In mice, the thyroid hormone T3 raises overall energy use by acting on a specific receptor, TRα1, in skeletal muscle. When this receptor is disabled in muscle tissue, the increase in energy use does...
Mechanism
Synthesis from 1 study
T3 makes the body burn more energy by turning on heat-producing genes in muscle through a receptor called TRα1—when this receptor is broken in muscle, T3 can’t increase energy use, even if the hormone is present. But T3 still raises body temperature through other parts of the body, showing that...
Most probable mechanism
When thyroid hormone T3 enters skeletal muscle, it binds to a receptor called TRα1, which turns on genes like sarcolipin and UCP3 that make muscle cells burn energy without producing movement, releasing heat instead. This heat production raises the body’s overall energy use. If TRα1 is broken in muscle, T3 can’t turn on these genes, so energy use doesn’t go up—even if T3 levels are normal. This was seen in mice where TRα1 was disabled only in muscle, and their energy expenditure didn’t rise with T3, while body temperature still increased through other pathways.
Thyroid hormone T3 binds to thyroid hormone receptor alpha 1 (TRα1) in skeletal muscle, initiating transcriptional changes that regulate thermogenic and metabolic genes.
TRα1 activation increases expression of sarcolipin and UCP3 in slow-twitch skeletal muscle, promoting uncoupling of mitochondrial respiration and SERCA-mediated ATP hydrolysis to generate heat.
Enhanced uncoupled ATP hydrolysis and mitochondrial respiration in soleus muscle increase ATP turnover and heat production, directly elevating whole-body energy expenditure.
Loss of TRα1 in skeletal muscle prevents T3-induced upregulation of sarcolipin, UCP3, and mitochondrial respiration, abolishing the increase in energy expenditure despite normal plasma T3 levels.
Less supported by current evidence, but not ruled out
When TRα1 is missing in muscle, sarcolipin levels rise on their own, which may help generate some baseline heat by uncoupling calcium pumps in muscle cells, but this does not restore the ability of T3 to increase energy expenditure.
Loss of TRα1 signaling in skeletal muscle leads to a >5-fold increase in sarcolipin expression in soleus, gastrocnemius, and quadriceps muscles, independent of T3 stimulation.
Elevated sarcolipin binds to SERCA pumps, uncoupling ATP hydrolysis from calcium transport to produce heat, which may maintain baseline metabolic rate but does not mediate T3’s effect on energy expenditure.
This compensatory mechanism increases circulating GDF15, a marker of mitochondrial stress, but does not restore T3-induced energy expenditure.
T3 still raises body temperature even when TRα1 is disabled in muscle, meaning another part of the body—likely the brain or other tissues—controls heat production separately from energy expenditure.
T3 administration increases core body temperature in mice with muscle-specific TRα1 loss-of-function to the same extent as in wild-type mice, despite no increase in energy expenditure.
No compensatory increase in brown adipose tissue UCP1 expression or mass occurs in TRα1-deficient mice, ruling out BAT as the source of T3-induced hyperthermia.
T3-induced hyperthermia and energy expenditure are dissociated, indicating separate mechanisms: muscle TRα1 controls energy use, while another tissue controls temperature.
Evidence from Studies
Supporting (1)
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Thyroid hormone receptor α in skeletal muscle is essential for T3‐mediated increase in energy expenditure
Contradicting (0)
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