A chronic increase in physical activity inhibits fedstate mTOR/S6K1 signaling and reduces IRS-1 serine phosphorylation in rat skeletal muscle

Erin L. Glynn, Heidi L. Lujan, Victoria J. Kramer, Micah J. Drummond, Stephen E. DiCarlo, Blake B. Rasmussen

Research output: Contribution to journalArticlepeer-review

35 Scopus citations


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 AMPKα, 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.

Original languageEnglish (US)
Pages (from-to)93-101
Number of pages9
JournalApplied Physiology, Nutrition and Metabolism
Issue number1
StatePublished - Feb 2008
Externally publishedYes


  • IRS-1
  • Insulin resistance
  • Physical activity
  • S6K1
  • Skeletal muscle
  • mTOR

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Nutrition and Dietetics
  • Physiology (medical)


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