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

• Published in: Applied physiology, nutrition, and metabolism nutrition, and metabolism, 2008-02, Vol.33 (1), p.93-101
• Main Authors: Glynn, Erin L, Lujan, Heidi L, Kramer, Victoria J, Drummond, Micah J, DiCarlo, Stephen E, Rasmussen, Blake B
• Format: Article
• Language: English
• Subjects: activité physique; Adaptor Proteins, Signal Transducing - metabolism; Animals; Biochemistry; Blood Glucose; Blotting, Western; Citrate (si)-Synthase - blood; Drug resistance; Insulin; Insulin - blood; Insulin Receptor Substrate Proteins; insulin resistance; Insulin Resistance - physiology; insulinorésistance; IRS-1; Lactic Acid - blood; Male; mTOR; muscle squelettique; Muscle, Skeletal - physiology; Musculoskeletal system; Phosphorylation; physical activity; Physical Conditioning, Animal - physiology; Protein Kinases - metabolism; Rats; Rats, Sprague-Dawley; Ribosomal Protein S6 Kinases - metabolism; Rodents; S6K1; Serine - metabolism; Signal transduction; skeletal muscle; STAT1 Transcription Factor - physiology; TOR Serine-Threonine Kinases
• ISSN: 1715-5312; 1715-5320
• DOI: 10.1139/H07-149

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 (Ser 2448 ), S6K1 (Thr 389 ), and IRS-1 (Ser 636-639 ) was reduced in Active rats (p < 0.05). Total protein abundance of mTOR, S6K1, IRS-1, 4E-BP1, eEF2, PKB/Akt and AMPK α, 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.