Ets2 Is an Activity‐Dependent Transcriptional Regulator of a Fast‐Twitch Muscle Program

The functional properties of excitable cells, including skeletal muscle, are regulated by electrical activity. Distinct motoneuron firing patterns control contraction speed, strength, and endurance of fast- and slow-twitch 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-dependent 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-muscle-specific transcription and responds selectively to brief, high-frequency (150 Hz) stimulation rather than to sustained low-frequency (20 Hz) activity. In this study, using mRNA microarray analysis of muscles subjected to different stimulation patterns, we identified E26 transformation-specific homolog 2 (Ets2) as a transcription factor rapidly and selectively induced by fast-patterned 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-patterned activity. Furthermore, Ets2 knockdown reduces transcription from both a trimerized Ets2-responsive 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-patterned 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.