Effect of short-term thyroxine administration on energy metabolism and mitochondrial efficiency in humans

Abstract

The physiologic effects of triiodothyronine (T3) on metabolic rate are well-documented; however, the effects of thyroxine (T4) are less clear despite its wide-spread use to treat thyroid-related disorders and other non-thyroidal conditions. Here, we investigated the effects of acute (3-day) T4 supplementation on energy expenditure at rest and during incremental exercise. Furthermore, we used a combination of in situ and in vitro approaches to measure skeletal muscle metabolism before and after T4 treatment. Ten healthy, euthyroid males were given 200 µg T4 (levothyroxine) per day for 3 days. Energy expenditure was measured at rest and during exercise by indirect calorimetry, and skeletal muscle mitochondrial function was assessed by in situ ATP flux ((31)P MRS) and in vitro respiratory control ratio (RCR, state 3/state 4 rate of oxygen uptake using a Clark-type electrode) before and after acute T4 treatment. Thyroxine had a subtle effect on resting metabolic rate, increasing it by 4% (p = 0.059) without a change in resting ATP demand (i.e., ATP flux) of the vastus lateralis. Exercise efficiency did not change with T4 treatment. The maximal capacity to produce ATP (state 3 respiration) and the coupled state of the mitochondria (RCR) were reduced by approximately 30% with T4 (p = 0.057 and p = 0.04, respectively). Together, the results suggest that T4, although less metabolically active than T3, reduces skeletal muscle efficiency and modestly increases resting metabolism even after short-term supplementation. Our findings may be clinically relevant given the expanding application of T4 to treat non-thyroidal conditions such as obesity and weight loss.

Figure 1. State 3 and state 4 respiration and FCCP-induced maximal respiration of mitochondria isolated from the vastus lateralis before and after 3 days of T4 treatment (n = 8).

State 3, or ADP-stimulated respiration was decreased (p = 0.057) with no change in state 4 (leak-dependent) respiration (p = 0.37). Maximal respiration induced by the addition of the uncoupler FCCP also tended to decrease with T4 treatment (p = 0.07).

Figure 2. Relationship between the change in resting metabolic rate and the change in free T4 after 3 days of T4 treatment, after controlling for baseline free T4 levels.

r = 0.61, p = 0.06.

Figure 3. Experimental protocol and timeline of testing procedures.