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

Barbara M.L.C. Bocco, Ruy A.N. Louzada, Diego H.S. Silvestre, Maria C.S. Santos, Elena Anne-Palmer, Igor F. Rangel, Sherine Abdalla, Andrea C. Ferreira, Miriam O. Ribeiro, Balázs Gereben, Denise P. Carvalho, Antonio C. Bianco, João P. Werneck-de-Castro

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Key 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.

Original languageEnglish
Pages (from-to)5255-5269
Number of pages15
JournalJournal of Physiology
Volume594
Issue number18
DOIs
Publication statusPublished - Sep 15 2016

Keywords

  • gating
  • heterogeneity
  • phosphorylation
  • trafficking

ASJC Scopus subject areas

  • Physiology

Fingerprint Dive into the research topics of 'Thyroid hormone activation by type 2 deiodinase mediates exercise-induced peroxisome proliferator-activated receptor-γ coactivator-1α expression in skeletal muscle'. Together they form a unique fingerprint.

  • Cite this

    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. (2016). Thyroid hormone activation by type 2 deiodinase mediates exercise-induced peroxisome proliferator-activated receptor-γ coactivator-1α expression in skeletal muscle. Journal of Physiology, 594(18), 5255-5269. https://doi.org/10.1113/JP272440