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

Marcinko K, Bujak AL, Lally JS, Ford RJ, Wong TH, Smith BK, Kemp BE, Jenkins Y, Li W, Kinsella TM, Hitoshi Y, Steinberg GR - Mol Metab (2015)

Bottom Line: 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.R419 also increases exercise capacity and improves mitochondrial function in obese WT mice; effects that are diminished in the absence of skeletal muscle AMPK.

View Article: PubMed Central - PubMed

Affiliation: Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, 1280 Main St. W., Hamilton, Ontario L8N 3Z5, Canada.

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 β1β2 muscle-specific (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.

No MeSH data available.


Related in: MedlinePlus

R419 acutely activates skeletal muscle AMPK but does not induce hypoglycemia. A lack of skeletal muscle AMPK or R419 treatment does not alter weight gain or adiposity in mice fed a HFD. (A) Plasma concentration of R419 when WT mice were given HFD + R419 at a dose of 100 mg/kg HFD (n = 5). (B) AMPK Thr172 relative to AMPKα (from separate gels) (p = 0.16) and ACC Ser79/212 relative to ACC (from separate gels) in TA muscle from WT and AMPK-MKO mice 3 h following HFD or HFD + R419 administration. ND, not detectable. (C) Blood glucose concentrations 3 h following HFD or HFD + R419 administration in WT and AMPK-MKO mice. (D) Body mass of HFD WT and AMPK-MKO mice treated with or without R419 (two-way repeated measures ANOVA). (E) Food intake of HFD WT and AMPK-MKO mice treated with or without R419. (F) Measured body percent adiposity with representative CT images. Highlighted red areas represent adipose region. Numbers within bars represent number of mice per group. Data are expressed as means ± SEM, ∗p < 0.05, for difference from HFD vs HFD + R419, as assessed by student's t-test (B).
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fig1: R419 acutely activates skeletal muscle AMPK but does not induce hypoglycemia. A lack of skeletal muscle AMPK or R419 treatment does not alter weight gain or adiposity in mice fed a HFD. (A) Plasma concentration of R419 when WT mice were given HFD + R419 at a dose of 100 mg/kg HFD (n = 5). (B) AMPK Thr172 relative to AMPKα (from separate gels) (p = 0.16) and ACC Ser79/212 relative to ACC (from separate gels) in TA muscle from WT and AMPK-MKO mice 3 h following HFD or HFD + R419 administration. ND, not detectable. (C) Blood glucose concentrations 3 h following HFD or HFD + R419 administration in WT and AMPK-MKO mice. (D) Body mass of HFD WT and AMPK-MKO mice treated with or without R419 (two-way repeated measures ANOVA). (E) Food intake of HFD WT and AMPK-MKO mice treated with or without R419. (F) Measured body percent adiposity with representative CT images. Highlighted red areas represent adipose region. Numbers within bars represent number of mice per group. Data are expressed as means ± SEM, ∗p < 0.05, for difference from HFD vs HFD + R419, as assessed by student's t-test (B).

Mentions: Treatment with R419 at 100 mg/kg HFD resulted in a plasma concentration of about 24 ng/mL and AUC of 600 ng*hr/mL over 24 h (Figure 1A), which is comparable to previous administration of R419 (5–10 mg/kg body weight) by oral gavage [30]. In WT, but not AMPK-MKO TA muscle, R419 resulted in a tendency for increased AMPK Thr172 phosphorylation and significant increases in ACC Ser79/212 phosphorylation compared to HFD alone (Figure 1B). It should be noted that ACC Ser79/212 phosphorylation is considered a more sensitive measure of cellular AMPK activity as it takes into account the significant role that allosteric and covalent regulation of AMPK has on its activity [37]. R419 treatment did not alter blood glucose in either WT or AMPK-MKO mice relative to HFD alone (Figure 1C).


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

Marcinko K, Bujak AL, Lally JS, Ford RJ, Wong TH, Smith BK, Kemp BE, Jenkins Y, Li W, Kinsella TM, Hitoshi Y, Steinberg GR - Mol Metab (2015)

R419 acutely activates skeletal muscle AMPK but does not induce hypoglycemia. A lack of skeletal muscle AMPK or R419 treatment does not alter weight gain or adiposity in mice fed a HFD. (A) Plasma concentration of R419 when WT mice were given HFD + R419 at a dose of 100 mg/kg HFD (n = 5). (B) AMPK Thr172 relative to AMPKα (from separate gels) (p = 0.16) and ACC Ser79/212 relative to ACC (from separate gels) in TA muscle from WT and AMPK-MKO mice 3 h following HFD or HFD + R419 administration. ND, not detectable. (C) Blood glucose concentrations 3 h following HFD or HFD + R419 administration in WT and AMPK-MKO mice. (D) Body mass of HFD WT and AMPK-MKO mice treated with or without R419 (two-way repeated measures ANOVA). (E) Food intake of HFD WT and AMPK-MKO mice treated with or without R419. (F) Measured body percent adiposity with representative CT images. Highlighted red areas represent adipose region. Numbers within bars represent number of mice per group. Data are expressed as means ± SEM, ∗p < 0.05, for difference from HFD vs HFD + R419, as assessed by student's t-test (B).
© Copyright Policy - CC BY-NC-ND
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fig1: R419 acutely activates skeletal muscle AMPK but does not induce hypoglycemia. A lack of skeletal muscle AMPK or R419 treatment does not alter weight gain or adiposity in mice fed a HFD. (A) Plasma concentration of R419 when WT mice were given HFD + R419 at a dose of 100 mg/kg HFD (n = 5). (B) AMPK Thr172 relative to AMPKα (from separate gels) (p = 0.16) and ACC Ser79/212 relative to ACC (from separate gels) in TA muscle from WT and AMPK-MKO mice 3 h following HFD or HFD + R419 administration. ND, not detectable. (C) Blood glucose concentrations 3 h following HFD or HFD + R419 administration in WT and AMPK-MKO mice. (D) Body mass of HFD WT and AMPK-MKO mice treated with or without R419 (two-way repeated measures ANOVA). (E) Food intake of HFD WT and AMPK-MKO mice treated with or without R419. (F) Measured body percent adiposity with representative CT images. Highlighted red areas represent adipose region. Numbers within bars represent number of mice per group. Data are expressed as means ± SEM, ∗p < 0.05, for difference from HFD vs HFD + R419, as assessed by student's t-test (B).
Mentions: Treatment with R419 at 100 mg/kg HFD resulted in a plasma concentration of about 24 ng/mL and AUC of 600 ng*hr/mL over 24 h (Figure 1A), which is comparable to previous administration of R419 (5–10 mg/kg body weight) by oral gavage [30]. In WT, but not AMPK-MKO TA muscle, R419 resulted in a tendency for increased AMPK Thr172 phosphorylation and significant increases in ACC Ser79/212 phosphorylation compared to HFD alone (Figure 1B). It should be noted that ACC Ser79/212 phosphorylation is considered a more sensitive measure of cellular AMPK activity as it takes into account the significant role that allosteric and covalent regulation of AMPK has on its activity [37]. R419 treatment did not alter blood glucose in either WT or AMPK-MKO mice relative to HFD alone (Figure 1C).

Bottom Line: 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.R419 also increases exercise capacity and improves mitochondrial function in obese WT mice; effects that are diminished in the absence of skeletal muscle AMPK.

View Article: PubMed Central - PubMed

Affiliation: Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, 1280 Main St. W., Hamilton, Ontario L8N 3Z5, Canada.

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 β1β2 muscle-specific (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.

No MeSH data available.


Related in: MedlinePlus