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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 improves exercise capacity via an AMPK dependent pathway involving increased content and activity of the electron transport chain. (A) Time to exhaustion. Significant interaction between treatment and genotype (p = 0.03). (B) Speed at exhaustion. Significant interaction between treatment and genotype (p = 0.02). (C) Distance traversed. Significant interaction between treatment and genotype (p = 0.02). (D) OXPHOS complex expression in quadriceps muscle. Representative image of OXPHOS blot from the same membrane. (E) COX Activity. Data are expressed as means ± SEM, †p < 0.05, ††p < 0.01 for difference from HFD control vs HFD + R419; *p < 0.05 for difference from HFD control post hoc within genotype; §p < 0.05, §§p < 0.01, §§§p < 0.001 for difference from WT vs AMPK-MKO, as determined by two-way ANOVA and Bonferroni post hoc test.
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fig3: R419 improves exercise capacity via an AMPK dependent pathway involving increased content and activity of the electron transport chain. (A) Time to exhaustion. Significant interaction between treatment and genotype (p = 0.03). (B) Speed at exhaustion. Significant interaction between treatment and genotype (p = 0.02). (C) Distance traversed. Significant interaction between treatment and genotype (p = 0.02). (D) OXPHOS complex expression in quadriceps muscle. Representative image of OXPHOS blot from the same membrane. (E) COX Activity. Data are expressed as means ± SEM, †p < 0.05, ††p < 0.01 for difference from HFD control vs HFD + R419; *p < 0.05 for difference from HFD control post hoc within genotype; §p < 0.05, §§p < 0.01, §§§p < 0.001 for difference from WT vs AMPK-MKO, as determined by two-way ANOVA and Bonferroni post hoc test.

Mentions: In agreement with our previous findings in chow-fed mice [25], time and speed at exhaustion were significantly impaired in AMPK-MKO compared to WT mice (Figure 3A,B). Despite obtaining a much lower maximal running speed, AMPK-MKO mice had elevated serum lactates and displayed significantly elevated blood glucose levels, consistent with their inability to stimulate muscle glucose uptake during treadmill running (Table 1), as previously reported [25]. R419 treatment increased time to exhaustion, speed at exhaustion and distance covered in WT but not AMPK-MKO mice (Figure 3A,B,C).


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 improves exercise capacity via an AMPK dependent pathway involving increased content and activity of the electron transport chain. (A) Time to exhaustion. Significant interaction between treatment and genotype (p = 0.03). (B) Speed at exhaustion. Significant interaction between treatment and genotype (p = 0.02). (C) Distance traversed. Significant interaction between treatment and genotype (p = 0.02). (D) OXPHOS complex expression in quadriceps muscle. Representative image of OXPHOS blot from the same membrane. (E) COX Activity. Data are expressed as means ± SEM, †p < 0.05, ††p < 0.01 for difference from HFD control vs HFD + R419; *p < 0.05 for difference from HFD control post hoc within genotype; §p < 0.05, §§p < 0.01, §§§p < 0.001 for difference from WT vs AMPK-MKO, as determined by two-way ANOVA and Bonferroni post hoc test.
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Related In: Results  -  Collection

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fig3: R419 improves exercise capacity via an AMPK dependent pathway involving increased content and activity of the electron transport chain. (A) Time to exhaustion. Significant interaction between treatment and genotype (p = 0.03). (B) Speed at exhaustion. Significant interaction between treatment and genotype (p = 0.02). (C) Distance traversed. Significant interaction between treatment and genotype (p = 0.02). (D) OXPHOS complex expression in quadriceps muscle. Representative image of OXPHOS blot from the same membrane. (E) COX Activity. Data are expressed as means ± SEM, †p < 0.05, ††p < 0.01 for difference from HFD control vs HFD + R419; *p < 0.05 for difference from HFD control post hoc within genotype; §p < 0.05, §§p < 0.01, §§§p < 0.001 for difference from WT vs AMPK-MKO, as determined by two-way ANOVA and Bonferroni post hoc test.
Mentions: In agreement with our previous findings in chow-fed mice [25], time and speed at exhaustion were significantly impaired in AMPK-MKO compared to WT mice (Figure 3A,B). Despite obtaining a much lower maximal running speed, AMPK-MKO mice had elevated serum lactates and displayed significantly elevated blood glucose levels, consistent with their inability to stimulate muscle glucose uptake during treadmill running (Table 1), as previously reported [25]. R419 treatment increased time to exhaustion, speed at exhaustion and distance covered in WT but not AMPK-MKO mice (Figure 3A,B,C).

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