ABSTRACT
The importance of thyroid hormone receptors for isometric force, endurance and content of specific muscle enzymes was studied in isolated slow-twitch soleus and fast-twitch extensor digitorum longus (EDL) muscles in mice deficient in all known subtypes of thyroid hormone receptors (i.e. TR alpha1, beta1, beta2 and beta3). The weights of soleus and EDL muscles were lower in TR-deficient (TRalpha1-/-beta-/-) mice than in wild-type controls. The force per cross-sectional area was not significantly different between TRalpha1-/-beta-/- and wild-type muscles. Soleus muscles of TRalpha1-/-beta-/- mice showed increased contraction and relaxation times and the force-frequency relationship was shifted to the left. Soleus muscles of TRalpha1-/-beta-/- mice were more fatigue resistant than wild-type controls. Protein analysis of TRalpha1-/-beta-/- soleus muscles showed a marked increase in expression of the slow isoform of the sarcoplasmic reticulum Ca2+ pump (SERCa2), whilst expression of the fast type (SERCa1) was decreased. There was also a major decrease in the alpha2-subunit of the Na+-K+ pump in TRalpha1-/-beta-/- soleus muscles. EDL muscles from TRalpha1-/-beta-/- and wild-type mice showed no significant difference in contraction and relaxation times, fatigue resistance and protein expression. In conclusion, the present data show changes in contractile characteristics of skeletal muscles of TRalpha1-/-beta-/- mice similar to those seen in hypothyroidism. We have previously shown that muscles of mice deficient in TRalpha1 or TRbeta display modest changes in muscle function. Thus, in skeletal muscle there seems to be functional overlap between TRalpha1 and TRbeta, so that the lack of one of the receptors to some extent can be compensated for by the presence of the other.
Subject(s)
Isometric Contraction/physiology , Muscle, Skeletal/physiology , Physical Endurance/physiology , Thyroid Hormone Receptors alpha/genetics , Animals , Blotting, Western , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Mutant Strains , Muscle Fatigue/physiology , Muscle Fibers, Fast-Twitch/chemistry , Muscle Fibers, Fast-Twitch/physiology , Muscle Fibers, Slow-Twitch/chemistry , Muscle Fibers, Slow-Twitch/physiology , Muscle Relaxation/physiology , Muscle, Skeletal/cytology , Thyroid Hormone Receptors alpha/analysis , Thyroid Hormone Receptors beta/analysis , Thyroid Hormone Receptors beta/geneticsABSTRACT
INTRODUCTION: Thyroid hormone affects the electrophysiologic properties of the heart. It is not known which of the different subtypes of thyroid hormone receptors mediate these effects. METHODS AND RESULTS: Using standard patch-clamp techniques, we studied time- and voltage-dependent properties of depolarization-activated K+ currents in ventricular heart cells isolated from mice lacking the thyroid hormone receptor alpha1 (TR alpha1) and compared these currents with those in respective wild-type cells. In both groups of cells, the time course of current decay could be described by two inactivating exponential components and a sustained current component. In TR alpha1-deficient cells, the total inactivation time course was accelerated due to both increase of the relative contribution of the fast component and shortening of the slow time constant. The peak amplitude of the total current was not altered. The main component of steady-state inactivation of the voltage-dependent K+ outward current was shifted to more hyperpolarized voltages by 7 mV in TR alpha1-deficient cells compared with that in wild-type cells. Under current-clamp conditions, action potential duration at 90% repolarization was prolonged in TR alpha1-deficient cells compared with that in wild-type cells by 3.6 msec. CONCLUSION: The resulting acceleration of the total inactivation time course is proposed to contribute to action potential prolongation and thus to the increased QTend-time observed previously on ECG of TR alpha1-deficient mice.
