Publications by authors named "David M Thomson"

42 Publications

Glycan degradation promotes macroautophagy.

Proc Natl Acad Sci U S A 2022 Jun 22;119(26):e2111506119. Epub 2022 Jun 22.

Tumour Cell Death and Autophagy Laboratory, Cancer Research UK Beatson Institute, Glasgow G61 1BD, United Kingdom.

Macroautophagy promotes cellular homeostasis by delivering cytoplasmic constituents to lysosomes for degradation [Mizushima, 20, 521-527 (2018)]. However, while most studies have focused on the mechanisms of protein degradation during this process, we report here that macroautophagy also depends on glycan degradation via the glycosidase, α-l-fucosidase 1 (FUCA1), which removes fucose from glycans. We show that cells lacking FUCA1 accumulate lysosomal glycans, which is associated with impaired autophagic flux. Moreover, in a mouse model of fucosidosis-a disease characterized by inactivating mutations in [Stepien , 11, E1383 (2020)]-glycan and autophagosome/autolysosome accumulation accompanies tissue destruction. Mechanistically, using lectin capture and mass spectrometry, we identified several lysosomal enzymes with altered fucosylation in FUCA1-null cells. Moreover, we show that the activity of some of these enzymes in the absence of FUCA1 can no longer be induced upon autophagy stimulation, causing retardation of autophagic flux, which involves impaired autophagosome-lysosome fusion. These findings therefore show that dysregulated glycan degradation leads to defective autophagy, which is likely a contributing factor in the etiology of fucosidosis.
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http://dx.doi.org/10.1073/pnas.2111506119DOI Listing
June 2022

Exercise, but Not Metformin Prevents Loss of Muscle Function Due to Doxorubicin in Mice Using an In Situ Method.

Int J Mol Sci 2021 Aug 25;22(17). Epub 2021 Aug 25.

Nutrition, Dietetics, and Food Science, Brigham Young University, Provo, UT 84602, USA.

Though effective in treating various types of cancer, the chemotherapeutic doxorubicin (DOX) is associated with skeletal muscle wasting and fatigue. The purpose of this study was to assess muscle function in situ following DOX administration in mice. Furthermore, pre-treatments with exercise (EX) or metformin (MET) were used in an attempt to preserve muscle function following DOX. Mice were assigned to the following groups: control, DOX, DOX + EX, or DOX + MET, and were given a single injection of DOX (15 mg/kg) or saline 3 days prior to sacrifice. Preceding the DOX injection, DOX + EX mice performed 60 min/day of running for 5 days, while DOX + MET mice received 5 daily oral doses of 500 mg/kg MET. Gastrocnemius-plantaris-soleus complex function was assessed in situ via direct stimulation of the sciatic nerve. DOX treatment increased time to half-relaxation following contractions, indicating impaired recovery ( < 0.05). Interestingly, EX prevented any increase in half-relaxation time, while MET did not. An impaired relaxation rate was associated with a reduction in SERCA1 protein content ( = 0.07) and AMPK phosphorylation ( < 0.05). There were no differences between groups in force production or mitochondrial respiration. These results suggest that EX, but not MET may be an effective strategy for the prevention of muscle fatigue following DOX administration in mice.
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http://dx.doi.org/10.3390/ijms22179163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8430759PMC
August 2021

Mice lacking melatonin MT2 receptors exhibit attentional deficits, anxiety and enhanced social interaction.

J Psychopharmacol 2021 Oct 24;35(10):1265-1276. Epub 2021 Jul 24.

Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.

Background: Aside from regulating circadian rhythms, melatonin also affects cognitive processes, such as alertness, and modulates the brain circuitry underlying psychiatric diseases, such as depression, schizophrenia and bipolar disorder, via mechanisms that are not fully clear. In particular, while melatonin MT1 receptors are thought primarily to mediate the circadian effects of the hormone, the contribution of the MT2 receptor to melatonin actions remains enigmatic.

Aims: To characterise the contribution of MT2 receptors to melatonin's effects on cognition and anxiety/sociability.

Methods: Mice with a genetic deletion of the MT2 receptor, encoded by the gene, were compared with wild-type littermates for performance in a translational touchscreen version of the continuous performance task (CPT) to assess attentional processes and then monitored over 3 days in an ethological home-cage surveillance system.

Results: knockout (KO) mice were able to perform at relatively normal levels in the CPT. However, they showed consistent evidence of more liberal/risky responding strategies relative to control mice, with increases in hit rates and false alarm rates, which were maintained even when the cognitive demands of the task were increased. Assessment in the home-cage monitoring system revealed that female KO mice have increased anxiety levels, whereas male KO mice show increased sociability.

Conclusions: The results confirm that the MT2 receptor plays a role in cognition and also modulates anxiety and social interactions. These data provide new insights into the functions of endogenous melatonin and will inform future drug development strategies focussed on the MT2 receptor.
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http://dx.doi.org/10.1177/02698811211032439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8521347PMC
October 2021

Impaired working memory, cognitive flexibility and reward processing in mice genetically lacking Gpr88: Evidence for a key role for Gpr88 in multiple cortico-striatal-thalamic circuits.

Genes Brain Behav 2021 02 3;20(2):e12710. Epub 2020 Nov 3.

Strathclyde Institute of Pharmacy and Biomedical Science, University of Strathclyde, Glasgow, G4 0RE, United Kingdom.

