Dissociation of AMP-activated protein kinase and p38 mitogen-activated protein kinase signaling in skeletal muscle

Ho, Richard C.; Fujii, Nobuharu; Witters, Lee A.; Hirshman, Michael F.; Goodyear, Laurie J.

doi:10.1016/j.bbrc.2007.07.154

Cited by 19 publications

(15 citation statements)

References 44 publications

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“…1B, adiponectin-stimulated p38 MAPK activation was not affected in the AMPK␣2-suppressed cells. This observation is consistent with a report that AMPK and p38 MAPK pathways are dissociated in skeletal muscle (9).…”

Section: Resultssupporting

confidence: 94%

“…It has been reported that AMPK functions as an upstream kinase of p38 MAPK in regulating glucose uptake stimulated by stretch and AICAR, however, it is still controversial whether AMPK-stimulated p38 MAPK activation is a common mechanism in skeletal muscle (4,9,12,26). Suppression of AMPK␣2 expression significantly affected AMPK activity and impaired the ischemia-induced p38 MAPK activation in ischemic heart (12), suggesting a role of AMPK␣2 in the activation of p38 MAPK.…”

Section: Discussionmentioning

confidence: 99%

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APPL1 mediates adiponectin-stimulated p38 MAPK activation by scaffolding the TAK1-MKK3-p38 MAPK pathway

Xin¹,

Zhou²,

Reyes³

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

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Xin X, Zhou L, Reyes CM, Liu F, Dong LQ. APPL1 mediates adiponectin-stimulated p38 MAPK activation by scaffolding the TAK1-MKK3-p38 MAPK pathway. Am J Physiol Endocrinol Metab 300: E103-E110, 2011. First published October 26, 2010 doi:10.1152/ajpendo.00427.2010.-The adaptor protein APPL1 mediates the stimulatory effect of adiponectin on p38 mitogen-activated protein kinase (MAPK) signaling, yet the underlying mechanism remains unclear. Here we show that, in C2C12 cells, overexpression or suppression of APPL1 enhanced or suppressed, respectively, adiponectin-stimulated p38 MAPK upstream kinase cascade, consisting of transforming growth factor-␤-activated kinase 1 (TAK1) and mitogen-activated protein kinase kinase 3 (MKK3). In vitro affinity binding and coimmunoprecipitation experiments revealed that TAK1 and MKK3 bind to different regions of APPL1, suggesting that APPL1 functions as a scaffolding protein to facilitate adiponectinstimulated p38 MAPK activation. Interestingly, suppressing APPL1 had no effect on TNF␣-stimulated p38 MAPK phosphorylation in C2C12 myotubes, indicating that the stimulatory effect of APPL1 on p38 MAPK activation is selective. Taken together, our study demonstrated that the TAK1-MKK3 cascade mediates adiponectin signaling and uncovers a scaffolding role of APPL1 in regulating the TAK1-MKK3-p38 MAPK pathway, specifically in response to adiponectin stimulation.APPL1; transforming growth factor-␤-activated kinase 1; mitogenactivated protein kinase kinase 3; p38 mitogen-activated protein kinase ADIPONECTIN IS AN ADIPOSE-derived hormone that plays an important role in the regulation of energy homeostasis (2, 10, 28). The binding of adiponectin to its membrane receptors, such as AdipoR1 and AdipoR2, leads to the activation of two major signal pathways in muscle cells, the AMP-activated protein kinase (AMPK) and the p38 mitogen-activated protein kinase (MAPK) pathways (16,27). Activation of these pathways has been shown to be essential for adiponectin-induced glucose uptake and fatty acid oxidation (16,27,28). APPL1 (adaptor protein containing PH domain, PTB domain and leucine zipper motif-1) is an adaptor protein containing multiple protein-protein interaction domains and was originally reported as an associating protein that interacts with the catalytic subunit of phosphatidylinositol 3-kinase (p110) and Akt (17). Our laboratory has recently shown that APPL1 mediates adiponectin signaling to activate both the AMPK and the p38 MAPK signaling pathways (7,16,29). However, despite the finding that APPL1 mediates adiponectin-stimulated AMPK activation by promoting the cytosolic translocation of AMPK upstream kinase LKB1 (29), the molecular mechanism underlying APPL1-regulated p38 MAPK activation remains elusive.The p38 MAPK is a major kinase in the MAPK family and plays essential roles in regulating cell proliferation, inflammation, and immune responses (19). Recent studies suggest that p38 MAPK acts as an essential mediator in regulating adiponectin-induced glucose uptake and fatty acid oxidation...

