title: A chronic increase in physical activity inhibits fed-state mTOR/S6K1 signaling and reduces IRS-1 serine phosphorylation in rat skeletal muscle.
abstract: A chronic increase in physical activity and (or) endurance training can improve insulin sensitivity in insulin-resistant skeletal muscle. Cellular mechanisms responsible for the development of insulin resistance are unclear, though one proposed mechanism is that nutrient overload chronically increases available energy, over-activating the mammalian target of rapamycin (mTOR) and ribosomal S6 kinase 1 (S6K1) signaling pathway leading to increased phosphorylation of serine residues on insulin receptor substrate-1 (IRS-1). The objective of this study was to determine if increased physical activity would inhibit mTOR/S6K1 signaling and reduce IRS-1 serine phosphorylation in rat skeletal muscle. Soleus muscle was collected from fed male Sprague-Dawley sedentary rats (Inactive) and rats with free access to running wheels for 9 weeks (Active). Immunoblotting methods were used to measure phosphorylation status of mTOR, S6K1, IRS-1, and PKB/Akt (protein kinase B/AKT), and total abundance of proteins associated with the mTOR pathway. Muscle citrate synthase activity and plasma insulin and glucose concentrations were measured. Phosphorylation of mTOR (Ser2448), S6K1 (Thr389), and IRS-1 (Ser636-639) was reduced in Active rats (p<0.05). Total protein abundance of mTOR, S6K1, IRS-1, 4E-BP1, eEF2, PKB/Akt and AMPKalpha, and phosphorylation of PKB/Akt were unaffected (p>0.05). Total SKAR protein, a downstream target of S6K1, and citrate synthase activity increased in Active rats (p<0.05), though plasma insulin and glucose levels were unchanged (p>0.05). Reduced mTOR/S6K1 signaling during chronic increases in physical activity may play an important regulatory role in the serine phosphorylation of IRS-1, which should be examined as a potential mechanism for attenuation of insulin resistance associated with increased IRS-1 serine phosphorylation.
authors.affiliation: Division of Rehabilitation Sciences, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555-1144, USA.
authors.forename: Erin L
authors.initials: EL
authors.lastname: Glynn
authors.forename: Heidi L
authors.initials: HL
authors.lastname: Lujan
authors.forename: Victoria J
authors.initials: VJ
authors.lastname: Kramer
authors.forename: Micah J
authors.initials: MJ
authors.lastname: Drummond
authors.forename: Stephen E
authors.initials: SE
authors.lastname: DiCarlo
authors.forename: Blake B
authors.initials: BB
authors.lastname: Rasmussen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose; D015153:Blotting, Western; D002950:Citrate (si)-Synthase / Q000097:blood; D007328:Insulin / Q000097:blood; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000502:physiology; D019344:Lactic Acid / Q000097:blood; D008297:Male; D018482:Muscle, Skeletal / Q000502:physiology*; D010766:Phosphorylation; D010805:Physical Conditioning, Animal / Q000502:physiology*; D011494:Protein Kinases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000502:physiology; D012694:Serine / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001786:Blood Glucose; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D050794:STAT1 Transcription Factor; D019344:Lactic Acid; D012694:Serine; D002950:Citrate (si)-Synthase; D011494:Protein Kinases; C546845:mTOR protein, rat; D019893:Ribosomal Protein S6 Kinases; C526901:Rps6kb1 protein, rat; D058570:TOR Serine-Threonine Kinases