The GPR88 orphan G protein-coupled receptor is expressed throughout the striatum, being preferentially localised in medium spiny neurons. It is also present in lower densities in frontal cortex and thalamus. Rare mutations in humans suggest a role in cognition and motor function, while common variants are associated with psychosis. Here we evaluate the influence of genetic deletion of GPR88 upon performance in translational tasks interrogating motivation, reward evaluation and cognitive function. In an automated radial arm maze 'N-back' working memory task, Gpr88 KO mice showed impaired correct responding, suggesting a role for GPR88 receptors in working memory circuitry. Associative learning performance was similar to wild-type controls in a touchscreen task but performance was impaired at the reversal learning stage, suggesting cognitive inflexibility. Gpr88 KO mice showed higher breakpoints, reduced latencies and lengthened session time in a progressive ratio task consistent with enhanced motivation. Simultaneously, locomotor hyperactivity was apparent in this task, supporting previous findings of actions of GPR88 in a cortico-striatal-thalamic motor loop. Evidence for a role of GPR88 in reward processing was demonstrated in a touchscreen-based equivalent of the Iowa gambling task. Although both Gpr88 KO and wild-type mice showed a preference for an optimum contingency choice, Gpr88 KO mice selected more risky choices at the expense of more advantageous lower risk options. Together these novel data suggest that striatal GPR88 receptors influence activity in a range of procedures integrated by prefrontal, orbitofrontal and anterior cingulate cortico-striatal-thalamic loops leading to altered cognitive, motivational and reward evaluation processes.
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http://dx.doi.org/10.1111/gbb.12710DOI Listing
February 2021

Ketones Elicit Distinct Alterations in Adipose Mitochondrial Bioenergetics.

Int J Mol Sci 2020 Aug 29;21(17). Epub 2020 Aug 29.

Department of Physiology and Developmental Biology, Brigham Young University, Provo, UT 84602, USA.

Objective: The rampant growth of obesity worldwide has stimulated explosive research into human metabolism. Energy expenditure has been shown to be altered by diets differing in macronutrient composition, with low-carbohydrate, ketogenic diets eliciting a significant increase over other interventions. The central aim of this study was to explore the effects of the ketone β-hydroxybutyrate (βHB) on mitochondrial bioenergetics in adipose tissue.

Methods: We employed three distinct systems-namely, cell, rodent, and human models. Following exposure to elevated βHB, we obtained adipose tissue to quantify mitochondrial function.

Results: In every model, βHB robustly increased mitochondrial respiration, including an increase of roughly 91% in cultured adipocytes, 113% in rodent subcutaneous adipose tissue (SAT), and 128% in human SAT. However, this occurred without a commensurate increase in adipose ATP production. Furthermore, in cultured adipocytes and rodent adipose, we quantified and observed an increase in the gene expression involved in mitochondrial biogenesis and uncoupling status following βHB exposure.

Conclusions: In conclusion, βHB increases mitochondrial respiration, but not ATP production, in mammalian adipocytes, indicating altered mitochondrial coupling. These findings may partly explain the increased metabolic rate evident in states of elevated ketones, and may facilitate the development of novel anti-obesity interventions.
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http://dx.doi.org/10.3390/ijms21176255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7503338PMC
August 2020

Drug-responsive autism phenotypes in the 16p11.2 deletion mouse model: a central role for gene-environment interactions.

Sci Rep 2020 07 23;10(1):12303. Epub 2020 Jul 23.

Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Sir James Black Building, Glasgow, G12 8QQ, UK.

There are no current treatments for autism, despite its high prevalence. Deletions of chromosome 16p11.2 dramatically increase risk for autism, suggesting that mice with an equivalent genetic rearrangement may offer a valuable model for the testing of novel classes of therapeutic drug. 16p11.2 deletion (16p11.2 DEL) mice and wild-type controls were assessed using an ethological approach, with 24 h monitoring of activity and social interaction of groups of mice in a home-cage environment. The ability of the excitation/inhibition modulator N-acetyl cysteine (NAC) and the 5-HT receptor agonist eletriptan to normalise the behavioural deficits observed was tested. 16p11.2 DEL mice exhibited largely normal behaviours, but, following the stress of an injection, showed hyperlocomotion, reduced sociability, and a strong anxiolytic phenotype. The hyperactivity and reduced sociability, but not the suppressed anxiety, were effectively attenuated by both NAC and eletriptan. The data suggest that 16p11.2 DEL mice show an autism-relevant phenotype that becomes overt after an acute stressor, emphasising the importance of gene-environmental interactions in phenotypic analysis. Further, they add to an emerging view that NAC, or 5-HT receptor agonist treatment, may be a promising strategy for further investigation as a future treatment.
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http://dx.doi.org/10.1038/s41598-020-69130-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378168PMC
July 2020

Lack of skeletal muscle liver kinase B1 alters gene expression, mitochondrial content, inflammation and oxidative stress without affecting high-fat diet-induced obesity or insulin resistance.

Biochim Biophys Acta Mol Basis Dis 2020 08 24;1866(8):165805. Epub 2020 Apr 24.

Department of Physiology and Developmental Biology, Brigham Young University, Provo, UT 84602, USA; Department of Nutrition, Dietetics and Food Science, Brigham Young University, Provo, UT 84602, USA. Electronic address:

Ad libitum high-fat diet (HFD) induces obesity and skeletal muscle metabolic dysfunction. Liver kinase B1 (LKB1) regulates skeletal muscle metabolism by controlling the AMP-activated protein kinase family, but its importance in regulating muscle gene expression and glucose tolerance in obese mice has not been established. The purpose of this study was to determine how the lack of LKB1 in skeletal muscle (KO) affects gene expression and glucose tolerance in HFD-fed, obese mice. KO and littermate control wild-type (WT) mice were fed a standard diet or HFD for 14 weeks. RNA sequencing, and subsequent analysis were performed to assess mitochondrial content and respiration, inflammatory status, glucose and insulin tolerance, and muscle anabolic signaling. KO did not affect body weight gain on HFD, but heavily impacted mitochondria-, oxidative stress-, and inflammation-related gene expression. Accordingly, mitochondrial protein content and respiration were suppressed while inflammatory signaling and markers of oxidative stress were elevated in obese KO muscles. KO did not affect glucose or insulin tolerance. However, fasting serum insulin and skeletal muscle insulin signaling were higher in the KO mice. Furthermore, decreased muscle fiber size in skmLKB1-KO mice was associated with increased general protein ubiquitination and increased expression of several ubiquitin ligases, but not muscle ring finger 1 or atrogin-1. Taken together, these data suggest that the lack of LKB1 in skeletal muscle does not exacerbate obesity or insulin resistance in mice on a HFD, despite impaired mitochondrial content and function and elevated inflammatory signaling and oxidative stress.
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http://dx.doi.org/10.1016/j.bbadis.2020.165805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8432303PMC
August 2020

16p11 Duplication Disrupts Hippocampal-Orbitofrontal-Amygdala Connectivity, Revealing a Neural Circuit Endophenotype for Schizophrenia.

