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

During moderate-intensity exercise, fatty acids are the predominant substrate for working skeletal muscle. The release of fatty acids from adipose tissue stores, combined with the ability of skeletal muscle to actively fine tune the gradient between fatty acid and carbohydrate metabolism, depending on substrate availability and energetic demands, requires a coordinated system of metabolic control. Over the past decade, since the discovery that AMP-activated protein kinase (AMPK) was increased in accordance with exercise intensity, there has been significant interest in the proposed role of this ancient stress-sensing kinase as a critical integrative switch controlling metabolic responses during exercise. In this review, studies examining the role of AMPK as a regulator of fatty acid metabolism in both adipose tissue and skeletal muscle during exercise will be discussed. Exercise induces activation of AMPK in adipocytes and regulates triglyceride hydrolysis and esterfication through phosphorylation of hormone sensitive lipase (HSL) and glycerol-3-phosphate acyl-transferase, respectively. In skeletal muscle, exercise-induced activation of AMPK is associated with increases in fatty acid uptake, phosphorylation of HSL, and increased fatty acid oxidation, which is thought to occur via the acetyl-CoA carboxylase-malony-CoA-CPT-1 signalling axis. Despite the importance of AMPK in regulating fatty acid metabolism under resting conditions, recent evidence from transgenic models of AMPK deficiency suggest that alternative signalling pathways may also be important for the control of fatty acid metabolism during exercise.

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The role of AMP-activated protein kinase in the coordination of skeletal muscle turnover and energy homeostasis

AJP Cell Physiology ◽

10.1152/ajpcell.00125.2012 ◽

2012 ◽

Vol 303 (5) ◽

pp. C475-C485 ◽

Cited By ~ 70

Author(s):

Anthony M. J. Sanchez ◽

Robin B. Candau ◽

Alfredo Csibi ◽

Allan F. Pagano ◽

Audrey Raibon ◽

...

Keyword(s):

Skeletal Muscle ◽

Protein Kinase ◽

Energy Homeostasis ◽

Therapeutic Potential ◽

Energy Status ◽

Muscle Plasticity ◽

Glucose And Lipid Metabolism ◽

Muscle Homeostasis ◽

Amp Activated Protein Kinase

The AMP-activated protein kinase (AMPK) is a serine/threonine protein kinase that acts as a sensor of cellular energy status switch regulating several systems including glucose and lipid metabolism. Recently, AMPK has been implicated in the control of skeletal muscle mass by decreasing mTORC1 activity and increasing protein degradation through regulation of ubiquitin-proteasome and autophagy pathways. In this review, we give an overview of the central role of AMPK in the control of skeletal muscle plasticity. We detail particularly its implication in the control of the hypertrophic and atrophic signaling pathways. In the light of these cumulative and attractive results, AMPK appears as a key player in regulating muscle homeostasis and the modulation of its activity may constitute a therapeutic potential in treating muscle wasting syndromes in humans.

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Role of Adenosine 5′-Monophosphate-Activated Protein Kinase in Interleukin-6 Release from Isolated Mouse Skeletal Muscle

Endocrinology ◽

10.1210/en.2008-1204 ◽

2009 ◽

Vol 150 (2) ◽

pp. 600-606 ◽

Cited By ~ 26

Author(s):

Stephan Glund ◽

Jonas T. Treebak ◽

Yun Chau Long ◽

Romain Barres ◽

Benoit Viollet ◽

...

Keyword(s):

Skeletal Muscle ◽

Protein Kinase ◽

Extensor Digitorum Longus ◽

Protein Release ◽

Extensor Digitorum ◽

Whole Body ◽

Wild Type ◽

Amp Activated Protein Kinase ◽

Respective Wild Type

IL-6 is released from skeletal muscle during exercise and has consequently been implicated to mediate beneficial effects on whole-body metabolism. Using 5-aminoimidazole-4-carboxamide-1-β-4-ribofuranoside (AICAR), a pharmacological activator of 5′-AMP-activated protein kinase (AMPK), we tested the hypothesis that AMPK modulates IL-6 release from isolated muscle. Skeletal muscle from AMPKα2 kinase-dead transgenic, AMPKα1 knockout (KO) and AMPKγ3 KO mice and respective wild-type littermates was incubated in vitro, in the absence or presence of 2 mmol/liter AICAR. Skeletal muscle from wild-type mice was also incubated with the AMPK activator A-769662. Incubation of mouse glycolytic extensor digitorum longus and oxidative soleus muscle for 2 h was associated with profound IL-6 mRNA production and protein release, which was suppressed by AICAR (P < 0.001). Basal IL-6 release from soleus was increased between AMPKα2 kinase-dead and AMPKα1 KO and their respective wild-type littermates (P < 0.05), suggesting AMPK participates in the regulation of IL-6 release from oxidative muscle. The effect of AICAR on muscle IL-6 release was similar between AMPKα2 KD, AMPKα1 KO, and AMPKγ3 KO mice and their respective wild-type littermates (P < 0.001), indicating AICAR-mediated suppression of IL-6 mRNA expression and protein release is independent of AMPK function. However, IL-6 release from soleus, but not extensor digitorum longus, was reduced 45% by A-769662. Our results on basal and A-769662-mediated IL-6 release provide evidence for a role of AMPK in the regulation of IL-6 release from oxidative skeletal muscle. Furthermore, in addition to activating AMPK, AICAR suppresses IL-6 release by an unknown, AMPK-independent mechanism. Using transgenic and knockout mouse models to perturb AMP-activated protein kinase (AMPK) signaling, we provide evidence that AMPK-dependent pathways regulate IL-6 release from isolated oxidative skeletal muscle.

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Transgenic models – a scientific tool to understand exercise-induced metabolism: the regulatory role of AMPK (5′-AMP-activated protein kinase) in glucose transport and glycogen synthase activity in skeletal muscle

Biochemical Society Transactions ◽

10.1042/bst0311290 ◽

2003 ◽

Vol 31 (6) ◽

pp. 1290-1294 ◽

Cited By ~ 18

Author(s):

J.F.P. Wojtaszewski ◽

J.N. Nielsen ◽

S.B. Jørgensen ◽

C. Frøsig ◽

J.B. Birk ◽

...

Keyword(s):

Skeletal Muscle ◽

Protein Kinase ◽

Glucose Transport ◽

Glycogen Synthase ◽

Muscle Metabolism ◽

Regulatory Role ◽

Amp Activated Protein Kinase ◽

Glycogen Synthase Activity

The AMPK (5´AMP-activated protein kinase) is becoming recognized as a critical regulator of energy metabolism. However, many of these effects in muscle metabolism have been ascribed to AMPK based on the use of the unspecific activator AICAR (5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside). Using mouse models in which AMPK activity has been specifically blocked (kinase dead) or knocked out we and others have been able to conduct studies gaining more conclusive data on the role of AMPK in muscle metabolism. In this mini-review focus is on AMPK and its regulatory role for glucose transport and GS (glycogen synthase) activity in skeletal muscle, indicating that AMPK is a GS kinase in vivo which might influence GS activity during exercise and that AMPK is involved in AICAR/hypoxia-induced glucose transport but not or only partially in contraction-stimulated glucose transport.

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