Impaired Overload-Induced Hypertrophy Is Associated With Diminished Mtor Signaling In Insulin Resistant Obese Zucker Rat

PURPOSE: Impaired overload-induced hypertrophy in insulin resistant skeletal muscle may result from diminished mTOR signaling which is the key regulator of protein translation. But, the potential insulin resistance-related signalling decrements have never been examined in direct parallel with impaired overload-induced hypertropy. METHODS: To this end, we examined the amount and regulation of mammalian target of rapamycin (mTOR), its downstream signaling intermediates (70 kDa ribosomal protein S6 kinase (S6k), ribosomal protein S6 (rpS6), eukaryotic elongation factor 2 (eEF2), and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1)) and its upstream signalling targets (PI3K/PTEN/Akt signaling, and tuberous sclerosis complex (TSC2/ Tuberin) in conjunction with impaired growth in 1 week and 3 week overloaded slow-twitch soleus muscles (via unilateral gastrocnemius ablation) of obese Zucker rats (OZR) versus lean Zucker rats (LZR). RESULTS: The significantly diminished growth (assessed by muscle wet weight) in 3 week overloaded muscles in OZR was accompanied by significant impairments in the phosphorylation states of mTOR (Ser2448), S6k (impaired at the mTOR-specific Thr389 residue but not at Thr421/Ser424), rpS6 (Ser235/236) and hyperphosphorylation of AMPK. Moreover, in overloaded muscles across both animal models, phospho-S6k at Thr389 (but not at Thr421/Ser424) and phospho- rpS6 at Ser235/236 status were all positively correlated with percentage muscle hypertrophy, and negatively correlated with the phosphorylation (Thr172) of 5'-AMP-activated protein kinase. CONCLUSIONS: These results provide evidence that impaired overload-induced hypertropy in insulin resistant skeletal muscle may partly result from multiple-level decrements in mTOR signaling.