibialis anterior muscle from male and female mice in multiple condition groups.

Which molecular processes changed according to the results?

Myonuclei subtypes and non-myonuclear populations shifted, including fiber-type switching, extracellular matrix remodeling, mitochondrial function, and immune signaling pathways.

How does TFEB overexpression relate to endurance exercise responses?

TFEB overexpression recapitulates many endurance-exercise transcriptional features, with shared molecular pathways but distinct responses across sexes.

Sep 28, 2026

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