Metabolic effects of mitochondrial uncoupling in murine skeletal muscle: Essential role of AMP-activated protein kinase in metabolic improvements of UCP1-transgenic mice?

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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Sex Differences in the Metabolic Effects of Testosterone in Sheep

Endocrinology ◽

10.1210/en.2011-1634 ◽

2012 ◽

Vol 153 (1) ◽

pp. 123-131 ◽

Cited By ~ 19

Author(s):

Scott D. Clarke ◽

Iain J. Clarke ◽

Alexandra Rao ◽

Michael A. Cowley ◽

Belinda A. Henry

Keyword(s):

Skeletal Muscle ◽

Protein Kinase ◽

Uncoupling Protein ◽

Specific Effect ◽

Metabolic Effects ◽

Mrna Levels ◽

Nonesterified Fatty Acids ◽

Glucose Levels ◽

Amp Activated Protein Kinase ◽

The Brain

Adiposity is regulated in a sexually divergent manner. This is partly due to sex steroids, but the differential effects of androgens in males and females are unclear. We investigated effects of testosterone on energy balance in castrated male (n = 6) and female sheep (n = 4), which received 3 × 200 mg testosterone implants for 2 wk or blank implants (controls). Temperature probes were implanted into retroperitoneal fat and skeletal muscle. Blood samples were taken to measure metabolites and insulin. In males, muscle and fat biopsies were collected to measure uncoupling protein (UCP) mRNA and phosphorylation of AMP-activated protein kinase and Akt. Testosterone did not change food intake in either sex. Temperature in muscle was higher in males than females, and testosterone reduced heat production in males only. In fat, however, temperature was higher in the castrate males compared with females, and there was no effect of testosterone treatment in either sex. Preprandial glucose levels were lower, but nonesterified fatty acids were higher in females compared with males, irrespective of testosterone. In males, the onset of feeding increased UCP1 and UCP3 mRNA levels in skeletal muscle, without an effect of testosterone. During feeding, testosterone reduced glucose levels in males only but did not alter the phosphorylation of AMP-activated protein kinase or Akt in muscle. Thus, testosterone maintains lower muscle and fat temperatures in males but not females. The mechanism underlying this sex-specific effect of testosterone is unknown but may be due to sexual differentiation of the brain centers controlling energy expenditure.

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Metformin promotes irisin release from murine skeletal muscle independently of AMP-activated protein kinase activation

Acta Physiologica ◽

10.1111/apha.12421 ◽

2014 ◽

Vol 213 (3) ◽

pp. 711-721 ◽

Cited By ~ 26

Author(s):

D.-J. Li ◽

F. Huang ◽

W.-J. Lu ◽

G.-J. Jiang ◽

Y.-P. Deng ◽

...

Keyword(s):

Skeletal Muscle ◽

Protein Kinase ◽

Kinase Activation ◽

Protein Kinase Activation ◽

Murine Skeletal Muscle ◽

Amp Activated Protein Kinase

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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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Skeletal muscle AMP-activated protein kinase γ1H151R overexpression enhances whole body energy homeostasis and insulin sensitivity

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00195.2015 ◽

2015 ◽

Vol 309 (7) ◽

pp. E679-E690 ◽

Cited By ~ 10

Author(s):

Milena Schönke ◽

Martin G. Myers ◽

Juleen R. Zierath ◽

Marie Björnholm

Keyword(s):

Skeletal Muscle ◽

Insulin Sensitivity ◽

Protein Kinase ◽

Transgenic Mice ◽

Energy Homeostasis ◽

Whole Body ◽

Α Subunit ◽

Peripheral Tissues ◽

Amp Activated Protein Kinase ◽

Body Energy

AMP-activated protein kinase (AMPK) is a major sensor of energy homeostasis and stimulates ATP-generating processes such as lipid oxidation and glycolysis in peripheral tissues. The heterotrimeric enzyme consists of a catalytic α-subunit, a β-subunit that is important for enzyme activity, and a noncatalytic γ-subunit that binds AMP and activates the AMPK complex. We generated a skeletal muscle Cre-inducible transgenic mouse model expressing a mutant γ1-subunit (AMPKγ1H151R), resulting in chronic AMPK activation. The expression of the predominant AMPKγ3 isoform in skeletal muscle was reduced in extensor digitorum longus (EDL) muscle (81–83%) of AMPKγ1H151R transgenic mice, whereas the abundance and phosphorylation of the AMPK target acetyl-CoA carboxylase was increased in tibialis anterior muscle. Glycogen content was increased 10-fold in gastrocnemius muscle. Whole body carbohydrate oxidation was increased by 11%, and whereas glucose tolerance was unaffected, insulin sensitivity was increased in AMPKγ1H151R transgenic mice. Furthermore, perigonadal white adipose tissue mass and serum leptin were reduced in female AMPKγ1H151R transgenic mice by 38 and 51% respectively. Conversely, in male AMPKγ1H151R transgenic mice, food intake was increased (14%), but body weight and body composition were unaltered, presumably because of increased energy expenditure. In conclusion, transgenic activation of skeletal muscle AMPKγ1 in this model plays an important sex-specific role in skeletal muscle metabolism and whole body energy homeostasis.

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

The FASEB Journal ◽

10.1096/fj.201700868rrr ◽

2018 ◽

Vol 32 (6) ◽

pp. 2950-2965 ◽

Cited By ~ 8

Author(s):

Athan G. Dial ◽

Paul Rooprai ◽

James S. Lally ◽

Adam L. Bujak ◽

Gregory R. Steinberg ◽

...

Keyword(s):

Skeletal Muscle ◽

Protein Kinase ◽

Protein Complex ◽

Amp Activated Protein Kinase

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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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Role of AMP-activated protein kinase in leptin-induced fatty acid oxidation in muscle

Biochemical Society Transactions ◽

10.1042/bst0310196 ◽

2003 ◽

Vol 31 (1) ◽

pp. 196-201 ◽

Cited By ~ 82

Author(s):

Y. Minokoshi ◽

B.B. Kahn

Keyword(s):

Fatty Acid ◽

Protein Kinase ◽

Fatty Acid Oxidation ◽

Metabolic Effects ◽

Acid Oxidation ◽

Amp Kinase ◽

Important Pathway ◽

Amp Activated Protein Kinase ◽

Stat Pathway

Leptin regulates energy homoeostasis through central and peripheral mechanisms. Initial steps in leptin action include signalling through a cytokine-like receptor which activates the JAK/STAT pathway. We investigated whether the metabolic effects of leptin in muscle could be mediated by the AMP-activated protein kinase (AMP kinase). Through studies involving leptin injection intrahypothalamically or intravenously, as well as incubation of soleus muscle or cultured muscle cells with leptin, we determined that leptin stimulates fatty acid oxidation in skeletal muscle by activating AMP kinase. Leptin exerts this effect directly at the level of muscle and also through the hypothalamic sympathetic nervous system, specifically engaging α-adrenergic receptors in muscle. This represents a novel and important pathway mediating leptin's metabolic actions.

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