Thyroid hormone activation by type 2 deiodinase mediates exercise-induced peroxisome proliferator-activated receptor-γ coactivator-1α expression in skeletal muscle

Bocco B.M.L.C.; Louzada R.A.N.; Silvestre D.H.S.; Santos M.C.S.; Anne-Palmer E.; Rangel I.F.; Abdalla S.; Ferreira A.C.; Ribeiro M.O.; Gereben B.; Carvalho D.P.; Bianco A.C.; Werneck-de-Castro J.P.

Thyroid hormone activation by type 2 deiodinase mediates exercise-induced peroxisome proliferator-activated receptor-γ coactivator-1α expression in skeletal muscle

Tipo

Artigo

Data de publicação

2016

Periódico

Journal of Physiology

Citações (Scopus)

37

Autores

Bocco B.M.L.C.
Louzada R.A.N.
Silvestre D.H.S.
Santos M.C.S.
Anne-Palmer E.
Rangel I.F.
Abdalla S.
Ferreira A.C.
Ribeiro M.O.
Gereben B.
Carvalho D.P.
Bianco A.C.
Werneck-de-Castro J.P.

Resumo

© 2016 The Authors. The Journal of Physiology © 2016 The Physiological SocietyKey points: In skeletal muscle, physical exercise and thyroid hormone mediate the peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1a) expression that is crucial to skeletal muscle mitochondrial function. The expression of type 2 deiodinase (D2), which activates thyroid hormone in skeletal muscle is upregulated by acute treadmill exercise through a β-adrenergic receptor-dependent mechanism. Pharmacological block of D2 or disruption of the Dio2 gene in skeletal muscle fibres impaired acute exercise-induced PGC-1a expression. Dio2 disruption also impaired muscle PGC-1a expression and mitochondrial citrate synthase activity in chronically exercised mice. Abstract: Thyroid hormone promotes expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1a), which mediates mitochondrial biogenesis and oxidative capacity in skeletal muscle (SKM). Skeletal myocytes express the type 2 deiodinase (D2), which generates 3,5,3′-triiodothyronine (T3), the active thyroid hormone. To test whether D2-generated T3 plays a role in exercise-induced PGC-1a expression, male rats and mice with SKM-specific Dio2 inactivation (SKM-D2KO or MYF5-D2KO) were studied. An acute treadmill exercise session (20 min at 70–75% of maximal aerobic capacity) increased D2 expression/activity (1.5- to 2.7-fold) as well as PGC-1a mRNA levels (1.5- to 5-fold) in rat soleus muscle and white gastrocnemius muscle and in mouse soleus muscle, which was prevented by pretreatment with 1 mg (100 g body weight)−1 propranolol or 6 mg (100 g body weight)−1 iopanoic acid (5.9- vs. 2.8-fold; P < 0.05), which blocks D2 activity. In the SKM-D2KO mice, acute treadmill exercise failed to induce PGC-1a fully in soleus muscle (1.9- vs. 2.8-fold; P < 0.05), and in primary SKM-D2KO myocytes there was only a limited PGC-1a response to 1 μm forskolin (2.2- vs. 1.3-fold; P < 0.05). Chronic exercise training (6 weeks) increased soleus muscle PGC-1a mRNA levels (∼25%) and the mitochondrial enzyme citrate synthase (∼20%). In contrast, PGC-1a expression did not change and citrate synthase decreased by ∼30% in SKM-D2KO mice. The soleus muscle PGC-1a response to chronic exercise was also blunted in MYF5-D2KO mice. In conclusion, acute treadmill exercise increases SKM D2 expression through a β-adrenergic receptor-dependent mechanism. The accelerated conversion of T4 to T3 within myocytes mediates part of the PGC-1a induction by treadmill exercise and its downstream effects on mitochondrial function.

Assuntos Scopus

Animals , Blood Glucose , Cells, Cultured , Citrate (si)-Synthase , Gene Expression , Iodide Peroxidase , Lactic Acid , Male , Mice, Inbred C57BL , Mice, Knockout , Muscle, Skeletal , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha , Physical Conditioning, Animal , Rats, Wistar , RNA, Messenger , Thyroxine , Triiodothyronine