Non-thyroidal illness syndrome has always seemed to mystify medicine. Dropping T3 precisely when it might be needed!
Dys-regulation of the DIO3 deiodinase enzyme might explain what is happening. And open the doors to a beneficial treatment. Simply increasing thyroid hormone medicines has not been successful - possibly even positively damaging.
Type 3 deiodinase activation mediated by the Shh/Gli1 axis promotes sepsis-induced metabolic dysregulation in skeletal muscles
Background: Non-thyroidal illness syndrome is commonly observed in critically ill patients, characterized by the inactivation of systemic thyroid hormones (TH), which aggravates metabolic dysfunction. Recent evidence indicates that enhanced TH inactivation is mediated by the reactivation of type 3 deiodinase (Dio3) at the tissue level, culminating in a perturbed local metabolic equilibrium. This study assessed whether targeted inhibition of Dio3 can maintain tissue metabolic homeostasis under septic conditions and explored the mechanism behind Dio3 reactivation.
Methods: A retrospective clinical study was conducted to investigate the attributes of rT3. The expression of Dio3 was detected by immunoblotting, immunofluorescence, and immunohistochemical staining in tissues extracted from CLP-induced septic rats and human biopsy samples. In addition, the effect of Dio3 inhibition on skeletal muscle metabolism was observed in rats with targeted Dio3 knockdown using an adeno-associated virus. The effectiveness of Sonic hedgehog (Shh) signaling inhibition on systemic TH levels was observed in CLP-induced septic rats receiving cyclopamine. The mechanisms underlying such inhibition were explored using immunoblotting, RNA-seq, and chromatin immunoprecipitation-qPCR assays.
Results: The main product of Dio3, rT3, is strongly associated with organ function. Early sepsis leads to significant upregulation of Dio3 in the skeletal muscles and lung tissues of septic rats. The targeted inhibition of Dio3 in skeletal muscle restores TH responsiveness, prevents fast-to-slow fiber conversion, preserves glucose transporter type 4 functionality, and maintains metabolic balance between protein synthesis and proteolysis, which leads to preserved muscle mass. The reactivation of Dio3 is transcriptionally regulated by the Shh pathway induced by the signal transducer and activator of transcription 3.
Conclusions: The suppression of Dio3 restores tissue TH actions, attenuates proteolysis, and ameliorates anabolic resistance in the skeletal muscles of septic rats, thereby improving local metabolic homeostasis. Our results provide insights into the mechanisms of Dio3 reactivation and its critical role in local metabolic alterations induced by sepsis, while also suggesting novel targets aimed at ameliorating tissue-specific metabolic disorders.
Keywords: Muscle wasting; Non-thyroidal illness syndrome; Sepsis; Sonic hedgehog; Type 3 deiodinase.
Maybe I am off base and not understanding this study but just in case -
Before my thyroidectomy I had sepsis twice. Unknown source. Potentially body induced from endometriosis, but unknown source regardless.
Even with the addition of cytomel & NDT at times T3 is normal but low in range. To me that is bizarre.
I have a perplexing issue since the second bout of sepsis. No muscle atrophy but muscles in legs not working properly. They have now found severe stenosis & other back issues so it literally could be nerves being choked, so to speak.
However, I also found a study at one point, about how t3 receptors can be damaged during sepsis. Causing muscle weakness, even without atrophy. Not sure I am fully understanding the study you posted. Is it similar in focus? Could you try to explain the gist to me in really simple terms. Not sure I am understanding fully
It is always difficult to be sure when we try to apply a paper which is inevitably incomplete to an individual.
But I would very much have thought that your case might be pretty much exactly what they were writing about.
Perhaps the first sepsis caused extensive damage that likely was not fully recognised?
I think that this might actually be an explanation how T3 receptors are damaged in sepsis.
(This sort of language is difficult because receptors are created and removed all the time. It is not entirely clear if they are referring to a permanent change with reduces the numbers and functionality of T3 receptors - or transient while sick).
Thank you. And there lies the issue. The medical community watches one be successful of getting through sepsis, and often thinking that's that. Recovered. And looks diligently at what happens during one's hospital stay & not after. Mainly because they hardly even want to admit to the word sepsis to begin with, for their own issues. But I know what I recovered the first time and absolutely did not the second. Both times hard work and pushing through (meaning literally walking through tears and pushing, as one needs to do)
And the paper I had found has 'without muscle atrophy' in its title which was so affirming for me. Over & over I would point out that the lack of atrophy has to be providing a clue here, that is only common sense.
Thank you, I might try to contact some of these researchers.
Muscle problems particularly in the legs is very common after sepsis, I had sepsis a year ago and my muscles are still not as they were before. Unfortunately Drs don’t like talking about sepsis and generally wont acknowledge post sepsis syndrome even exists, it does !
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