The mechanism underlying the regulation of basal metabolic rate by thyroid
hormone remains unclear. Although it has been suggested that thyroid hormon
e might uncouple substrate oxidation from ATP synthesis, there are no data
from studies on humans to support this hypothesis. To examine this possibil
ity, we used a novel combined C-13/P-31 nuclear magnetic resonance (NMR) ap
proach to assess mitochondrial energy coupling in skeletal muscle of seven
healthy adults before and after three days of triiodothyronine (T-3) treatm
ent. Rates of ATP synthesis and tricarboxylic acid (TCA) cycle fluxes were
measured by P-31 and C-13 NMR spectroscopy, respectively, and mitochondrial
energy coupling was assessed as the ratio. Muscle TCA cycle flux increased
by approximately 70% following T-3 treatment. In contrast, the rate of ATP
synthesis remained unchanged. Given the disproportionate increase in TCA c
ycle flux compared with ATP synthesis, these data suggest that T-3 promotes
increased thermogenesis in part by promoting mitochondrial energy uncoupli
ng in skeletal muscle.