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the active hormone T3 (triiodothyronine) play in skeletal muscle development, daily function, energy metabolism, and repair.T3 within muscle cells themselves, driven by enzymes called deiodinases. This cell autonomous regulation turns out to be a major key to understanding how muscle grows, adapts, and heals.
•Local Control of the Thyroid Hormone signaling
Skeletal muscle is one of the body’s primary targets for thyroid hormones (THs), which explains why both hypothyroidism and thyrotoxicosis produce clear muscle-related symptoms. But the review shows that muscle doesn’t jst simply rely on circulating hormone it actively regulates T3 at the cellular level through the iodothyronine deiodinases:
• DIO2 (Type2 lodothyronine Deiodinase)
DIO2 activates T4 (tetraiodothyronine) by converting it into T3, the biologically active form. This enzyme contributes significantly to intracellular T3 levels, especially during myoblast differentiation and in mouse muscle. In rodents, DIO2 is upregulated during hypothyroidism as a compensatory mechanism. Human data are somewhat mixed, but individuals homozygous for the Thr92Ala polymorphism show reduced DIO2 activity.
• DIO3 (Type 3) Lodothyronine Deiodinase)
DIO3 works in the opposite direction: it inactivates T3 by removing an iodine from the inner ring. Its activity increases during severe illness, presumably as a protective mechanism during metabolic stress.
• Why This Matters:
The push and pull between DIO2 and DIO3 gives muscle fibers a precise, pre-receptor way to regulate their own intracellular T3 levels, independent of whatever levels happen to be circulating in the bloodstream. This cell level control is central to muscle development, phenotype, and repair.
• T3 and the Skeletal Muscle Phenotype
T3 exerts its influence primarily by binding to nuclear thyroid hormone receptors especially THRA1thereby regulating gene transcription.
• Muscle Fibre Phenotype
Skeletal muscle is capable of dramatic plasticity, consisting of four major fiber types:
Type I (slow) and Type IIa, IIx, and IIb (progressively faster, more glycolytic).
T3 pushes the muscle toward a faster, more metabolically active phenotype by altering gene expression.
Genes T3 Increases:
Genes T3 Decreases:
IMPACT
These changes align perfectly with what we see clinically hypothyroidism slows muscle contraction and relaxation, while thyrotoxicosis accelerates them. T3 essentially shifts muscle toward a faster, more glycolytic phenotype with higher ATP consumption and increased oxidative capacity.
• Energy turnover and glucose metabolism
Thyroid hormones significantly increase resting energy expenditure. They also reduce the efficiency of contraction by increasing ATP consumption through the sodium-potassium and calcium ATPases, and possibly through UCP3-mediated uncoupling.
Because skeletal muscle is the largest metabolic organ in the body, these T3-driven changes account for most of the metabolic consequences of hypo or hyperthyroidism.
"Glucose Homeostasis
T3 status has a direct influence on insulin sensitivity both too little and too much can cause insulin resistance.
Local DIO2 activity is essential here
This mechanistic insight is reinforced by the DIO2 Thr92Ala polymorphism in humans, which is linked to lower enzyme activity, reduced insulin sensitivity, and skeletal abnormalities.
T3 and Skeletal Muscle Repair.
Muscle regeneration depends on satellite cells quiescent muscle stem cells that activate, proliferate, and differentiate into myoblasts after injury.
T3 plays a pivotal role in every stage of this process, primarily through its control of muscle-specific genes and its ability
to induce MYOD1.
• DIO2
During differentiation, DIO2 expression spikes. This enzyme is induced by FOXO3, a downstream target of PI3K AKT signaling. Without DIO2 (or FOXO3), myoblast differentiation stalls, MYOD1 doesn’t rise, and precursor cells remain stuck in a proliferative state resulting in poor muscle regeneration.
• DIO3
Preliminary data show that DIO3 appears early, during the proliferative phase of satellite cells, and then declines during differentiation.
• Sequential logic: DIO3 → DIO2
This suggests a controlled sequence where initial low T3 (via DIO3) allows satellite cells to expand, followed by high T3 (via DIO2) that triggers differentiation and fusion.
