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Distinct motoneuron firing patterns control contraction speed, strength, and endurance of fast\u2010 and slow\u2010twitch myofibers by activating transcriptional programs that specify contractile and metabolic protein isoforms. Although transcriptional regulators of slow muscle adaptation are well characterized, less is known about activity\u2010dependent mechanisms controlling expression of fast muscle genes. We previously showed that the quail fast troponin I (TnIf) intronic regulatory element (FIRE) is both necessary and sufficient for fast\u2010muscle\u2010specific transcription and responds selectively to brief, high\u2010frequency (150\u2009Hz) stimulation rather than to sustained low\u2010frequency (20\u2009Hz) activity. In this study, using mRNA microarray analysis of muscles subjected to different stimulation patterns, we identified E26 transformation\u2010specific homolog 2 (Ets2) as a transcription factor rapidly and selectively induced by fast\u2010patterned activity. Ets2 accumulates in nuclei of slow soleus muscle following fast, but not slow, stimulation, and it is expressed more abundantly in fast muscle. Ets2 binds a consensus Ets site within the TnIf FIRE, and mutation of this site abolishes enhancer activation by fast\u2010patterned activity. Furthermore, Ets2 knockdown reduces transcription from both a trimerized Ets2\u2010responsive reporter and a TnIf FIRE reporter specifically in fast muscles. To our knowledge, these findings identify Ets2 as the first transcription factor shown to selectively promote fast muscle gene expression in response to fast\u2010patterned activity. Together with NFATc1, Ets2 may contribute to a dynamic regulatory mechanism that enables skeletal muscles to adapt their functional properties to changing physiological demands.<\/jats:p>","DOI":"10.1096\/fj.202602267r","type":"journal-article","created":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T08:43:10Z","timestamp":1791967390000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Ets2 Is an Activity\u2010Dependent Transcriptional Regulator of a Fast\u2010Twitch Muscle Program"],"prefix":"10.1096","volume":"40","author":[{"given":"Zaheer A.","family":"Rana","sequence":"first","affiliation":[{"name":"Section on Molecular Neurobiology National Institute of Child Health and Human Development, NIH  Bethesda Maryland USA"},{"name":"Department of Biosciences University of Oslo  Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jo 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