Thyroid hormone effects on LKB1, MO25, phospho-AMPK, phospho-CREB, and PGC-1alpha in rat muscle.
Expression of all of the isoforms of the subunits of AMP-activated protein kinase (AMPK) and AMPK activity is increased in skeletal muscle of hyperthyroid rats. Activity of AMPK in skeletal muscle is regulated principally by the upstream kinase, LKB1. This experiment was designed to determine whether the increase in AMPK activity is accompanied by increased expression of the LKB1, along with binding partner proteins. LKB1, MO25, and downstream targets were determined in muscle extracts in control rats, in rats given 3 mg of thyroxine and 1 mg of triiodothyronine per kilogram chow for 4 wk, and in rats given 0.01% propylthiouracil (PTU; an inhibitor of thyroid hormone synthesis) in drinking water for 4 wk (hypothyroid group). LKB1 and MO25 increased in the soleus of thyroid hormone-treated rats vs. the controls. In other muscle types, LKB1 responses were variable, but MO25 increased in all. In soleus, MO25 mRNA increased with thyroid hormone treatment, and STRAD mRNA increased with PTU treatment. Phospho-AMPK and phospho-ACC were elevated in soleus and gastrocnemius of hyperthyroid rats. Thyroid hormone treatment also increased the amount of phospho-cAMP response element binding protein (CREB) in the soleus, heart, and red quadriceps. Four proteins having CREB response elements (CRE) in promoter regions of their genes (peroxisome proliferator-activated receptor-gamma coactivator-1alpha, uncoupling protein 3, cytochrome c, and hexokinase II) were all increased in soleus in response to thyroid hormones. These data provide evidence that thyroid hormones increase soleus muscle LKB1 and MO25 content with subsequent activation of AMPK, phosphorylation of CREB, and expression of mitochondrial protein genes having CRE in their promoters.
Branvold
D J
DJ
Department of Physiology and Developmental Biology, Brigham Young University, Provo, UT 84602, USA.
Allred
D R
DR
Beckstead
D J
DJ
Kim
H J
HJ
Fillmore
N
N
Condon
B M
BM
Brown
J D
JD
Sudweeks
S N
SN
Thomson
D M
DM
Winder
W W
WW
D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000818:Animals; D013956:Antithyroid Agents; D015153:Blotting, Western; D002135:Calcium-Binding Proteins; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004558:Electric Stimulation; D006980:Hyperthyroidism / Q000139:chemically induced / Q000201:enzymology*; D007037:Hypothyroidism / Q000139:chemically induced / Q000201:enzymology*; D008297:Male; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000201:enzymology*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011441:Propylthiouracil; D000071636:Protein Phosphatase 2C; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013974:Thyroxine; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014284:Triiodothyronine
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D013956:Antithyroid Agents; C508137:Creb1 protein, rat; C000622396:Cab39 protein, rat; D002135:Calcium-Binding Proteins; D017362:Cyclic AMP Response Element-Binding Protein; D024101:Mitochondrial Proteins; D009097:Multienzyme Complexes; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D014284:Triiodothyronine; D011441:Propylthiouracil; D017346:Protein Serine-Threonine Kinases; C488755:Stk11 protein, rat; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C; D013974:Thyroxine