Dataset Information

The AMPK activator R419 improves exercise capacity and skeletal muscle insulin sensitivity in obese mice.

ABSTRACT:

Objective

Skeletal muscle AMP-activated protein kinase (AMPK) is important for regulating glucose homeostasis, mitochondrial content and exercise capacity. R419 is a mitochondrial complex-I inhibitor that has recently been shown to acutely activate AMPK in myotubes. Our main objective was to examine whether R419 treatment improves insulin sensitivity and exercise capacity in obese insulin resistant mice and whether skeletal muscle AMPK was important for mediating potential effects.

Methods

Glucose homeostasis, insulin sensitivity, exercise capacity, and electron transport chain content/activity were examined in wildtype (WT) and AMPK ?1?2 muscle-specific null (AMPK-MKO) mice fed a high-fat diet (HFD) with or without R419 supplementation.

Results

There was no change in weight gain, adiposity, glucose tolerance or insulin sensitivity between HFD-fed WT and AMPK-MKO mice. In both HFD-fed WT and AMPK-MKO mice, R419 enhanced insulin tolerance, insulin-stimulated glucose disposal, skeletal muscle 2-deoxyglucose uptake, Akt phosphorylation and glucose transporter 4 (GLUT4) content independently of alterations in body mass. In WT, but not AMPK-MKO mice, R419 improved treadmill running capacity. Treatment with R419 increased muscle electron transport chain content and activity in WT mice; effects which were blunted in AMPK-MKO mice.

Conclusions

Treatment of obese mice with R419 improved skeletal muscle insulin sensitivity through a mechanism that is independent of skeletal muscle AMPK. R419 also increases exercise capacity and improves mitochondrial function in obese WT mice; effects that are diminished in the absence of skeletal muscle AMPK. These findings suggest that R419 may be a promising therapy for improving whole-body glucose homeostasis and exercise capacity.

SUBMITTER: Marcinko K

PROVIDER: S-EPMC4563030 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Publications

The AMPK activator R419 improves exercise capacity and skeletal muscle insulin sensitivity in obese mice.

Marcinko Katarina K Bujak Adam L AL Lally James S V JS Ford Rebecca J RJ Wong Tammy H TH Smith Brennan K BK Kemp Bruce E BE Jenkins Yonchu Y Li Wei W Kinsella Todd M TM Hitoshi Yasumichi Y Steinberg Gregory R GR

Molecular metabolism 20150615 9

<h4>Objective</h4>Skeletal muscle AMP-activated protein kinase (AMPK) is important for regulating glucose homeostasis, mitochondrial content and exercise capacity. R419 is a mitochondrial complex-I inhibitor that has recently been shown to acutely activate AMPK in myotubes. Our main objective was to examine whether R419 treatment improves insulin sensitivity and exercise capacity in obese insulin resistant mice and whether skeletal muscle AMPK was important for mediating potential effects.<h4>Me ...[more]

PMID: 26413470

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Project description:Systemic lupus erythematosus (SLE) patients may show increased insulin resistance (IR) when compared with their healthy peers. Exercise training has been shown to improve insulin sensitivity in other insulin-resistant populations, but it has never been tested in SLE. Therefore, the aim of the present study was to assess the efficacy of a moderate-intensity exercise training program on insulin sensitivity and potential underlying mechanisms in SLE patients with mild/inactive disease. A 12-week, randomized controlled trial was conducted. Nineteen SLE patients were randomly assigned into two groups: trained (SLE-TR, n?=?9) and non-trained (SLE-NT, n?=?10). Before and after 12?weeks of the exercise training program, patients underwent a meal test (MT), from which surrogates of insulin sensitivity and beta-cell function were determined. Muscle biopsies were performed after the MT for the assessment of total and membrane GLUT4 and proteins related to insulin signaling [Akt and AMP-activated protein kinase (AMPK)]. SLE-TR showed, when compared with SLE-NT, significant decreases in fasting insulin [-39 vs. +14%, p?=?0.009, effect size (ES)?=?-1.0] and in the insulin response to MT (-23 vs. +21%, p?=?0.007, ES?=?-1.1), homeostasis model assessment IR (-30 vs. +15%, p?=?0.005, ES?=?-1.1), a tendency toward decreased proinsulin response to MT (-19 vs. +6%, p?=?0.07, ES?=?-0.9) and increased glucagon response to MT (+3 vs. -3%, p?=?0.09, ES?=?0.6), and significant increases in the Matsuda index (+66 vs. -31%, p?=?0.004, ES?=?0.9) and fasting glucagon (+4 vs. -8%, p?=?0.03, ES?=?0.7). No significant differences between SLT-TR and SLT-NT were observed in fasting glucose, glucose response to MT, and insulinogenic index (all p?>?0.05). SLE-TR showed a significant increase in AMPK Thr 172 phosphorylation when compared to SLE-NT (+73 vs. -12%, p?=?0.014, ES?=?1.3), whereas no significant differences between groups were observed in Akt Ser 473 phosphorylation, total and membrane GLUT4 expression, and GLUT4 translocation (all p?>?0.05). In conclusion, a 12-week moderate-intensity aerobic exercise training program improved insulin sensitivity in SLE patients with mild/inactive disease. This effect appears to be partially mediated by the increased insulin-stimulated skeletal muscle AMPK phosphorylation. Clinical Trial Registration:www.ClinicalTrials.gov, identifier NCT01515163.

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Dataset Information

The AMPK activator R419 improves exercise capacity and skeletal muscle insulin sensitivity in obese mice.

Objective

Methods

Results

Conclusions

Publications

The AMPK activator R419 improves exercise capacity and skeletal muscle insulin sensitivity in obese mice.

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