Elsevier

Molecular Metabolism

Volume 6, Issue 11, November 2017, Pages 1443-1453
Molecular Metabolism

Original Article
Absence of the kinase S6k1 mimics the effect of chronic endurance exercise on glucose tolerance and muscle oxidative stress

https://doi.org/10.1016/j.molmet.2017.08.008Get rights and content
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open access

Highlights

  • Absence of S6k1 upregulates oxidative substrate utilization under HFD consumption.

  • S6k1 knockout mice show enhanced running performance and improved glycemia already in the sedentary state.

  • Aerobic endurance exercise training of S6k1 knockout mice further improves running performance but not glycemia.

  • Metabolic improvements are associated with lower rates of TCA-linked mitochondrial H2O2 production and increased ketogenesis.

Abstract

Objective

Ribosomal protein S6 Kinase-1 (S6K1) has been linked to resistance exercise-mediated improvements in glycemia. We hypothesized that S6K1 may also play a role in regulating glycemic control in response to endurance exercise training.

Methods

S6k1-knockout (S6K1KO) and WT mice on a 60 cal% high-fat diet were trained for 4 weeks on treadmills, metabolically phenotyped, and compared to sedentary controls.

Results

WT mice showed improved glucose tolerance after training. In contrast, S6K1KO mice displayed equally high glucose tolerance already in the sedentary state with no further improvement after training. Similarly, training decreased mitochondrial ROS production in skeletal muscle of WT mice, whereas ROS levels were already low in the sedentary S6K1KO mice with no further decrease after training. Nevertheless, trained S6K1KO mice displayed an increased running capacity compared to trained WT mice, as well as substantially reduced triglyceride contents in liver and skeletal muscle. The improvements in glucose handling and running endurance in S6K1KO mice were associated with markedly increased ketogenesis and a higher respiratory exchange ratio.

Conclusions

In high-fat fed mice, loss of S6K1 mimics endurance exercise training by reducing mitochondrial ROS production and upregulating oxidative utilization of ketone bodies. Pharmacological targeting of S6K1 may improve the outcome of exercise-based interventions in obesity and diabetes.

Keywords

S6K1
Exercise
Glycemic control
Metabolic phenotyping
Reactive oxidative species

Abbreviations

HFD
high-fat diet
ROS
reactive oxygen species
TCA
tricarboxylic acid cycle
mTOR
mammalian target of rapamycin

Cited by (0)

5

These authors contributed equally.