Cell Rep 2020 04;31(3):107536

Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, West Medical Building, Glasgow G12 8QQ, UK. Electronic address:

Chromosome 16p11.2 duplications dramatically increase risk for schizophrenia, but the mechanisms remain largely unknown. Here, we show that mice with an equivalent genetic mutation (16p11.2 duplication mice) exhibit impaired hippocampal-orbitofrontal and hippocampal-amygdala functional connectivity. Expression of schizophrenia-relevant GABAergic cell markers (parvalbumin and calbindin) is selectively decreased in orbitofrontal cortex, while somatostatin expression is decreased in lateral amygdala. When 16p11.2 duplication mice are tested in cognitive tasks dependent on hippocampal-orbitofrontal connectivity, performance is impaired in an 8-arm maze "N-back" working memory task and in a touchscreen continuous performance task. Consistent with hippocampal-amygdala dysconnectivity, deficits in ethologically relevant social behaviors are also observed. Overall, the cellular/molecular, brain network, and behavioral alterations markedly mirror those observed in schizophrenia patients. Moreover, the data suggest that 16p11.2 duplications selectively impact hippocampal-amygdaloid-orbitofrontal circuitry, supporting emerging ideas that dysfunction in this network is a core element of schizophrenia and defining a neural circuit endophenotype for the disease.
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http://dx.doi.org/10.1016/j.celrep.2020.107536DOI Listing
April 2020

Sestrin prevents atrophy of disused and aging muscles by integrating anabolic and catabolic signals.

Nat Commun 2020 01 13;11(1):189. Epub 2020 Jan 13.

Department of Experimental & Health Sciences, University Pompeu Fabra, CIBERNED, 08003, Barcelona, Spain.

A unique property of skeletal muscle is its ability to adapt its mass to changes in activity. Inactivity, as in disuse or aging, causes atrophy, the loss of muscle mass and strength, leading to physical incapacity and poor quality of life. Here, through a combination of transcriptomics and transgenesis, we identify sestrins, a family of stress-inducible metabolic regulators, as protective factors against muscle wasting. Sestrin expression decreases during inactivity and its genetic deficiency exacerbates muscle wasting; conversely, sestrin overexpression suffices to prevent atrophy. This protection occurs through mTORC1 inhibition, which upregulates autophagy, and AKT activation, which in turn inhibits FoxO-regulated ubiquitin-proteasome-mediated proteolysis. This study reveals sestrin as a central integrator of anabolic and degradative pathways preventing muscle wasting. Since sestrin also protected muscles against aging-induced atrophy, our findings have implications for sarcopenia.
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http://dx.doi.org/10.1038/s41467-019-13832-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6955241PMC
January 2020

Map2k7 Haploinsufficiency Induces Brain Imaging Endophenotypes and Behavioral Phenotypes Relevant to Schizophrenia.

Schizophr Bull 2020 01;46(1):211-223

Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, UK.

c-Jun N-terminal kinase (JNK) signaling contributes to functional plasticity in the brain and cognition. Accumulating evidence implicates a role for MAP kinase kinase 7 (MAP2K7), a JNK activator encoded by the Map2k7 gene, and other JNK pathway components in schizophrenia (ScZ). Mice haploinsufficient for Map2k7 (Map2k7+/- mice) display ScZ-relevant cognitive deficits, although the mechanisms are unclear. Here we show that Map2k7+/- mice display translationally relevant alterations in brain function, including hippocampal and mesolimbic system hypermetabolism with a contrasting prefrontal cortex (PFC) hypometabolism, reminiscent of patients with ScZ. In addition Map2k7+/- mice show alterations in functional brain network connectivity paralleling those reported in early ScZ, including PFC and hippocampal hyperconnectivity and compromised mesolimbic system functional connectivity. We also show that although the cerebral metabolic response to ketamine is preserved, the response to dextroamphetamine (d-amphetamine) is significantly attenuated in Map2k7+/- mice, supporting monoamine neurotransmitter system dysfunction but not glutamate/NMDA receptor (NMDA-R) dysfunction as a consequence of Map2k7 haploinsufficiency. These effects are mirrored behaviorally with an attenuated impact of d-amphetamine on sensorimotor gating and locomotion, whereas similar deficits produced by ketamine are preserved, in Map2k7+/- mice. In addition, Map2k7+/- mice show a basal hyperactivity and sensorimotor gating deficit. Overall, these data suggest that Map2k7 modifies brain and monoamine neurotransmitter system function in a manner relevant to the positive and cognitive symptoms of ScZ.
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http://dx.doi.org/10.1093/schbul/sbz044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6942167PMC
January 2020

Cannabis and hemp seed allergy.

J Allergy Clin Immunol Pract 2019 Sep - Oct;7(7):2429-2430.e1. Epub 2019 Mar 22.

Montreal General Hospital Allergy and Immunology Department, McGill University, Montreal, QC, Canada.

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http://dx.doi.org/10.1016/j.jaip.2019.02.045DOI Listing
October 2020

Multitissue analysis of exercise and metformin on doxorubicin-induced iron dysregulation.

Am J Physiol Endocrinol Metab 2019 05 19;316(5):E922-E930. Epub 2019 Mar 19.

Department of Nutrition, Dietetics, and Food Science, Brigham Young University , Provo, Utah.

