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



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.
Division of Endocrinology and Metabolism, Rush University Medical Center, Chicago, IL, USA.|Department of Translational Medicine, Federal University of São Paulo, Brazil.
Barbara M L C
BM
Bocco
Institute of Biophysics Carlos Chagas Filho and School of Physical Education and Sports, Federal University of Rio de Janeiro, Brazil.
Ruy A N
RA
Louzada
Division of Endocrinology and Metabolism, Rush University Medical Center, Chicago, IL, USA.|Institute of Biophysics Carlos Chagas Filho and School of Physical Education and Sports, Federal University of Rio de Janeiro, Brazil.
Diego H S
DH
Silvestre
Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Brazil.
Maria C S
MC
Santos
Division of Endocrinology and Metabolism, Rush University Medical Center, Chicago, IL, USA.
Elena
E
Anne-Palmer
Institute of Biophysics Carlos Chagas Filho and School of Physical Education and Sports, Federal University of Rio de Janeiro, Brazil.
Igor F
0000-0001-9133-1558
IF
Rangel
Division of Endocrinology, Diabetes and Metabolism, University of Miami Miller School of Medicine, Miami, FL, USA.
Sherine
S
Abdalla
Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Brazil.
Andrea C
AC
Ferreira
Developmental Disorders Program, Center for Biological and Health Sciences, Mackenzie Presbyterian University, Sao Paulo, Brazil.
Miriam O
MO
Ribeiro
Department of Endocrine Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary.
Balázs
B
Gereben
Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Brazil.
Denise P
0000-0002-9405-9438
DP
Carvalho
Division of Endocrinology and Metabolism, Rush University Medical Center, Chicago, IL, USA.
Antonio C
AC
Bianco
Division of Endocrinology and Metabolism, Rush University Medical Center, Chicago, IL, USA. joao_werneck-de-castro@rush.edu.|Institute of Biophysics Carlos Chagas Filho and School of Physical Education and Sports, Federal University of Rio de Janeiro, Brazil. joao_werneck-de-castro@rush.edu.
João P
JP
Werneck-de-Castro
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002478:Cells, Cultured; D002950:Citrate (si)-Synthase / Q000378:metabolism; D015870:Gene Expression; D007453:Iodide Peroxidase / Q000235:genetics / Q000378:metabolism*; D019344:Lactic Acid / Q000097:blood; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000235:genetics*; D010805:Physical Conditioning, Animal / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D017208:Rats, Wistar; D013974:Thyroxine / Q000097:blood / Q000378:metabolism*; D014284:Triiodothyronine / Q000097:blood / Q000378:metabolism*; D000097564:Iodothyronine Deiodinase Type II
D001786:Blood Glucose; D002950:Citrate (si)-Synthase; D007453:Iodide Peroxidase; D019344:Lactic Acid; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012333:RNA, Messenger; D013974:Thyroxine; D014284:Triiodothyronine; D000097564:Iodothyronine Deiodinase Type II; C485290:Ppargc1a protein, mouse
gating; heterogeneity; phosphorylation; trafficking