Question: How does thyroid hormone regulate mitochondrial biogenesis in the myocardium?

Context:
L-T3 significantly increased the expression of factors involved in mitochondrial DNA transcription and biogenesis, such as hypoxic inducible factor-1α, mitochondrial transcription factor A and peroxisome proliferator activated receptor γ coactivator-1α, in the LV peri-infarct zone
the T(3)-induced phosphorylation of p38 and AMPK in both slow- and fast-twitch skeletal muscles suggests that these events may be important in mediating hormone-induced increases in mitochondrial biogenesis in skeletal muscle.
Our findings indicate parallel increases in myocardial mitochondrial bioenergetic capacity, oxygen consumption and markers of mitochondrial biogenesis with 15-day T4
The marked, parallel increases in PPARalpha levels suggest its potential involvement in mediating myocardial-specific remodeling of mitochondria in response to T4
T3 mediates an early stimulation of enzymes containing mtDNA encoded subunits (e.g. complex IV and V) in contrast to a different regulatory pattern for the entirely nuclear-encoded enzymes
Activity of respiratory complexes II, IV, V and citrate synthase (CS), levels of mitochondrial enzyme subunits (e.g. COXI, COXIV) and nuclear-encoded transcription factors, involved in mitochondrial biogenesis (e.g. PGC-1, mtTFA and PPAR-alpha), were significantly elevated with 72 h T3 treatment
T(3) increased PGC-1alpha content similarly in both fast- and slow-twitch muscle, as well as in the liver, but not in heart.
Thyroid hormone [3,5,3'-triiodo-l-thyronine (T(3))] induces phenotypic alterations in cardiac mitochondria, in part by influencing protein import and the expression of the import motor mitochondrial heat shock protein (mtHsp70).
These findings indicate that import machinery components are differentially regulated in response to stimuli that induce mitochondrial biogenesis, like T(3) and differentiation.
We have previously identified a mitochondrial triiodothyronine receptor (p43) regulating mitochondrial transcription and mitochondrial biogenesis. When overexpressed in skeletal muscle, it increases mitochondrial DNA content, stimulates mitochondrial respiration,
Here we show that a p43 depletion in mice decreases mitochondrial DNA replication and respiratory chain activity in skeletal muscle
The contribution of TFAM, TFB2M, and helicase Twinkle in thyroid-induced mtDNA biogenesis was assessed. The activation of TFAM and TFB2M expression is shown to be required for the induction of mtDNA biogenesis. The role of helicase Twinkle, the expression induction of which is also observed after triiodothyronine addition, remains unclear. The analysis of factors that activate TFAM and TFB2M expression showed that NRF-1 is the determinative regulator:
in rat cerebellum show that hypothyroidism causes reduction in expression of nuclear encoded genes controlling mitochondrial biogenesis like PGC-1alpha, NRF-1alpha and Tfam
These results thus indicate an integrated nuclear-mitochondrial cross talk in regulation of mitochondrial transcription by TH during brain development.
T(3) acts to reduce cellular oxidative stress, which may help attenuate ROS-mediated damage, along with improving mitochondrial function and energy status in cells with mtDNA defects.
These findings suggest the existence of compensatory mechanisms operating at the translational and/or post-translational levels which promote proliferation of mitochondria in the hypothyroid liver. However, when the liver mass was considered, hypothyroidism significantly reduced overall mitochondrial proliferation in rat liver.
Total liver mitochondrial DNA levels in thyroid-treated animals were greater than age-paired controls by 79% at 7 days but only 67% at 14 days since a small gain occurred in control animals and no further increase occurred in treated rats during the second week.
thyroid hormone treatment produces hyperplasia and an increase in mitochondrial number and mass in rat liver
It is concluded that T3 exerts a direct, rather than permissive, effect on mitochondrial biogenesis, and that high affinity binding sites for GH are not present in rat liver mitochondria.
These data strengthen the view that thyroid hormone regulates synthesis of specific components within each respiratory-chain complex and that these products apparently play key roles in inner-membrane biogenesis and assembly
It is concluded that thyroid hormone causes an increase in the mitochondrial mass, mitochondrial cytochrome content, and respiratory rate, and consequently expands the capacity of oxidative metabolism without an uncoupling effect on oxidative phosphorylation.

Answer: T4 increases myocardial mitochondrial bioenergetic capacity, oxygen consumption and markers of mitochondrial biogenesis. The marked, parallel increases in PPARalpha levels suggest its potential involvement in mediating myocardial-specific remodeling of mitochondria in response to T4.  T3 induces mitochondrial biogenesis. In fact, T3 treatment for 72h  increases activity of respiratory complexes II, IV, V and citrate synthase (CS), levels of mitochondrial enzyme subunits (e.g. COXI, COXIV) and nuclear-encoded transcription factors, involved in mitochondrial biogenesis (e.g. PGC-1, mtTFA and PPAR-alpha).  Furthermore, L-T3 increases  the expression of factors involved in mitochondrial DNA transcription and biogenesis, such as hypoxic inducible factor-1α, mitochondrial transcription factor A and peroxisome proliferator activated receptor γ coactivator-1α, in the LV peri-infarct zone.
The activation of TFAM and TFB2M expression is shown to be required for the induction of mtDNA biogenesis by T3. Truncated forms of the nuclear receptor TRα1, with molecular weights of 43 kDa (p43) and 28 Kda have been previously identified in mitochondria. P43 is a mitochondrial T3 receptor which stimulates mitochondrial transcription and protein synthesis in the presence of T3. p43 depletion in mice decreases mitochondrial DNA replication and respiratory chain activity.