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

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.

SUBMITTER: Binsch C

PROVIDER: S-EPMC5681242 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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

Binsch C C Jelenik T T Pfitzer A A Dille M M Müller-Lühlhoff S S Hartwig S S Karpinski S S Lehr S S Kabra D G DG Chadt A A Roden M M Al-Hasani H H Castañeda T R TR

Molecular metabolism 20170825 11

<h4>Objective</h4>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.<h4>Methods</h4>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.<h4>Results</h4>WT mice showed improved glucose tolerance after trainin ...[more]

PMID: 29107291

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Project description:BackgroundPatients with multiple sclerosis (MS) experience reduced exercise tolerance that substantially reduces quality of life. The mechanisms underpinning exercise intolerance in MS are not fully clear. This study aimed to determine the contributions of the cardiopulmonary system and peripheral muscle in MS-induced exercise intolerance before and after exercise training.MethodsTwenty-three patients with MS (13 women) and 20 age-matched and sex-matched healthy controls (13 women) performed a cardiopulmonary exercise test. Muscle fibre type composition, size, succinate dehydrogenase (SDH) activity, capillarity, and gene expression and proteins related to mitochondrial density were determined in vastus lateralis muscle biopsies. Nine MS patients (five women) were re-examined following a 12 week exercise training programme consisting of high-intensity cycling interval and resistance training.ResultsPatients with MS had lower maximal oxygen uptake compared with healthy controls (V̇O2peak , 25.0 ± 8.5 vs. 35.7 ± 6.4 mL/kg/min, P < 0.001). The lower gas exchange threshold (MS: 14.5 ± 5.5 vs. controls: 19.7 ± 2.9 mL/kg/min, P = 0.01) and slope of V̇O2 versus work rate (MS: 9.5 ± 1.7 vs. controls: 10.8 ± 1.1 mL/min/W, P = 0.01) suggested an intramuscular contribution to exercise intolerance in patients with MS. Muscle SDH activity was 22% lower in MS (P = 0.004), and strongly correlated with several indices of whole-body exercise capacity in MS patients (e.g. V̇O2peak , Spearman's ρ = 0.81, P = 0.002), but not healthy controls (ρ = 0.24, P = 0.38). In addition, protein levels of mitochondrial OXPHOS complexes I (-40%, P = 0.047) and II (-45%, P = 0.026) were lower in MS patients versus controls. Muscle capillary/fibre ratio correlated with V̇O2peak in healthy controls (ρ = 0.86, P < 0.001) but not in MS (ρ = 0.35, P = 0.22), and did not differ between groups (1.41 ± 0.30 vs. 1.47 ± 0.38, P = 0.65). Expression of genes involved in mitochondrial function, such as PPARA, PPARG, and TFAM, was markedly reduced in muscle tissue samples of MS patients (all P < 0.05). No differences in muscle fibre type composition or size were observed between groups (all P > 0.05). V̇O2peak increased by 23% following exercise training in MS (P < 0.001); however, no changes in muscle capillarity, SDH activity, gene or protein expression were observed (all P > 0.05).ConclusionsSkeletal muscle oxidative phenotype (mitochondrial complex I and II content, SDH activity) is lower in patients with MS, contributing to reduced exercise tolerance. However, skeletal muscle mitochondria appeared resistant to the beneficial effects of exercise training, suggesting that other physiological systems, at least in part, drive the improvements in exercise capacity following exercise training in MS.

Project description:Background Glucose and lipid tolerance reportedly exhibit diurnal variations, being lower in the evening than in the morning. Therefore, the effects of exercise on glucose and blood lipid levels at different times of the day may differ. This study aimed to investigate the effects of short-term endurance exercise intervention in the morning versus late afternoon on 24-h blood glucose variability and blood lipid levels. Methods Twelve healthy young men participated in a randomized crossover trial. The participants were assigned to morning (09:00–11:00) or late afternoon (16:00–18:00) endurance exercise for a week, consisting of supervised exercise sessions on Mondays, Wednesdays, and Fridays. In the morning and evening trials, the participants walked for 60 min on a treadmill at approximately 60% of maximal oxygen uptake (VO2max). Following a 2-week wash-out period, the participants performed the exercise training regimen at another time point. Continuous glucose monitoring was used to evaluate blood glucose fluctuations during each 24-h trial period. Blood samples were collected before and after each intervention to examine blood lipid and hormonal responses. Results Examination of the area under the curve (AUC) of the glucose level changes for 24 h after the late afternoon versus morning exercise intervention revealed significantly lower values for the former versus the latter (P < 0.01). The AUC of glucose level changes after each meal was also lower after the late afternoon versus morning intervention, and significantly lower values were observed in the late afternoon versus morning trial for breakfast and dinner (P < 0.05, P < 0.01). In addition, a significant decrease in triglycerides (TG) and TG/high-density lipoprotein cholesterol (HDL-C) was noted after versus before the late afternoon intervention (P < 0.05). Conclusions These results suggest that late afternoon endurance exercise is more effective than morning endurance exercise at improving 24-h glucose and triglyceride levels.

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

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

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