LKB1 and AMPK and the regulation of skeletal muscle metabolism.
ABSTRACT 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.
SourceAvailable from: Marianne Agerholm Andersen[Show abstract] [Hide abstract]
ABSTRACT: The mitochondrial protein deacetylase sirtuin (SIRT) 3 may mediate exercise training-induced increases in mitochondrial biogenesis and improvements in reactive oxygen species (ROS) handling. We determined the requirement of AMP-activated protein kinase (AMPK) for exercise training-induced increases in skeletal muscle abundance of SIRT3 and other mitochondrial proteins. Exercise training for 6.5 weeks increased SIRT3 (p < 0.01) and superoxide dismutase 2 (MnSOD; p < 0.05) protein abundance in quadriceps muscle of wild-type (WT; n = 13–15), but not AMPK α2 kinase dead (KD; n = 12–13) mice. We also observed a strong trend for increased MnSOD abundance in exercise-trained skeletal muscle of healthy humans (p = 0.051; n = 6). To further elucidate a role for AMPK in mediating these effects, we treated WT (n = 7–8) and AMPK α2 KD (n = 7–9) mice with 5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide (AICAR). Four weeks of daily AICAR injections (500 mg/kg) resulted in AMPK-dependent increases in SIRT3 (p < 0.05) and MnSOD (p < 0.01) in WT, but not AMPK α2 KD mice. We also tested the effect of repeated AICAR treatment on mitochondrial protein levels in mice lacking the transcriptional coactivator peroxisome proliferator-activated receptor γ-coactivator 1α (PGC-1α KO; n = 9–10). Skeletal muscle SIRT3 and MnSOD protein abundance was reduced in sedentary PGC-1α KO mice (p < 0.01) and AICAR-induced increases in SIRT3 and MnSOD protein abundance was only observed in WT mice (p < 0.05). Finally, the acetylation status of SIRT3 target lysine residues on MnSOD (K122) or oligomycin-sensitivity conferring protein (OSCP; K139) was not altered in either mouse or human skeletal muscle in response to acute exercise. We propose an important role for AMPK in regulating mitochondrial function and ROS handling in skeletal muscle in response to exercise training.Frontiers in Physiology 03/2015; 6. DOI:10.3389/fphys.2015.00085
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ABSTRACT: Excessive intramyocellular triglycerides (muscle lipids) are associated with reduced contractile function, insulin resistance and Type 2 diabetes, but what governs lipid accumulation in muscle is unclear. Here we report a role of Lkb1 in regulating lipid metabolism in muscle stem cells and their descendent mature muscles. We used MyodCre and Lkb1flox/flox mice to specifically delete Lkb1 in myogenic cells including stem and differentiated cells, and examined the lipid accumulation and gene expression of myoblasts cultured from muscle stem cells (satellite cells). Genetic deletion of Lkb1 in myogenic progenitors led to elevated expression of lipogenic genes and ectopic lipid accumulation in proliferating myoblasts. Interestingly, the Lkb1-deficient myoblasts differentiated into adipocyte-like cells upon adipogenic induction. However, these adipocyte-like cells maintained myogenic gene expression with reduced ability to form myotubes efficiently. Activation of AMPK by AICAR prevented ectopic lipid formation in the Lkb1 null myoblasts. Notably, Lkb1-deficient muscles accumulated excessive lipids in vivo in response to high-fat diet feeding. These results demonstrate that Lkb1 acts through AMPK to limit lipid deposition in muscle stem cells and their derivative mature muscles, and point to the possibility of controlling muscle lipid content using AMPK activating drugs. J. Cell. Physiol. © 2014 Wiley Periodicals, Inc.Journal of Cellular Physiology 09/2014; 230(5). DOI:10.1002/jcp.24831 · 3.87 Impact Factor
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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.The Journal of Physiology 08/2013; 591(20). DOI:10.1113/jphysiol.2013.259515 · 4.54 Impact Factor