Type 3 deiodinase activation mediated by the Shh/Gli1 axis promotes sepsis-induced metabolic dysregulation in skeletal muscles.

Summary

In septic rats and human tissues, Dio3 was upregulated early, with rT3 associating with organ dysfunction. Skeletal-muscle–targeted Dio3 inhibition restored thyroid hormone responsiveness, preserved GLUT4 function and muscle mass, and maintained protein turnover balance. Dio3 reactivation was transcriptionally driven by Shh/Gli1 induced by STAT3, and Shh inhibition improved systemic TH actions.

Key Findings

• Early sepsis upregulated Dio3 in skeletal muscle and lung, with rT3 strongly associated with organ function.
• Muscle-targeted Dio3 inhibition restored tissue TH actions, preserved GLUT4 function, prevented fast-to-slow fiber shift, and maintained protein synthesis–proteolysis balance, preserving muscle mass.
• Dio3 reactivation was transcriptionally driven by Shh/Gli1 induced by STAT3; Shh inhibition (cyclopamine) improved systemic TH responsiveness.

Clinical Implications

While preclinical, targeting Dio3 or upstream Shh/Gli1 signaling could mitigate septic muscle catabolism and anabolic resistance; biomarker-guided approaches using rT3 may stratify patients for future trials.

Limitations

• Preclinical study; translational applicability and safety of Dio3/Shh targeting remain untested in humans
• Human tissue sampling details and sample sizes are not specified in the abstract

Future Directions

Phase 0/1 studies to assess target engagement and safety of Dio3/Shh modulation; exploration of rT3 as a stratification biomarker; integration with nutrition and rehabilitation strategies in sepsis.