Doxorubicin (DOX) is an effective chemotherapeutic treatment with lasting side effects in heart and skeletal muscle. DOX is known to bind with iron, contributing to oxidative damage resulting in cardiac and skeletal muscle toxicity. However, major cellular changes to iron regulation in response to DOX are poorly understood in liver, heart, and skeletal muscle. Additionally, two cotreatments, exercise (EX) and metformin (MET), were studied for their effectiveness in reducing DOX toxicity by ameliorating iron dysregulation and preventing oxidative stress. The purposes of this study were to ) characterize the DOX-induced changes of the major iron regulation pathway in liver, heart, and skeletal muscle and ) to determine whether EX and MET exert their benefits by minimizing DOX-induced iron dysregulation. Mice were assigned to receive saline or DOX (15 mg/kg) treatments, paired with either EX (5 days) or MET (500 mg/kg), and were euthanized 3 days after DOX treatment. Results suggest that the cellular response to DOX is protective against oxidative stress by reducing iron availability. DOX increased iron storage capacity through elevated ferritin levels in liver, heart, and skeletal muscle. DOX reduced iron transport capacity through reduced transferrin receptor levels in heart and skeletal muscle. EX and MET cotreatments had protective effects in the liver through reduced transferrin receptor levels. At 3 days after DOX, oxidative stress was mild, as shown by normal glutathione and lipid peroxidation levels. Together these results suggest that the cellular response to reduce iron availability in response to DOX treatment is sufficient to match oxidative stress.
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http://dx.doi.org/10.1152/ajpendo.00140.2018DOI Listing
May 2019

The Role of AMPK in the Regulation of Skeletal Muscle Size, Hypertrophy, and Regeneration.

Authors:
David M Thomson

Int J Mol Sci 2018 Oct 11;19(10). Epub 2018 Oct 11.

Department of Physiology & Developmental Biology, Brigham Young University, Provo, UT 84602, USA.

AMPK (5'-adenosine monophosphate-activated protein kinase) is heavily involved in skeletal muscle metabolic control through its regulation of many downstream targets. Because of their effects on anabolic and catabolic cellular processes, AMPK plays an important role in the control of skeletal muscle development and growth. In this review, the effects of AMPK signaling, and those of its upstream activator, liver kinase B1 (LKB1), on skeletal muscle growth and atrophy are reviewed. The effect of AMPK activity on satellite cell-mediated muscle growth and regeneration after injury is also reviewed. Together, the current data indicate that AMPK does play an important role in regulating muscle mass and regeneration, with AMPKα1 playing a prominent role in stimulating anabolism and in regulating satellite cell dynamics during regeneration, and AMPKα2 playing a potentially more important role in regulating muscle degradation during atrophy.
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http://dx.doi.org/10.3390/ijms19103125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6212977PMC
October 2018

β-Hydroxybutyrate Elicits Favorable Mitochondrial Changes in Skeletal Muscle.

Int J Mol Sci 2018 Aug 1;19(8). Epub 2018 Aug 1.

Department of Physiology and Developmental Biology, Brigham Young University, Provo, UT 84604, USA.

The clinical benefit of ketosis has historically and almost exclusively centered on neurological conditions, lending insight into how ketones alter mitochondrial function in neurons. However, there is a gap in our understanding of how ketones influence mitochondria within skeletal muscle cells. The purpose of this study was to elucidate the specific effects of β-hydroxybutyrate (β-HB) on muscle cell mitochondrial physiology. In addition to increased cell viability, murine myotubes displayed beneficial mitochondrial changes evident in reduced H₂O₂ emission and less mitochondrial fission, which may be a result of a β-HB-induced reduction in ceramides. Furthermore, muscle from rats in sustained ketosis similarly produced less H₂O₂ despite an increase in mitochondrial respiration and no apparent change in mitochondrial quantity. In sum, these results indicate a general improvement in muscle cell mitochondrial function when β-HB is provided as a fuel.
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http://dx.doi.org/10.3390/ijms19082247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6121962PMC
August 2018

Disruption of the Zdhhc9 intellectual disability gene leads to behavioural abnormalities in a mouse model.

Exp Neurol 2018 10 23;308:35-46. Epub 2018 Jun 23.

Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, United Kingdom. Electronic address:

Protein S-acylation is a widespread post-translational modification that regulates the trafficking and function of a diverse array of proteins. This modification is catalysed by a family of twenty-three zDHHC enzymes that exhibit both specific and overlapping substrate interactions. Mutations in the gene encoding zDHHC9 cause mild-to-moderate intellectual disability, seizures, speech and language impairment, hypoplasia of the corpus callosum and reduced volume of sub-cortical structures. In this study, we have undertaken behavioural phenotyping, magnetic resonance imaging (MRI) and isolation of S-acylated proteins to investigate the effect of disruption of the Zdhhc9 gene in mice in a C57BL/6 genetic background. Zdhhc9 mutant male mice exhibit a range of abnormalities compared with their wild-type littermates: altered behaviour in the open-field test, elevated plus maze and acoustic startle test that is consistent with a reduced anxiety level; a reduced hang time in the hanging wire test that suggests underlying hypotonia but which may also be linked to reduced anxiety; deficits in the Morris water maze test of hippocampal-dependent spatial learning and memory; and a 36% reduction in corpus callosum volume revealed by MRI. Surprisingly, membrane association and S-acylation of H-Ras was not disrupted in either whole brain or hippocampus of Zdhhc9 mutant mice, suggesting that other substrates of this enzyme are linked to the observed changes. Overall, this study highlights a key role for zDHHC9 in brain development and behaviour, and supports the utility of the Zdhhc9 mutant mouse line to investigate molecular and cellular changes linked to intellectual disability and other deficits in the human population.
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http://dx.doi.org/10.1016/j.expneurol.2018.06.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6104741PMC
October 2018

Induced Cre-mediated knockdown of Brca1 in skeletal muscle reduces mitochondrial respiration and prevents glucose intolerance in adult mice on a high-fat diet.

FASEB J 2018 06 26;32(6):3070-3084. Epub 2018 Jan 26.

Department of Kinesiology, School of Public Health, University of Maryland, College Park, Maryland, USA.

