["The Journal of Physiology, EarlyView. ", "\nAbstract figure legend Thyroid hormone (TH)‐dependent remodelling of potassium (K+) channel networks regulates skeletal muscle (SkM) excitability. Triiodothyronine (T3), locally generated from thyroxine (T4) by type 2 deiodinase (D2), binds thyroid hormone receptors (TRα/β) and modulates transcription via thyroid response elements (TREs). Under TH‐sufficient conditions, T3 upregulates Kcnh2 (mERG1) and Kcnk1 (TWIK‐1), while repressing Kcnab1 (encoding the regulatory KvB1 subunit), promoting increased delayed rectifier and leak K+ currents. This enhances membrane repolarization and stabilizes resting membrane potential. In contrast, TH deficiency reduces Kcnh2 and Kcnk1 expression and increases Kcnab1 levels, impairing repolarizing K+ conductance. Electrophysiological recordings confirm that TH enhances outward K+ currents, including mERG1‐mediated and leak components, consistent with increased repolarizing capacity. These changes are predicted to shorten action potential duration and accelerate electrical recovery. Overall, TH‐driven transcriptional control of K+ channel expression provides a mechanistic link between endocrine signalling and SkM excitability.\n\n\n\n\n\n\n\n\n\nAbstract\nThyroid hormone (TH) is a critical regulator of skeletal muscle (SkM) physiology, influencing muscle development, metabolism and contractile function. However, the molecular mechanisms by which TH modulates muscle excitability and contraction remain incompletely defined. Here, we investigated the role of TH signalling in regulating SkM electrical activity through transcriptional control of ion channels. Using RNA sequencing of gastrocnemius muscles from wild‐type (CTR), muscle‐specific deiodinase type 2‐deficient (mD2KO), and thyroid hormone receptor α/β‐deficient (TRαKO/TRβKO) mice, we identified a shared transcriptional signature of TH deficiency characterized by the dysregulation of multiple ion channel genes. Notably, two potassium (K+) channel‐related genes Kcnh2 and Kcnk1, which encode for mERG1 and TWIK‐1, respectively, were downregulated, while Kcnab1 was consistently upregulated in both mD2KO and TRαKO/TRβKO muscles compared with CTR, suggesting a common TH‐dependent regulatory mechanism. To investigate whether such transcriptional remodelling of K+ channels translates into functional changes, we assessed the direct effects of TH on K+ currents using patch‐clamp recordings in differentiated C2C12 cells exposed to TH as a model of physiological TH signalling. Interestingly, we found that TH treatment significantly increased mERG current density in differentiated C2C12 cells, supporting a role for TH signalling in the modulation of SkM electrical activity. Collectively, these results provide a mechanistic framework through which TH contributes to the regulation of muscle electrical stability, with potential implications for thyroid‐related myopathies.\n\n\n\n\n\n\n\n\n\nKey points\n\nThyroid hormone (TH) regulates skeletal muscle excitability through transcriptional modulation of potassium (K+) channel‐related genes.\nRNA‐seq analyses identified a TH‐dependent signature with downregulation of Kcnh2 (mERG1) and Kcnk1 (TWIK‐1), and upregulation of Kcnab1 under TH‐deficient conditions.\nChromatin immunoprecipitation demonstrates direct binding of TH receptors to regulatory regions of these channel genes.\nElectrophysiological recordings in differentiated C2C12 cells show that TH treatment increases mERG current density.\nThis coordinated remodelling of K+ channel expression provides a mechanistic basis for TH‐driven optimization of muscle electrical stability and contractile performance. These findings support a role for TH signalling in the regulation of skeletal muscle electrical stability, with potential implications for thyroid‐related myopathies.\n\n\n"]