Circadian Phase Shapes Muscle-Derived Extracellular Vesicle microRNA Profiles with Context-Dependent Modulation by...

Area of Science:

• Exercise Physiology
• Chronobiology
• Molecular Biology
• Metabolic Research

Background:

• Skeletal muscle releases extracellular vesicles (EVs) containing microRNAs (miRNAs) that mediate metabolic communication.
• Both circadian rhythms and exercise impact metabolism, but their combined effect on muscle-derived EV miRNA profiles, especially in obesity, is unclear.

Purpose of the Study:

• To investigate the joint modulation of muscle-derived EV miRNA profiles by circadian rhythms and chronic exercise in an obese mouse model.
• To determine the relative contributions of circadian phase and exercise to the variance in EV miRNA profiles under high-fat diet conditions.

Main Methods:

• Utilized a 2x2 factorial design with sedentary and exercise conditions across two circadian phases (ZT3 vs. ZT15) in high-fat diet-fed mice.
• Isolated EV-enriched fractions from ex vivo quadriceps muscle cultures.
• Performed comprehensive miRNA profiling using small RNA sequencing.

Main Results:

• Circadian phase explained a larger proportion of global variance in EV miRNA profiles than exercise.
• Specific miRNAs (e.g., miR-1a-3p, miR-1b-5p, miR-29 family) showed altered expression, primarily driven by circadian phase differences in sedentary conditions.
• Exercise introduced context-dependent modulations, with associated miRNAs targeting signaling and inflammatory pathways, while phase-associated miRNAs targeted metabolic and iron-heme pathways.

Conclusions:

• Circadian phase is the dominant factor influencing muscle-derived EV miRNA profiles in obesity, with exercise providing adaptive modulation.
• Highlights the critical role of temporal specificity in understanding EV-mediated communication and exercise physiology under metabolic stress.