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<p>Thyroid hormones (THs) are critical regulators of vertebrate embryonic development, governing cell proliferation, lineage commitment, and tissue maturation, including skeletal muscle formation. Disruption of TH homeostasis during early development can therefore have profound consequences for myogenesis and locomotor function. In this study, we investigated the effects of amiodarone, a known disruptor of TH metabolism, on muscle development and motility in zebrafish (<i>Danio rerio</i>) embryos. A dose-range analysis identified 0.01 mM amiodarone as a sublethal concentration suitable for mechanistic investigation, and LC-MS analysis confirmed compound uptake in embryos. Amiodarone exposure resulted in distinct developmental abnormalities, including craniofacial defects at 48 hpf and axial curvature and tail malformations by 72 hpf, accompanied by significantly reduced hatching success and bradycardia. Consistent with impaired neuromuscular function, treated larvae exhibited a markedly attenuated touch-evoked escape response with reduced swimming distance and velocity. Hormonal profiling revealed a significant reduction in triiodothyronine (T3) levels with a modest accumulation of thyroxine (T4), indicating disruption of TH homeostasis. At the molecular level, amiodarone altered the expression of Notch-associated regulators and key myogenic and cell-cycle genes, including downregulation of <i>her6</i>,<i> her9</i>,<i> her12</i>,<i> hey2</i>,<i> sox9</i>, and <i>pcna</i>, alongside upregulation of <i>hey1</i>,<i> heyl</i>,<i> tp53</i>, and <i>casp3</i>. These transcriptional changes were supported by reduced MYOD and PCNA protein levels and increased cleaved CASPASE-3, indicating impaired myogenic progression, reduced proliferation, and enhanced apoptosis. Collectively, these findings demonstrate that disruption of TH homeostasis by amiodarone compromises muscle development and locomotor function during zebrafish embryogenesis, underscoring the central role of endocrine regulation in early myogenic programs.</p> Graphical abstract <p></p>

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Amiodarone disrupts thyroid hormone homeostasis and impairs myogenic progression and locomotor function in zebrafish embryos

  • 期刊论文

  • 发表日期：

    2026年3月21日

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  • Juhi Vaishnav,
  • Abhinav Upadhyay,
  • Arya Bhatt,
  • Suresh Balakrishnan

摘要

Thyroid hormones (THs) are critical regulators of vertebrate embryonic development, governing cell proliferation, lineage commitment, and tissue maturation, including skeletal muscle formation. Disruption of TH homeostasis during early development can therefore have profound consequences for myogenesis and locomotor function. In this study, we investigated the effects of amiodarone, a known disruptor of TH metabolism, on muscle development and motility in zebrafish (Danio rerio) embryos. A dose-range analysis identified 0.01 mM amiodarone as a sublethal concentration suitable for mechanistic investigation, and LC-MS analysis confirmed compound uptake in embryos. Amiodarone exposure resulted in distinct developmental abnormalities, including craniofacial defects at 48 hpf and axial curvature and tail malformations by 72 hpf, accompanied by significantly reduced hatching success and bradycardia. Consistent with impaired neuromuscular function, treated larvae exhibited a markedly attenuated touch-evoked escape response with reduced swimming distance and velocity. Hormonal profiling revealed a significant reduction in triiodothyronine (T3) levels with a modest accumulation of thyroxine (T4), indicating disruption of TH homeostasis. At the molecular level, amiodarone altered the expression of Notch-associated regulators and key myogenic and cell-cycle genes, including downregulation of her6, her9, her12, hey2, sox9, and pcna, alongside upregulation of hey1, heyl, tp53, and casp3. These transcriptional changes were supported by reduced MYOD and PCNA protein levels and increased cleaved CASPASE-3, indicating impaired myogenic progression, reduced proliferation, and enhanced apoptosis. Collectively, these findings demonstrate that disruption of TH homeostasis by amiodarone compromises muscle development and locomotor function during zebrafish embryogenesis, underscoring the central role of endocrine regulation in early myogenic programs.

Graphical abstract