Abstract
Acute aerobic exercise (AE) increases skeletal muscle insulin sensitivity for several hours, caused by acute activation of AMP-activated protein kinase (AMPK). Acute resistance exercise (RE) also activates AMPK, possibly improving insulin-stimulated glucose uptake. However, RE-induced rapamycin-sensitive mechanistic target of rapamycin complex 1 (mTORC1) activation is higher and has a longer duration than after AE. In molecular studies, mTORC1 was shown to be upstream of insulin receptor substrate 1 (IRS-1) Ser phosphorylation residue, inducing insulin resistance. Therefore, we hypothesised that although RE increases insulin sensitivity through AMPK activation, prolonged mTORC1 activation after RE reduces RE-induced insulin sensitising effect. In this study, we used an electrical stimulation–induced RE model in rats, with rapamycin as an inhibitor of mTORC1 activation. Our results showed that RE increased insulin-stimulated glucose uptake following AMPK signal activation. However, mTORC1 activation and IRS-1 Ser632/635 and Ser612 phosphorylation were elevated 6 h after RE, with concomitant impairment of insulin-stimulated Akt signal activation. By contrast, rapamycin inhibited these prior exercise responses. Furthermore, increases in insulin-stimulated skeletal muscle glucose uptake 6 h after RE were higher in rats with rapamycin treatment than with placebo treatment. Our data suggest that mTORC1/IRS-1 signaling inhibition enhances skeletal muscle insulin-sensitising effect of RE.
Highlights
A single bout of exercise, especially aerobic exercise (AE), increases the effect of insulin on skeletal muscle glucose uptake[1,2,3,4,5,6,7,8,9]
MTORC1 activation decreases insulin-stimulated glucose uptake in various insulin-sensitive tissues, respectively[38,39,40,41]; insulin resistance is explained by a negative feedback loop from Mechanistic target of rapamycin complex 1 (mTORC1) activation to insulin receptor substrate 1 (IRS-1) Ser phosphorylation residues (e.g., Ser[616], Ser636/639, and Ser1101 in human) that counteract with insulin-stimulated IRS-1 Try phosphorylation and following downstream signal activation (e.g., PI3K, Akt, and GLUT4 trafficking)[38,39,40,41,42,43,44]
We found that acute Resistance exercise (RE) significantly increased phosphorylation of AMPKα Thr[172] (Fig. 1b) and the downstream targets acetyl-CoA carboxylase (ACC) Ser[79] (Fig. 1c), TBC1 domain family member 1 (TBC1D1) Ser[231] (Fig. 1d), TBC1 domain family member 4 (TBC1D4) Ser[597] (Fig. 1e) and TBC1D4 Thr[651] (Fig. 1f)
Summary
A single bout of exercise, especially aerobic exercise (AE), increases the effect of insulin on skeletal muscle glucose uptake[1,2,3,4,5,6,7,8,9]. MTORC1 activation decreases insulin-stimulated glucose uptake in various insulin-sensitive tissues, respectively[38,39,40,41]; insulin resistance is explained by a negative feedback loop from mTORC1 activation to insulin receptor substrate 1 (IRS-1) Ser phosphorylation residues (e.g., Ser[616], Ser636/639, and Ser1101 in human) that counteract with insulin-stimulated IRS-1 Try phosphorylation and following downstream signal activation (e.g., PI3K, Akt, and GLUT4 trafficking)[38,39,40,41,42,43,44] According to these findings, prolonged mTORC1 pathway activation after acute RE may inhibit or disrupt increases in skeletal muscle insulin sensitivity, competing with AMPK pathway activation. We used rapamycin to identify the effect of rapamycin-sensitive mTORC1 pathway activation on the insulin-sensitising effect of an acute bout of RE in rat skeletal muscle
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