LKB1 and AMPK and the regulation of skeletal muscle metabolism

Harvard University, Cambridge, Massachusetts, United States
Current Opinion in Clinical Nutrition and Metabolic Care (Impact Factor: 3.99). 06/2008; 11(3):227-32. DOI: 10.1097/MCO.0b013e3282fb7b76
Source: PubMed


To address the role of LKB1 and AMP-activated protein kinase (AMPK) in glucose transport, fatty acid oxidation, and metabolic adaptations in skeletal muscle.
Contraction-mediated skeletal muscle glucose transport is decreased in muscle-specific LKB1 knockout mice, but not in whole body AMPKalpha2 knockout mice or AMPKalpha2 inactive transgenic mice. Chronic activation of AMPK by 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) and beta-guanadinopropionic acid enhances mitochondrial function in skeletal muscle, but AICAR or exercise-induced increases in mitochondrial markers are preserved in skeletal muscles from whole body AMPKalpha2 or muscle-specific LKB1 knockout mice. Pharmacological activation of AMPK increases glucose transport and fatty acid oxidation in skeletal muscle. Therefore, chronic activation of AMPK may be beneficial in the treatment of obesity and type 2 diabetes.
LKB1 and AMPK play important roles in regulating metabolism in resting and contracting skeletal muscle.

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    • "In addition, we see an upregulation of phosphorylated AMP activated kinase (p-AMPK) protein levels in cold adapted muscles (Figure 2e). AMPK is a major regulator of skeletal muscle metabolism and has been shown to be activated to phosphorylatated form (p-AMPK) during conditions of increased energy demand including cold challenge (Koh et al., 2008; Kus et al., 2008; Oliveira et al., 2004). Upregulation of p- AMPK levels along with increased SERCA 2a levels further indicate that muscle-based thermogenesis is increasingly recruited in the neonates with response to cold challenge. "
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    ABSTRACT: Neonatal mice have a greater thermogenic need and may require additional means of heat production, other than the established mechanism of brown adipose tissue (BAT). Others and we recently discovered a novel mediator of skeletal muscle-based thermogenesis called sarcolipin (SLN) that acts by uncoupling sarcoendoplasmic reticulum Ca(2+) ATPase (SERCA). In addition, we have shown that SLN expression is downregulated during neonatal development in rats. In this study we probed two questions; 1) whether SLN expression is developmentally regulated in neonatal mice 2) if yes, will cold adaptation override developmental regulation of SLN expression. Our data shows that SLN expression is higher during early neonatal stages and is gradually downregulated in fast twitch skeletal muscles. Interestingly, we demonstrate that cold acclimatization of neonatal mice can prevent downregulation of SLN expression. This observation suggests that SLN-mediated thermogenesis can be recruited to a greater extent during extreme physiological need, in addition to BAT. © 2015. Published by The Company of Biologists Ltd.
    No preview · Article · May 2015 · Journal of Experimental Biology
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    • "However, basal glucose uptake, i.e., that which occurs in the absence of insulin, has been ascribed to other glucose transporters, such as Glut1, which have higher constitutive association with the sarcolemma (Scheepers et al., 2004; Marette et al., 1992; Wang et al., 1996). Exercise is also an important factor in glucose transport, inducing AMP-dependent kinase (AMPK) activation and Glut4 vesicle translocation via phosphorylation of AS160 and TBC1D1, which is independent of insulin (Fujii et al., 2006; Koh et al., 2008). "
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    ABSTRACT: Insulin and insulin-like growth factor 1 (IGF-1) are major regulators of muscle protein and glucose homeostasis. To determine how these pathways interact, we generated mice with muscle-specific knockout of IGF-1 receptor (IGF1R) and insulin receptor (IR). These MIGIRKO mice showed >60% decrease in muscle mass. Despite a complete lack of insulin/IGF-1 signaling in muscle, MIGIRKO mice displayed normal glucose and insulin tolerance. Indeed, MIGIRKO mice showed fasting hypoglycemia and increased basal glucose uptake. This was secondary to decreased TBC1D1 resulting in increased Glut4 and Glut1 membrane localization. Interestingly, overexpression of a dominant-negative IGF1R in muscle induced glucose intolerance in MIGIRKO animals. Thus, loss of insulin/IGF-1 signaling impairs muscle growth, but not whole-body glucose tolerance due to increased membrane localization of glucose transporters. Nonetheless, presence of a dominant-negative receptor, even in the absence of functional IR/IGF1R, induces glucose intolerance, indicating that interactions between these receptors and other proteins in muscle can impair glucose homeostasis. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Preview · Article · May 2015 · Cell Reports
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    • "Although the role of SIRT1 in mediating exercise-induced increases in mitochondrial biogenesis has been challenged (Philp et al. 2011), SIRT1-dependent responses to exercise and fasting are compromised in AMP-activated protein kinase (AMPK)-deficient skeletal muscle (Cantó et al. 2010). AMPK is a heterotrimeric protein consisting of multiple isoforms of catalytic (α1, α2) and regulatory (β1, β2 and γ1, γ2, γ3) subunits, which mainly functions as a major sensor of cellular fuel status (Koh et al. 2008). In human and rodent skeletal muscle, AMPK trimers containing α2 catalytic subunits are dominant (Wojtaszewski et al. 2005; Treebak et al. 2009). "
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    ABSTRACT: Deacetylases such as sirtuins convert nicotinamide adenine dinucleotide (NAD) to nicotinamide (NAM). Nicotinamide phosphoribosyl transferase (Nampt) is the rate-limiting enzyme in the NAD salvage pathway responsible for converting NAM to NAD to maintain cellular redox state. Activation of AMP-activated protein kinase (AMPK) increases sirtuin activity by elevating NAD levels. As NAM directly inhibits sirtuins, increased Nampt activation or expression could be a metabolic stress response. Evidence suggests that AMPK regulates Nampt mRNA content, but whether repeated AMPK activation is necessary for increasing Nampt protein levels is unknown. To this end, we assessed whether exercise training- or 5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide (AICAR)-mediated increases in skeletal muscle Nampt abundance are AMPK dependant. One-legged knee-extensor exercise training in humans increased Nampt protein by 16% (p<0.05) in the trained, but not the untrained leg. Moreover, increases in Nampt mRNA following acute exercise or AICAR treatment (p<0.05 for both) were maintained in mouse skeletal muscle lacking a functional AMPK α2 subunit. Despite a reduction in Nampt protein in skeletal muscle of sedentary AMPK α2 kinase dead (KD), 6.5 weeks of endurance exercise training increased skeletal muscle Nampt protein to a similar extent in both wild-type (WT) (24%) and AMPK α2 KD (18%) mice. In contrast, four weeks of daily AICAR treatment increased Nampt protein in skeletal muscle in WT mice (27%), but this effect was abolished in AMPK α2 KD mice. In conclusion, functional α2-containing AMPK heterotrimers are required for elevation of skeletal muscle Nampt protein, but not mRNA induction. These findings suggest AMPK plays a post-translational role in the regulation of skeletal muscle Nampt protein abundance and further indicate that the regulation of cellular energy charge and nutrient sensing is mechanistically related.
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