This timing is essential. Disrupt it, and regeneration becomes uncoordinated.
Implications for Muscle Pathology
In conditions like muscular dystrophy, altering thyroid hormone levels worsens the phenotype:
This supports the idea that precise T3 control not too much, not too little is required for balanced muscle repair.
Therapeutic Potential
Because deiodinases determine local T3 levels, targeting DIO2 and DIO3 may allow clinicians to enhance muscle repair, treat muscle atrophy, or support regeneration in disease and injury.
Key Points Summary:
Broader implications for Muscle and Bone
The same principles appear to apply to bone:
Key Implication for Growth and Development:
These findings suggest that local T3 regulation through DIO2 is a unifying mechanism that supports the development, function, and repair of both muscle and bone.
FINAL SUMMARY.
For growing tissues like developing muscle fibers, regenerating muscle after injury, or the continuously remodeling skeleton the presence of T3 is absolutely essential. But even more crucial is the discovery that cells do not simply rely on circulating hormone. Instead, they precisely tune their own intracellular T3 levels through a coordinated interplay between DIO2 and DIO3.
This allows stem cells to:
This sequential, cell autonomous control system is what ensures proper muscle growth, repair, and metabolic function and likely supports healthy bone development as well.
CREDITS @Hunter He found the Article and Helped me alot on this Thread
here's the article: https://pmc.ncbi.nlm.nih.gov/articles/PMC4037849/
•Local Control of the Thyroid Hormone signaling
Skeletal muscle is one of the body’s primary targets for thyroid hormones (THs), which explains why both hypothyroidism and thyrotoxicosis produce clear muscle-related symptoms. But the review shows that muscle doesn’t jst simply rely on circulating hormone it actively regulates T3 at the cellular level through the iodothyronine deiodinases:
• DIO2 (Type2 lodothyronine Deiodinase)
DIO2 activates T4 (tetraiodothyronine) by converting it into T3, the biologically active form. This enzyme contributes significantly to intracellular T3 levels, especially during myoblast differentiation and in mouse muscle. In rodents, DIO2 is upregulated during hypothyroidism as a compensatory mechanism. Human data are somewhat mixed, but individuals homozygous for the Thr92Ala polymorphism show reduced DIO2 activity.
• DIO3 (Type 3) Lodothyronine Deiodinase)
DIO3 works in the opposite direction: it inactivates T3 by removing an iodine from the inner ring. Its activity increases during severe illness, presumably as a protective mechanism during metabolic stress.
• Why This Matters:
The push and pull between DIO2 and DIO3 gives muscle fibers a precise, pre-receptor way to regulate their own intracellular T3 levels, independent of whatever levels happen to be circulating in the bloodstream. This cell level control is central to muscle development, phenotype, and repair.
• T3 and the Skeletal Muscle Phenotype
T3 exerts its influence primarily by binding to nuclear thyroid hormone receptors especially THRA1thereby regulating gene transcription.
• Muscle Fibre Phenotype
Skeletal muscle is capable of dramatic plasticity, consisting of four major fiber types:
Type I (slow) and Type IIa, IIx, and IIb (progressively faster, more glycolytic).
T3 pushes the muscle toward a faster, more metabolically active phenotype by altering gene expression.
Genes T3 Increases:
- SERCA1a, SERCA2a (calcium pumps crucial for contraction/relaxation speed)
- UCP3 (uncoupling protein affecting energy expenditure)
- GLUT4 (glucose transporter linked to metabolic health)
- ME1 and mGPDH (key metabolic enzymes)
- MYOD1/Myogenin (regulators of muscle differentiation)
Genes T3 Decreases:
- myosin-7 (a Type I fiber isoform)
IMPACT
These changes align perfectly with what we see clinically hypothyroidism slows muscle contraction and relaxation, while thyrotoxicosis accelerates them. T3 essentially shifts muscle toward a faster, more glycolytic phenotype with higher ATP consumption and increased oxidative capacity.
• Energy turnover and glucose metabolism
Thyroid hormones significantly increase resting energy expenditure. They also reduce the efficiency of contraction by increasing ATP consumption through the sodium-potassium and calcium ATPases, and possibly through UCP3-mediated uncoupling.
