Reduced skeletal muscle AMPK and mitochondrial markers do not promote age-induced insulin resistance

Bujak, Adam L.; Blümer, Regje M. E.; Marcinko, Katarina; Fullerton, Morgan D.; Kemp, Bruce E.; Steinberg, Gregory R.

doi:10.1152/japplphysiol.01101.2013

Cited by 8 publications

(6 citation statements)

References 50 publications

(66 reference statements)

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“…Despite the well-documented role of AMPK activators improving insulin sensitivity, most studies have found that mice having reductions in skeletal muscle AMPK activity fed a control chow [25,34,40] or obesity-promoting HFD diet [40,41] have normal skeletal muscle insulin sensitivity compared to wildtype littermates; although it should be noted that some studies have detected modest reductions in muscle insulin sensitivity [17,42,43] . While previous studies have investigated the effects of an obesity-inducing HFD on a genetic background of lower muscle AMPK activity, it is possible that small amounts of residual AMPK activity may have been sufficient to maintain skeletal muscle insulin sensitivity in these previous reports [40,41] .…”

Section: Discussionmentioning

confidence: 99%

“…Values were expressed to blood glucose and 2-[ 14 C] DG infusion in the blood. Additionally, lysates were used to measure cytochrome c oxidase (COX) activity, as described previously [34] . Blood was collected for serum biochemistry measurements post-hyperinsulinemic euglycemic clamp, including NEFA and insulin (Iso-insulin ELISA kit (Mercodia)).…”

Section: Methodsmentioning

confidence: 99%

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

Marcinko

Bujak

Lally

et al. 2015

Molecular Metabolism

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ObjectiveSkeletal 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.MethodsGlucose homeostasis, insulin sensitivity, exercise capacity, and electron transport chain content/activity were examined in wildtype (WT) and AMPK β1β2 muscle-specific null (AMPK-MKO) mice fed a high-fat diet (HFD) with or without R419 supplementation.ResultsThere 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.ConclusionsTreatment 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.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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

Marcinko

Bujak

Lally

et al. 2015

Molecular Metabolism

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“…AMPK is required for endurance exercise, because mice lacking AMPK subunits in skeletal muscle have a dramatically impaired ability to perform muscle contractions and forced treadmill running and also display reduced voluntary wheel running (O'Neill et al 2011;Lantier et al 2014). Despite these impairments, surprisingly, genetic removal of skeletal muscle AMPK does not promote the development of insulin resistance (O'Neill et al 2011;Bujak et al 2014;Lantier et al 2014).…”

Section: Introductionmentioning

confidence: 99%

The role of AMPK in controlling metabolism and mitochondrial biogenesis during exercise

Marcinko

Steinberg

2014

Experimental Physiology

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New Findings r What is the topic of this review?The topic of this review is the metabolic effects of AMP-activated protein kinase (AMPK) on glucose and fatty acid (FA) uptake, FA oxidation and mitochondrial biogenesis in skeletal muscle at rest and during exercise/muscle contractions. r What advances does it highlight?This review describes recent studies examining the molecular mechanisms by which AMPK regulates muscle metabolism. It specifically discusses the role of exercise on acetyl-CoA carboxylase and malonyl-CoA in the regulation of FA oxidation. It also discusses the role of AMPK in regulating glucose and FA uptake during exercise. Finally, the review describes the interaction between AMPK, peroxisome proliferator-activated receptor γ co-activator-1α and sirtuin 1 in controlling mitochondrial biogenesis.Insulin resistance is associated with defects in skeletal muscle fatty acid (FA) metabolism that contribute to the development of type 2 diabetes. Endurance exercise increases FA and glucose metabolism, muscle mitochondrial content and insulin sensitivity. In skeletal muscle, basal rates of FA oxidation are dependent on AMP-activated protein kinase (AMPK) phosphorylation of acetyl-CoA carboxylase 2, the rate-limiting enzyme controlling the production of the metabolic intermediate malonyl-CoA. Likewise, AMPK is essential for maintaining muscle mitochondrial content in untrained mice; effects that may be mediated through regulation of the peroxisome proliferator-activated receptor γ co-activator-1α. However, the importance of AMPK in regulating glucose and FA uptake, FA oxidation and mitochondrial biogenesis during and following endurance exercise training is not fully understood. A better understanding of the mechanisms by which endurance exercise regulates substrate utilization and mitochondrial biogenesis may lead to improved therapeutic and preventative strategies for the treatment of insulin resistance and type 2 diabetes.

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“…The most common AMPK heterotrimer in skeletal muscle is the a 2 , b 2 , g 1 (28). During aging, attenuation of skeletal muscle AMPK activity (29) is associated with alterations in the sarcolemmal environment, including reduced DAPC protein content (30)(31)(32)(33)(34). AMPK is a potent regulator of skeletal muscle phenotype primarily through phosphorylation-mediated changes in the expression and activity of downstream proteins capable of regulating phenotype maintenance and remodeling.…”

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The role of AMP‐activated protein kinase in the expression of the dystrophin‐associated protein complex in skeletal muscle

et al. 2018

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Stimulation of AMPK induces the expression of dystrophin-associated protein complex (DAPC) components in skeletal muscle, whereas reductions in AMPK are associated with DAPC dysfunction. We sought to determine whether AMPK was necessary for the maintenance of DAPC expression in skeletal muscle. Fast, glycolytic extensor digitorum longus (EDL) and slow, oxidative soleus (Sol) muscles from wild-type mice and from littermates with skeletal muscle-specific knockout of the AMPK β1 and β2 subunits (AMPK β1 β2M-KO; MKO) were analyzed. DAPC mRNA and protein expression were similar between genotypes, with the exception of elevated neuronal nitric oxide synthase expression at the sarcolemma in MKO muscles. The content of transcriptional and post-transcriptional regulators of the DAPC was also not affected by the loss of AMPK. However, MyoD and myogenin expression was diminished in MKO muscles, consistent with previous reports of myopathy in these animals. Furthermore, we observed decrements in extrasynaptic utrophin expression selectively in MKO Sol muscles, likely due to the adaptive accumulation of peroxisome proliferator-activated receptor γ coactivator-1α at the sarcolemma of MKO EDL muscles. Collectively, the evidence indicates that AMPK is sufficient but not essential for the maintenance of DAPC expression in skeletal muscle, yet it is required for preserving extrasynaptic utrophin levels in slow oxidative muscles.-Dial, A. G., Rooprai, P., Lally, J. S., Bujak, A. L., Steinberg, G. R., Ljubicic, V. The role of AMP-activated protein kinase in the expression of the dystrophin-associated protein complex in skeletal muscle.

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Reduced skeletal muscle AMPK and mitochondrial markers do not promote age-induced insulin resistance

Abstract: GR. Reduced skeletal muscle AMPK and mitochondrial markers do not promote age-induced insulin resistance.

Cited by 8 publications

References 50 publications

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

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

The role of AMPK in controlling metabolism and mitochondrial biogenesis during exercise

The role of AMP‐activated protein kinase in the expression of the dystrophin‐associated protein complex in skeletal muscle

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