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Using global nuclear run-on (GRO-seq) in mouse skeletal muscle after treadmill running, we profiled enhancer RNA (eRNA), a sensitive marker of enhancer activity. Activation protein-1 (AP-1), a family of pioneering factors for senescence, emerged as the top transcription factor with motif enrichment in exercise-activated enhancers. Our screen in the contracting C2C12 myotubes pinpointed cFos\/JunD as the primary AP-1 factor responsible for contraction-induced transcriptional changes. Muscle-specific overexpression of A-Fos, a dominant-negative mutant of cFos, disrupted transcriptomic responses to exercise and attenuated exercise-mediated improvement in muscle functions. Interestingly, intermittent but not continuous overexpression of cFos\/JunD in mouse muscles mimicked exercise-induced transcriptomic changes, increased mitochondrial volume density, enhanced muscle strength and fatigue resistance, and improved glucose tolerance. These results define a transcriptional regulatory signaling pathway linking exercise intermittency to beneficial adaptations and highlight the necessary recovery cycles in training. The paradoxical anti- and pro-aging roles of AP-1 offer insights into the timing and dynamics of stressors and stress responses in shaping senescence and healthspan.<\/jats:p>","DOI":"10.64898\/2026.01.05.696542","type":"posted-content","created":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T10:25:14Z","timestamp":1767695114000},"source":"Crossref","is-referenced-by-count":0,"title":["Intermittent AP-1 activation in muscles contributes to exercise-induced health benefits"],"prefix":"10.64898","author":[{"given":"Abhinav","family":"Choubey","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Baylor College of Medicine, Houston, Texas 77030, USA"},{"name":"Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Udhaya","family":"Kumar S.","sequence":"additional","affiliation":[{"name":"Department of Medicine, 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