Because skeletal muscle is the largest metabolic organ in the body, these T3-driven changes account for most of the metabolic consequences of hypo or hyperthyroidism.
"Glucose Homeostasis
T3 status has a direct influence on insulin sensitivity both too little and too much can cause insulin resistance.
Local DIO2 activity is essential here
- It boosts GLUT4 expression.
- It enables normal insulin signaling through pathways such as phosphorylated AKT.
- Mouse models lacking DIO2 become insulin resistant.
This mechanistic insight is reinforced by the DIO2 Thr92Ala polymorphism in humans, which is linked to lower enzyme activity, reduced insulin sensitivity, and skeletal abnormalities.
T3 and Skeletal Muscle Repair.
Muscle regeneration depends on satellite cells quiescent muscle stem cells that activate, proliferate, and differentiate into myoblasts after injury.
T3 plays a pivotal role in every stage of this process, primarily through its control of muscle-specific genes and its ability
to induce MYOD1.
• DIO2
During differentiation, DIO2 expression spikes. This enzyme is induced by FOXO3, a downstream target of PI3K AKT signaling. Without DIO2 (or FOXO3), myoblast differentiation stalls, MYOD1 doesn’t rise, and precursor cells remain stuck in a proliferative state resulting in poor muscle regeneration.
• DIO3
Preliminary data show that DIO3 appears early, during the proliferative phase of satellite cells, and then declines during differentiation.
• Sequential logic: DIO3 → DIO2
This suggests a controlled sequence where initial low T3 (via DIO3) allows satellite cells to expand, followed by high T3 (via DIO2) that triggers differentiation and fusion.
This timing is essential. Disrupt it, and regeneration becomes uncoordinated.
Implications for Muscle Pathology
In conditions like muscular dystrophy, altering thyroid hormone levels worsens the phenotype:
- Hypothyroidism prolongs satellite cell replication and delays fusion.
- Thyrotoxicosis causes premature fusion, which also disrupts regeneration.
This supports the idea that precise T3 control not too much, not too little is required for balanced muscle repair.
Therapeutic Potential
Because deiodinases determine local T3 levels, targeting DIO2 and DIO3 may allow clinicians to enhance muscle repair, treat muscle atrophy, or support regeneration in disease and injury.
Key Points Summary:
- TH signaling is essential for skeletal muscle development, fiber type specification, contractile speed, and regeneration.
- Variations in basal metabolic rate during thyroid dysfunction arise largely from skeletal muscle.
- T3 signals mainly through THRA1 in muscle.
- DIO2 rises in developing or injured muscle.
- Local T4→T3 conversion is vital for satellite cell differentiation; without it, muscle regeneration is impaired.
- Dynamic control of T3 by deiodinases could become a powerful therapeutic tool.
Broader implications for Muscle and Bone
The same principles appear to apply to bone:
- T3 is required for normal skeletal development and adult bone turnover.
- Too much T3 accelerates turnover → osteoporosis.
- Too little T3 slows turnover → poor bone quality and healing.
- The DIO2 Thr92Ala polymorphism is also linked to reduced bone density and osteoarthritis, highlighting a shared vulnerability in muscle and bone.
Key Implication for Growth and Development:
These findings suggest that local T3 regulation through DIO2 is a unifying mechanism that supports the development, function, and repair of both muscle and bone.
FINAL SUMMARY.
For growing tissues like developing muscle fibers, regenerating muscle after injury, or the continuously remodeling skeleton the presence of T3 is absolutely essential. But even more crucial is the discovery that cells do not simply rely on circulating hormone. Instead, they precisely tune their own intracellular T3 levels through a coordinated interplay between DIO2 and DIO3.
This allows stem cells to:
- proliferate when T3 is kept low (DIO3 phase)
- differentiate and mature when T3 is increased locally (DIO2 phase)
This sequential, cell autonomous control system is what ensures proper muscle growth, repair, and metabolic function and likely supports healthy bone development as well.
CREDITS @Hunter He found the Article and Helped me alot on this Thread
here's the article: https://pmc.ncbi.nlm.nih.gov/articles/PMC4037849/
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