The breast cancer type 1 susceptibility protein (Brca1) is a regulator of DNA repair in mammary gland cells; however, recent cell culture evidence suggests that Brca1 influences other processes, including those in nonmammary cells. In this study, we sought to determine whether Brca1 is necessary for metabolic regulation of skeletal muscle using a novel in vivo mouse model. We developed an inducible skeletal muscle-specific Brca1knockout (BRCA1KO) model to test whether Brca1 expression is necessary for maintenance of metabolic function of skeletal muscle when exposed to a high-fat diet (HFD). Our data demonstrated that deletion of Brca1 prevented HFD-induced alterations in glucose and insulin tolerance. Irrespective of diet, BRCA1KO mice exhibited significantly lower ADP-stimulated complex I mitochondrial respiration rates compared to age-matched wild-type (WT) mice. The data show that Brca1 has the ability to localize to the mitochondria in skeletal muscle and that BRCA1KO mice exhibit higher whole-body CO production, respiratory exchange ratio, and energy expenditure, compared with the WT mice. Our results demonstrate that loss of Brca1 in skeletal muscle leads to dysregulated metabolic function, characterized by decreased mitochondrial respiration. Thus, any condition that results in loss of Brca1 function could induce metabolic imbalance in skeletal muscle.-Jackson, K. C., Tarpey, M. D., Valencia, A. P., Iñigo, M. R., Pratt, S. J., Patteson, D. J., McClung, J. M., Lovering, R. M., Thomson, D. M., Spangenburg, E. E. Induced Cre-mediated knockdown of Brca1 in skeletal muscle reduces mitochondrial respiration and prevents glucose intolerance in adult mice on a high-fat diet.
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http://dx.doi.org/10.1096/fj.201700464RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5956240PMC
June 2018

The effect of caffeine on skeletal muscle anabolic signaling and hypertrophy.

Appl Physiol Nutr Metab 2017 Jun 26;42(6):621-629. Epub 2017 Jan 26.

Department of Physiology and Developmental Biology, 4005 LSB, Brigham Young University, Provo, UT 84602, USA.

Caffeine is a widely consumed stimulant with the potential to enhance physical performance through multiple mechanisms. However, recent in vitro findings have suggested that caffeine may block skeletal muscle anabolic signaling through AMP-activated protein kinase (AMPK)-mediated inhibition of mechanistic target of rapamycin (mTOR) signaling pathway. This could negatively affect protein synthesis and the capacity for muscle growth. The primary purpose of this study was to assess the effect of caffeine on in vivo AMPK and mTOR pathway signaling, protein synthesis, and muscle growth. In cultured C2C12 muscle cells, physiological levels of caffeine failed to impact mTOR activation or myoblast proliferation or differentiation. We found that caffeine administration to mice did not significantly enhance the phosphorylation of AMPK or inhibit signaling proteins downstream of mTOR (p70S6k, S6, or 4EBP1) or protein synthesis after a bout of electrically stimulated contractions. Skeletal muscle-specific knockout of LKB1, the primary AMPK activator in skeletal muscle, on the other hand, eliminated AMPK activation by contractions and enhanced S6k, S6, and 4EBP1 activation before and after contractions. In rats, the addition of caffeine did not affect plantaris hypertrophy induced by the tenotomy of the gastrocnemius and soleus muscles. In conclusion, caffeine administration does not impair skeletal muscle load-induced mTOR signaling, protein synthesis, or muscle hypertrophy.
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http://dx.doi.org/10.1139/apnm-2016-0547DOI Listing
June 2017

Liver kinase B1 inhibits the expression of inflammation-related genes postcontraction in skeletal muscle.

J Appl Physiol (1985) 2016 Apr 21;120(8):876-88. Epub 2016 Jan 21.

Department of Physiology and Developmental Biology, Brigham Young University, Provo, Utah;

Skeletal muscle-specific liver kinase B1 (LKB1) knockout mice (skmLKB1-KO) exhibit elevated mitogen-activated protein kinase (MAPK) signaling after treadmill running. MAPK activation is also associated with inflammation-related signaling in skeletal muscle. Since exercise can induce muscle damage, and inflammation is a response triggered by damaged tissue, we therefore hypothesized that LKB1 plays an important role in dampening the inflammatory response to muscle contraction, and that this may be due in part to increased susceptibility to muscle damage with contractions in LKB1-deficient muscle. Here we studied the inflammatory response and muscle damage with in situ muscle contraction or downhill running. After in situ muscle contractions, the phosphorylation of both NF-κB and STAT3 was increased more in skmLKB1-KO vs. wild-type (WT) muscles. Analysis of gene expression via microarray and RT-PCR shows that expression of many inflammation-related genes increased after contraction only in skmLKB1-KO muscles. This was associated with mild skeletal muscle fiber membrane damage in skmLKB1-KO muscles. Gene markers of oxidative stress were also elevated in skmLKB1-KO muscles after contraction. Using the downhill running model, we observed significantly more muscle damage after running in skmLKB1-KO mice, and this was associated with greater phosphorylation of both Jnk and STAT3 and increased expression of SOCS3 and Fos. In conclusion, we have shown that the lack of LKB1 in skeletal muscle leads to an increased inflammatory state in skeletal muscle that is exacerbated by muscle contraction. Increased susceptibility of the muscle to damage may underlie part of this response.
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http://dx.doi.org/10.1152/japplphysiol.00727.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5005267PMC
April 2016

The zDHHC family of S-acyltransferases.

Biochem Soc Trans 2015 Apr;43(2):217-21

*Strathclyde Institute of Pharmacy & Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, U.K.

The discovery of the zDHHC family of S-acyltransferase enzymes has been one of the major breakthroughs in the S-acylation field. Now, more than a decade since their discovery, major questions centre on profiling the substrates of individual zDHHC enzymes (there are 24 ZDHHC genes and several hundred S-acylated proteins), defining the mechanisms of enzyme-substrate specificity and unravelling the importance of this enzyme family for cellular physiology and pathology.
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http://dx.doi.org/10.1042/BST20140270DOI Listing
April 2015

Metabolic-stress-induced rearrangement of the 14-3-3ζ interactome promotes autophagy via a ULK1- and AMPK-regulated 14-3-3ζ interaction with phosphorylated Atg9.

Mol Cell Biol 2014 Dec 29;34(24):4379-88. Epub 2014 Sep 29.

Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah, USA

14-3-3ζ promotes cell survival via dynamic interactions with a vast network of binding partners, many of which are involved in stress regulation. We show here that hypoxia (low glucose and oxygen) triggers a rearrangement of the 14-3-3ζ interactome to favor an interaction with the core autophagy regulator Atg9A. Our data suggest that the localization of mammalian Atg9A to autophagosomes requires phosphorylation on the C terminus of Atg9A at S761, which creates a 14-3-3ζ docking site. Under basal conditions, this phosphorylation is maintained at a low level and is dependent on both ULK1 and AMPK. However, upon induction of hypoxic stress, activated AMPK bypasses the requirement for ULK1 and mediates S761 phosphorylation directly, resulting in an increase in 14-3-3ζ interactions, recruitment of Atg9A to LC3-positive autophagosomes, and enhanced autophagosome production. These data suggest a novel mechanism whereby the level of autophagy induction can be modulated by AMPK/ULK1-mediated phosphorylation of mammalian Atg9A.
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http://dx.doi.org/10.1128/MCB.00740-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4248729PMC
December 2014

Fixed drug eruption to quinine: a case report and review of the literature.

J Allergy Clin Immunol Pract 2014 Jul-Aug;2(4):469-70. Epub 2014 Apr 25.

Montreal General Hospital Allergy and Immunology Department, McGill University, Montreal, Quebec, Canada.

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http://dx.doi.org/10.1016/j.jaip.2014.02.013DOI Listing
April 2015

The effects of age and muscle contraction on AMPK activity and heterotrimer composition.

Exp Gerontol 2014 Jul 18;55:120-8. Epub 2014 Apr 18.

Department of Physiology and Developmental Biology, Brigham Young University, Provo, UT, 84602, USA. Electronic address:

Sarcopenia is characterized by increased skeletal muscle atrophy due in part to alterations in muscle metabolism. AMP-activated protein kinase (AMPK) is a master regulator of skeletal muscle metabolic pathways which regulate many cellular processes that are disrupted in old-age. Functional AMPK is a heterotrimer composed of α, β and γ subunits, and each subunit can be represented in the heterotrimer by one of two (α1/α2, β1/β2) or three (γ1/γ2/γ3) isoforms. Altered isoform composition affects AMPK localization and function. Previous work has shown that overall AMPK activation with endurance-type exercise is blunted in old vs. young skeletal muscle. However, details regarding the activation of the specific isoforms of AMPK, as well as the heterotrimeric composition of AMPK in old skeletal muscle, are unknown. Our purpose here, therefore, was to determine the effect of old-age on 1) the activation of the α1 and α2 catalytic subunits of AMPK in skeletal muscle by a continuous contraction bout, and 2) the heterotrimeric composition of skeletal muscle AMPK. We studied gastrocnemius (GAST) and tibialis anterior (TA) muscles from young adult (YA; 8months old) and old (O; 30months old) male Fischer344×Brown Norway F1 hybrid rats after an in situ bout of endurance-type contractions produced via electrical stimulation of the sciatic nerve (STIM). AMPKα phosphorylation and AMPKα1 and α2 activities were unaffected by age at rest. However, AMPKα phosphorylation and AMPKα2 protein content and activity were lower in O vs. YA after STIM. Conversely, AMPKα1 content was greater in O vs. YA muscle, and α1 activity increased with STIM in O but not YA muscles. AMPKγ3 overall concentration and its association with AMPKα1 and α2 were lower in O vs. YA GAST. We conclude that activation of AMPKα1 is enhanced, while activation of α2 is suppressed immediately after repeated skeletal muscle contractions in O vs. YA skeletal muscle. These changes are associated with changes in the AMPK heterotrimer composition. Given the known roles of AMPK α1, α2 and γ3, this may contribute to sarcopenia and associated muscle metabolic dysfunction.
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http://dx.doi.org/10.1016/j.exger.2014.04.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4081450PMC
July 2014

BRCA1 is a novel regulator of metabolic function in skeletal muscle.

J Lipid Res 2014 Apr 24;55(4):668-80. Epub 2014 Feb 24.

Department of Kinesiology, School of Public Health, University of Maryland, College Park, MD.

Breast cancer type 1 (BRCA1) susceptibility protein is expressed across multiple tissues including skeletal muscle. The overall objective of this investigation was to define a functional role for BRCA1 in skeletal muscle using a translational approach. For the first time in both mice and humans, we identified the presence of multiple isoforms of BRCA1 in skeletal muscle. In response to an acute bout of exercise, we found increases in the interaction between the native forms of BRCA1 and the phosphorylated form of acetyl-CoA carboxylase. Decreasing BRCA1 content using a shRNA approach in cultured primary human myotubes resulted in decreased oxygen consumption by the mitochondria and increased reactive oxygen species production. The decreased BRCA1 content also resulted in increased storage of intracellular lipid and reduced insulin signaling. These results indicate that BRCA1 plays a critical role in the regulation of metabolic function in skeletal muscle. Collectively, these data reveal BRCA1 as a novel target to consider in our understanding of metabolic function and risk for development of metabolic-based diseases.
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http://dx.doi.org/10.1194/jlr.M043851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3966701PMC
April 2014

Mitochondrial and performance adaptations to exercise training in mice lacking skeletal muscle LKB1.

Am J Physiol Endocrinol Metab 2013 Oct 27;305(8):E1018-29. Epub 2013 Aug 27.

Department of Physiology and Developmental Biology, Brigham Young University, Provo, Utah.

LKB1 and its downstream targets of the AMP-activated protein kinase family are important regulators of many aspects of skeletal muscle cell function, including control of mitochondrial content and capillarity. LKB1 deficiency in skeletal and cardiac muscle (mLKB1-KO) greatly impairs exercise capacity. However, cardiac dysfunction in that genetic model prevents a clear assessment of the role of skeletal muscle LKB1 in the observed effects. Our purposes here were to determine whether skeletal muscle-specific knockout of LKB1 (skmLKB1-KO) decreases exercise capacity and mitochondrial protein content, impairs accretion of mitochondrial proteins after exercise training, and attenuates improvement in running performance after exercise training. We found that treadmill and voluntary wheel running capacity was reduced in skmLKB1-KO vs. control (CON) mice. Citrate synthase activity, succinate dehydrogenase activity, and pyruvate dehydrogenase kinase content were lower in KO vs. CON muscles. Three weeks of treadmill training resulted in significantly increased treadmill running performance in both CON and skmLKB1-KO mice. Citrate synthase activity increased significantly with training in both genotypes, but protein content and activity for components of the mitochondrial electron transport chain increased only in CON mice. Capillarity and VEGF protein was lower in skmLKB1-KO vs. CON muscles, but VEGF increased with training only in skmLKB1-KO. Three hours after an acute bout of muscle contractions, PGC-1α, cytochrome c, and VEGF gene expression all increased in CON but not skmLKB1-KO muscles. Our findings indicate that skeletal muscle LKB1 is required for accretion of some mitochondrial proteins but not for early exercise capacity improvements with exercise training.
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http://dx.doi.org/10.1152/ajpendo.00227.2013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3798697PMC
October 2013

The effects of chronic AMPK activation on hepatic triglyceride accumulation and glycerol 3-phosphate acyltransferase activity with high fat feeding.