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Section: Resultssupporting

confidence: 94%

Section: Discussionmentioning

confidence: 99%

APPL1 mediates adiponectin-stimulated p38 MAPK activation by scaffolding the TAK1-MKK3-p38 MAPK pathway

Xin¹,

Zhou²,

Reyes³

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

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“…Because a single AICAR injection does not induce HIF-1␣ in normoxic conditions (29,38) and a single AICAR injection induced AMPK phosphorylation and not p38 MAPK in the present study (in accordance with previous findings) (1,20,54), the AICAR injection protocol applies a model more specific than an exercise protocol to investigate the potential role of AMPK/PGC-1␣ signaling in regulation of VEGF expression. Because a single AICAR injection does not induce HIF-1␣ in normoxic conditions (29,38) and a single AICAR injection induced AMPK phosphorylation and not p38 MAPK in the present study (in accordance with previous findings) (1,20,54), the AICAR injection protocol applies a model more specific than an exercise protocol to investigate the potential role of AMPK/PGC-1␣ signaling in regulation of VEGF expression.…”

Section: Pgc-1␣ Is Required For Ampk-mediated Increases In Vegf Expresupporting

confidence: 91%

PGC-1α mediates exercise-induced skeletal muscle VEGF expression in mice

Leick

Hellsten²,

Fentz³

et al. 2009

American Journal of Physiology-Endocrinology and Metabolism

102

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The aim of the present study was to test the hypothesis that PGC-1alpha is required for exercise-induced VEGF expression in both young and old mice and that AMPK activation leads to increased VEGF expression through a PGC-1alpha-dependent mechanism. Whole body PGC-1alpha knockout (KO) and littermate wild-type (WT) mice were submitted to either 1) 5 wk of exercise training, 2) lifelong (from 2 to 13 mo of age) exercise training in activity wheel, 3) a single exercise bout, or 4) 4 wk of daily subcutaneous AICAR or saline injections. In skeletal muscle of PGC-1alpha KO mice, VEGF protein expression was approximately 60-80% lower and the capillary-to-fiber ratio approximately 20% lower than in WT. Basal VEGF mRNA expression was similar in WT and PGC-1alpha KO mice, but acute exercise and AICAR treatment increased the VEGF mRNA content in WT mice only. Exercise training of young mice increased skeletal muscle VEGF protein expression approximately 50% in WT mice but with no effect in PGC-1alpha KO mice. Furthermore, a training-induced prevention of an age-associated decline in VEGF protein content was observed in WT but not in PGC-1alpha KO muscles. In addition, repeated AICAR treatments increased skeletal muscle VEGF protein expression approximately 15% in WT but not in PGC-1alpha KO mice. This study shows that PGC-1alpha is essential for exercise-induced upregulation of skeletal muscle VEGF expression and for a training-induced prevention of an age-associated decline in VEGF protein content. Furthermore, the findings suggest an AMPK-mediated regulation of VEGF expression through PGC-1alpha.

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“…It has been suggested by some (26), but not all (20), that AMPK may lie upstream of p38 MAPK. It has been suggested by some (26), but not all (20), that AMPK may lie upstream of p38 MAPK.…”

Section: Discussionmentioning

confidence: 99%

Epinephrine-mediated regulation of PDK4 mRNA in rat adipose tissue

Wan

Thrush

Legare

et al. 2010

American Journal of Physiology-Cell Physiology

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Fatty acid reesterification in adipose tissue is dependent on the generation of glycerol 3-phosphate, and, at least in rodent adipose tissue, this appears to occur primarily through glyceroneogenesis. A key enzyme in this process is pyruvate dehydrogenase kinase 4 (PDK4). PDK4 is induced in white adipose tissue by thiazolidinediones (TZDs) and the inhibition or knockdown of PDK4 inhibits TZD-induced increases in glyceroneogenesis. Since TZDs have many unwanted side effects, we were interested in identifying alternative mechanisms that could regulate PDK4 mRNA expression in white adipose tissue. In this regard we hypothesized that exercise, fasting, and epinephrine would increase PDK4 mRNA levels in rat epididymal adipose tissue. We further postulated that the p38 mitogen-activated protein kinase (MAPK) and 5'-AMP-activated protein kinase (AMPK) signaling pathways would control PDK4 mRNA expression in cultured adipose tissue. Exercise, fasting, and in or ex vivo epinephrine treatment increased PDK4 mRNA levels. These perturbations did not increase the expression of PDK1, -2, or -3. Pyruvate dehydrogenase phosphorylation was increased after an overnight fast and 4 h after the cessation of exercise. In cultured adipose tissue, epinephrine increased p38 and AMPK signaling; however, the direct activation of AMPK by AICAR or metformin led to reductions in PDK4 mRNA levels. The p38 inhibitor SB202190 reduced epinephrine-mediated increases in p38 MAPK activation without altering hormone-sensitive lipase or AMPK phosphorylation or attenuating epinephrine-induced increases in lipolysis. Reductions in p38 MAPK signaling were associated with decreases in PDK4 mRNA expression. The inhibition of peroxisome proliferator-activated receptor-γ (PPARγ) also attenuated the induction of PDK4. Our results are the very first to demonstrate an epinephrine-mediated regulation of PDK4 mRNA levels in white adipose tissue and suggest that p38 MAPK and PPARγ could be involved in this pathway.

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Dissociation of AMP-activated protein kinase and p38 mitogen-activated protein kinase signaling in skeletal muscle

Cited by 19 publications

References 44 publications

APPL1 mediates adiponectin-stimulated p38 MAPK activation by scaffolding the TAK1-MKK3-p38 MAPK pathway

APPL1 mediates adiponectin-stimulated p38 MAPK activation by scaffolding the TAK1-MKK3-p38 MAPK pathway

PGC-1α mediates exercise-induced skeletal muscle VEGF expression in mice

Epinephrine-mediated regulation of PDK4 mRNA in rat adipose tissue

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