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Effect of the cardioselective Δ337T thyroid receptor (TR)β1 mutation on cardiac substrate fluxes and work efficiency
Author(s) -
Hyyti Outi Maria,
Ning XueHan,
Ge Ming,
Portman Michael A.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a741
Subject(s) - substrate (aquarium) , medicine , thyroid , chemistry , cardiology , endocrinology , biology , ecology
Hypothyroidism depresses cardiac work efficiency (CWE) in situ and in isolated rat heart models. The mechanisms are unclear, but may involve thyroid receptor control of substrate metabolism. To test this hypothesis and to avoid confounding systemic factor effects on cardiac metabolism, we studied mice expressing a cardioselective dominant negative TRβ1 mutation, Δ337T. We used a working mouse heart with 13Carbon (30 min infusion) isotopomer analyses by MR spectroscopy to determine function, oxygen consumption, fluxes and fractional contribution (Fc) of acetyl‐CoA to the citric acid cycle simultaneously for multiple substrates (1,3‐13C‐acetoacetate, L‐3‐13C‐lactate, U‐13C‐free fatty acids and unlabeled glucose). Heart rate, –dP/dt and pressure rate product were reduced in Δ337T (n=4) compared to wild type (WT, n=5). However, Δ337T CWE (10 3 mmHg×ml/μmolO 2 ×min −1 g −1 ) exceeded WT [230 vs 102 (P<0.007)]. No differences in flux for any substrate or for anaplerosis occurred, though Fc for free fatty acids tended to be increased in Δ337T. Shifts in flux among these major substrate pathways do not seem to play a major role in the marked changes in CWE with thyroid receptor dysfunction. These data show that although cardioselective hypothyroidism depresses diastolic function, CWE is increased. Furthermore, thyroid receptor dysfunction can alter CWE at sites of either ATP utilization or respiratory coupling, substrate oxidation pathways playing a less significant part. Supported by NIH HL60666.