Diabetol Metab Syndr 2013 31;5:29. Epub 2013 May 31.

Department of Nutrition, Dietetics, and Food Science, Brigham Young University, Provo, UT 84602, USA.

Background: High fat feeding increases hepatic fat accumulation and is associated with hepatic insulin resistance. AMP Activated Protein Kinase (AMPK) is thought to inhibit lipid synthesis by the acute inhibition of glycerol-3-phosphate acyltransferase (GPAT) activity and transcriptional regulation via sterol regulatory element binding protein-1c (SREBP-1c).

Methods: The purpose of this study was to determine if chronic activation of AMPK prevented an increase in GPAT1 activity in rats fed a high fat diet. Rats were fed a control (C), or a high fat (HF) diet (60% fat) for 6 weeks and injected with saline or a daily aminoimidazole carboxamide ribnucleotide (AICAR) dose of 0.5 mg/g body weight.

Results: Chronic AMPK activation by AICAR injections resulted in a significant reduction in hepatic triglyceride accumulation in both the C and HF fed animals (C, 5.5±0.7; C+AICAR, 2.7 ±0.3; HF, 21.8±3.3; and HF+AICAR, 8.0±1.8 mg/g liver). HF feeding caused an increase in total GPAT and GPAT1 activity, which was not affected by chronic AMPK activation (GPAT1 activity vs. C, C+AICAR, 92±19%; HF, 186±43%; HF+AICAR, 234±62%). Markers of oxidative capacity, including citrate synthase activity and cytochrome c abundance, were not affected by chronic AICAR treatment. Interestingly, HF feeding caused a significant increase in long chain acyl-CoA dehydrogenase or LCAD (up 66% from C), a marker of fatty acid oxidation capacity.

Conclusions: These results suggest that chronic AMPK activation limits hepatic triglyceride accumulation independent of a reduction in total GPAT1 activity.
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http://dx.doi.org/10.1186/1758-5996-5-29DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3679947PMC
May 2014

LKB1 regulates lipid oxidation during exercise independently of AMPK.

Diabetes 2013 May 24;62(5):1490-9. Epub 2013 Jan 24.

August Krogh Centre and Molecular Physiology Group, Department of Exercise and Sport Sciences, University of Copenhagen, Copenhagen, Denmark.

Lipid metabolism is important for health and insulin action, yet the fundamental process of regulating lipid metabolism during muscle contraction is incompletely understood. Here, we show that liver kinase B1 (LKB1) muscle-specific knockout (LKB1 MKO) mice display decreased fatty acid (FA) oxidation during treadmill exercise. LKB1 MKO mice also show decreased muscle SIK3 activity, increased histone deacetylase 4 expression, decreased NAD⁺ concentration and SIRT1 activity, and decreased expression of genes involved in FA oxidation. In AMP-activated protein kinase (AMPK)α2 KO mice, substrate use was similar to that in WT mice, which excluded that decreased FA oxidation in LKB1 MKO mice was due to decreased AMPKα2 activity. Additionally, LKB1 MKO muscle demonstrated decreased FA oxidation in vitro. A markedly decreased phosphorylation of TBC1D1, a proposed regulator of FA transport, and a low CoA content could contribute to the low FA oxidation in LKB1 MKO. LKB1 deficiency did not reduce muscle glucose uptake or oxidation during exercise in vivo, excluding a general impairment of substrate use during exercise in LKB1 MKO mice. Our findings demonstrate that LKB1 is a novel molecular regulator of major importance for FA oxidation but not glucose uptake in muscle during exercise.
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http://dx.doi.org/10.2337/db12-1160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3636614PMC
May 2013

Ectopic lipid deposition and the metabolic profile of skeletal muscle in ovariectomized mice.

Am J Physiol Regul Integr Comp Physiol 2013 Feb 28;304(3):R206-17. Epub 2012 Nov 28.

Univ. of Maryland, School of Public Health, Dept. of Kinesiology, College Park, MD 20742, USA.

Disruptions of ovarian function in women are associated with increased risk of metabolic disease due to dysregulation of peripheral glucose homeostasis in skeletal muscle. Our previous evidence suggests that alterations in skeletal muscle lipid metabolism coupled with altered mitochondrial function may also develop. The objective of this study was to use an integrative metabolic approach to identify potential areas of dysfunction that develop in skeletal muscle from ovariectomized (OVX) female mice compared with age-matched ovary-intact adult female mice (sham). The OVX mice exhibited significant increases in body weight, visceral, and inguinal fat mass compared with sham mice. OVX mice also had significant increases in skeletal muscle intramyocellular lipids (IMCL) compared with the sham animals, which corresponded to significant increases in the protein content of the fatty acid transporters CD36/FAT and FABPpm. A targeted metabolic profiling approach identified significantly lower levels of specific acyl carnitine species and various amino acids in skeletal muscle from OVX mice compared with the sham animals, suggesting a potential dysfunction in lipid and amino acid metabolism, respectively. Basal and maximal mitochondrial oxygen consumption rates were significantly impaired in skeletal muscle fibers from OVX mice compared with sham animals. Collectively, these data indicate that loss of ovarian function results in increased IMCL storage that is coupled with alterations in mitochondrial function and changes in the skeletal muscle metabolic profile.
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http://dx.doi.org/10.1152/ajpregu.00428.2012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3567349PMC
February 2013

Iron deficiency causes a shift in AMP-activated protein kinase (AMPK) subunit composition in rat skeletal muscle.

