Increased adipogenesis in bone marrow but decreased bone mineral density in mice devoid of thyroid hormone receptors.

Mice deficient for all known thyroid hormone receptors, TRalpha1-/-beta-/- mice, display a clear skeletal phenotype characterized by growth retardation, delayed maturation of long bones and decreased trabecular and total bone mineral density (BMD; -14.6 +/- 2.8%, -14.4 +/- 1.5%). The aim of the present study was to investigate the molecular mechanisms behind the skeletal phenotype in TRalpha1-/-beta-/- mice. Global gene expression analysis was performed on total vertebrae from wild-type (WT) and TRalpha1-/-beta-/- mice using DNA microarray and the results were verified by real-time PCR. The mRNA levels of six genes (AdipoQ, Adipsin, Fat-Specific Protein 27 (FSP 27), lipoprotein lipase (LPL), retinol-binding protein (RBP) and phosphoenolpyruvate carboxykinase (PEPCK)) expressed by mature adipocytes were increased in TRalpha1-/-beta-/- compared with WT mice. An increased amount of fat (225% over WT) due to an increased number but unchanged mean size of adipocytes in the bone marrow of TRalpha1-/-beta-/- mice was revealed. Interestingly, the mRNA levels of the key regulator of osteoclastogenesis, receptor activator of NF-varkappab ligand (RANKL), were dramatically decreased in TRalpha1-/-beta-/- mice. In conclusion, TRalpha1-/-beta-/- mice demonstrated increased expression of adipocyte specific genes and an increased amount of bone marrow fat. Thus, these mice have increased adipogenesis in bone marrow associated with decreased trabecular bone mineral density (BMD). One may speculate that these effects either could be caused by an imbalance in the differentiation of the osteoblast and the adipocyte lineages at the expense of osteoblastogenesis, or by independent effects on the regulation of both osteoblastogenesis and adipogenesis.

Isometric force and endurance in skeletal muscle of mice devoid of all known thyroid hormone receptors.

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.