Nutr Metab (Lond) 2012 Nov 21;9(1):104. Epub 2012 Nov 21.

Department of Nutrition, Dietetics, and Food Science, Brigham Young University, Provo, Utah, USA.

Unlabelled:

Background: As a cellular energy sensor, the 5'AMP-activated protein kinase (AMPK) is activated in response to energy stresses such as hypoxia and muscle contraction. To determine effects of iron deficiency on AMPK activation and signaling, as well as the AMPK subunit composition in skeletal muscle, rats were fed a control (C=50-58 mg/kg Fe) or iron deficient (ID=2-6 mg/kg Fe) diet for 6-8 wks.

Results: Their respective hematocrits were 47.5% ± 1.0 and 16.5% ± 0.6. Iron deficiency resulted in 28.3% greater muscle fatigue (p<0.01) in response to 10 min of stimulation (1 twitch/sec) and was associated with a greater reduction in phosphocreatine (C: Resting 24.1 ± 0.9 μmol/g, Stim 13.1 ± 1.5 μmol/g; ID: Resting 22.7 ± 1.0 μmol/g, Stim 3.2 ± 0.7 μmol/g; p<0.01) and ATP levels (C: Resting 5.89 ± 0.48 μmol/g, Stim 6.03 ± 0.35 μmol/g; ID: Resting 5.51 ± 0.20 μmol/g, Stim 4.19 ± 0.47 μmol/g; p<0.05). AMPK activation increased with stimulation in muscles of C and ID animals. A reduction in Cytochrome c and other iron-dependent mitochondrial proteins was observed in ID animals (p<0.01). The AMPK catalytic subunit (α) was examined because both isoforms are known to play different roles in responding to energy challenges. In ID animals, AMPKα2 subunit protein content was reduced to 71.6% of C (p<0.05), however this did not result in a significant difference in resting AMPKα2 activity. AMPKα1 protein was unchanged, however an overall increase in AMPKα1 activity was observed (C: 0.91 pmol/mg/min; ID: 1.63 pmol/mg/min; p<0.05). Resting phospho Acetyl CoA Carboxylase (pACC) was unchanged. In addition, we observed significant reductions in the β2 and γ3 subunits of AMPK in response to iron deficiency.

Conclusions: This study indicates that chronic iron deficiency causes a shift in the expression of AMPKα, β, and γ subunit composition. Iron deficiency also causes chronic activation of AMPK as well as an increase in AMPKα1 activity in exercised skeletal muscle.
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http://dx.doi.org/10.1186/1743-7075-9-104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3575277PMC
November 2012

Phosphorylation of VASP by AMPK alters actin binding and occurs at a novel site.

Biochem Biophys Res Commun 2011 Oct 17;414(1):215-9. Epub 2011 Sep 17.

Physiology and Developmental Biology, Brigham Young University, 574 WIDB, Provo, UT 84602, USA.

Vasodilator-stimulated phosphoprotein (VASP) is an actin regulatory protein that functions in adhesion and migration. In epithelial cells, VASP participates in cell-cell adhesion. At the molecular level, VASP drives actin bundling and polymerization. VASP activity is primarily regulated by phosphorylation. Three physiologically relevant phosphorylation sites significantly reduce actin regulatory activity and are targeted by several kinases, most notable Abl and protein kinases A and G (PKA and PKG). AMP-dependent kinase (AMPK) is best characterized as a cellular sensor of ATP depletion, but also alters actin dynamics in epithelial cells and participates in cell polarity pathways downstream of LKB1. While little is known about how AMPK direct changes in actin dynamics, AMPK has been shown to phosphorylate VASP at one of these three well-characterized PKA/PKG phosphorylation sites. Here we show that phosphorylation of VASP by AMPK occurs at a novel site, serine 322, and that phosphorylation at this site alters actin filament binding. We also show that inhibition of AMPK activity results in the accumulation of VASP at cell-cell adhesions and a concomitant increase in cell-cell adhesion.
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http://dx.doi.org/10.1016/j.bbrc.2011.09.059DOI Listing
October 2011

Characterization of the liver kinase B1-mouse protein-25 -Ste-20-related adaptor protein complex in adult mouse skeletal muscle.

J Appl Physiol (1985) 2011 Dec 8;111(6):1622-8. Epub 2011 Sep 8.

Department of Physiology and Developmental Biology, Brigham Young University, Provo, Utah, USA.

In liver, the AMP-activated protein kinase kinase (AMPKK) complex was identified as the association of liver kinase B1 (LKB1), mouse protein 25 (MO25α/β), and Ste-20-related adaptor protein (STRADα/β); however, this complex has yet to be characterized in skeletal muscle. We demonstrate the expression of the LKB1-MO25-STRAD complex in skeletal muscle, confirm the absence of mRNA splice variants, and report the relative mRNA expression levels of these proteins in control and muscle-specific LKB1 knockout (LKB1(-/-)) mouse muscle. LKB1 detection in untreated control and LKB1(-/-) muscle lysates revealed two protein bands (50 and 60 kDa), although only the heavier band was diminished in LKB1(-/-) samples [55 ± 2.5 and 13 ± 1.5 arbitrary units (AU) in control and LKB1(-/-), respectively, P < 0.01], suggesting that LKB1 is not represented at 50 kDa, as previously cited. The 60-kDa LKB1 band was further confirmed following purification using polyethylene glycol (43 ± 5 and 8.4 ± 4 AU in control and LKB1(-/-), respectively, P < 0.01) and ion-exchange fast protein liquid chromatography. Mass spectrometry confirmed LKB1 protein detection in the 60-kDa protein band, while none was detected in the 50-kDa band. Coimmunoprecipitation assays demonstrated LKB1-MO25-STRAD complex formation. Quantitative PCR revealed significantly reduced LKB1, MO25α, and STRADβ mRNA in LKB1(-/-) muscle. These findings demonstrate that the LKB1-MO25-STRAD complex is the principal AMPKK in skeletal muscle.
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http://dx.doi.org/10.1152/japplphysiol.00160.2011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3233888PMC
December 2011
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