Exercise-induced AMPK and pyruvate dehydrogenase regulation is maintained during short-term low-grade inflammation.

The aim of the present study was to examine the effect of lipopolysaccharide (LPS)-induced inflammation on AMP-activated protein kinase (AMPK) and pyruvate dehydrogenase (PDH) regulation in human skeletal muscle at rest and during exercise. Nine young healthy physically inactive male subjects completed two trials. In an LPS trial, the subjects received a single LPS injection (0.3 ng/kg body weight) and blood samples and vastus lateralis muscle biopsies were obtained before and 2 h after the LPS injection and immediately after a 10-min one-legged knee extensor exercise bout performed approximately 2½ h after the LPS injection. The exercise bout with muscle samples obtained before and immediately after was repeated in a control trial without LPS injection. The plasma tumor necrosis factor α concentration increased 17-fold 2 h after LPS relative to before. Muscle lactate and muscle glycogen were unchanged from before to 2 h after LPS and exercise increased muscle lactate and decreased muscle glycogen in the control (P < 0.05) and the LPS (0.05 ≤ P < 0.1) trial with no differences between the trials. AMPK, acetyl-CoA carboxylase (ACC) and PDH phosphorylation as well as PDHa activity were unaffected 2 h after LPS relative to before. Exercise decreased (P < 0.05) PDH and increased (P < 0.05) AMPK and ACC phosphorylation as well as increased (P < 0.05) PDHa activity similarly in the LPS and control trial. In conclusion, LPS-induced inflammation does not affect resting or exercise-induced AMPK and PDH regulation in human skeletal muscle. This suggests that metabolic flexibility during exercise is maintained during short-term low-grade inflammation in humans.

Mechanisms behind the superior effects of interval vs continuous training on glycaemic control in individuals with type 2 diabetes: a randomised controlled trial.

AIMS/HYPOTHESIS: By use of a parallel and partly crossover randomised, controlled trial design we sought to elucidate the underlying mechanisms behind the advantageous effects of interval walking training (IWT) compared with continuous walking training (CWT) on glycaemic control in individuals with type 2 diabetes. We hypothesised that IWT, more than CWT, would improve insulin sensitivity including skeletal muscle insulin signalling, insulin secretion and disposition index (DI). METHODS: By simple randomisation (sequentially numbered, opaque sealed envelopes), eligible individuals (diagnosed with type 2 diabetes, no exogenous insulin treatment) were allocated to three groups: a control group (CON, n = 8), an IWT group (n = 12) and an energy expenditure-matched CWT group (n = 12). Training groups were prescribed free-living training, five sessions per week (60 min/session). A three-stage hyperglycaemic clamp, including glucose isotope tracers and skeletal muscle biopsies, was performed before and after a 4 month intervention in a hospitalised setting. No blinding was performed. RESULTS: The improved glycaemic control, which was only seen in the IWT group, was consistent with IWT-induced increases in insulin sensitivity index (49.8 ± 14.6%; p < 0.001), peripheral glucose disposal (14.5 ± 4.9%; p < 0.05) and DI (66.2 ± 21.8%; p < 0.001), with no changes in the CWT or CON group. Moreover, only IWT improved insulin signalling in skeletal muscle via increased insulin-stimulated phosphorylation of AS160 (29.0 ± 10.8%; p < 0.05). No changes were seen in insulin secretion during hyperglycaemia alone, hyperglycaemia + glucagon-like peptide 1 infusion or arginine injection. CONCLUSIONS/INTERPRETATION: IWT maintains insulin secretion and improves insulin sensitivity and DI, in contrast to energy expenditure-matched CWT. These results suggest that training with alternating intensity, and not just training volume and mean intensity, is a key determinant of changes in whole body glucose disposal in individuals with type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials (NCT01234155).

Exercise training, but not resveratrol, improves metabolic and inflammatory status in skeletal muscle of aged men.

The aim was to investigate the metabolic and anti-inflammatory effects of resveratrol alone and when combined with exercise training in skeletal muscle of aged human subjects. Healthy, physically inactive men (60-72 years old) were randomized to either 8 weeks of daily intake of 250 mg resveratrol or placebo or to 8 weeks of high-intensity exercise training with 250 mg resveratrol or placebo. Before and after the interventions, resting blood samples and muscle biopsies were obtained and a one-legged knee-extensor endurance exercise test was performed. Exercise training increased skeletal muscle peroxisome proliferator-activated receptor-γ co-activator-1α mRNA ~1.5-fold, cytochrome c protein ~1.3-fold, cytochrome c oxidase I protein ~1.5-fold, citrate synthase activity ~1.3-fold, 3-hydroxyacyl-CoA dehydrogenase activity ~1.3-fold, inhibitor of κB-α and inhibitor of κB-ß protein content ~1.3-fold and time to exhaustion in the one-legged knee-extensor endurance exercise test by ∼1.2-fold, with no significant additive or adverse effects of resveratrol on these parameters. Despite an overall ~25% reduction in total acetylation level in skeletal muscle with resveratrol, no exclusive resveratrol-mediated metabolic effects were observed on the investigated parameters. Notably, however, resveratrol blunted an exercise training-induced decrease (~20%) in protein carbonylation and decrease (~40%) in tumour necrosis factor α mRNA content in skeletal muscle. In conclusion, resveratrol did not elicit metabolic improvements in healthy aged subjects; in fact, resveratrol even impaired the observed exercise training-induced improvements in markers of oxidative stress and inflammation in skeletal muscle. Collectively, this highlights the metabolic efficacy of exercise training in aged subjects and does not support the contention that resveratrol is a potential exercise mimetic in healthy aged subjects.

Resveratrol modulates the angiogenic response to exercise training in skeletal muscles of aged men.

In animal studies, the polyphenol resveratrol has been shown to influence several pathways of importance for angiogenesis in skeletal muscle. The aim of the present study was to examine the angiogenic effect of resveratrol supplementation with parallel exercise training in aged men. Forty-three healthy physically inactive aged men (65 ± 1 yr) were divided into 1) a training group that conducted 8 wk of intense exercise training where half of the subjects received a daily intake of either 250 mg trans-resveratrol (n = 14) and the other half received placebo (n = 13) and 2) a nontraining group that received either 250 mg trans-resveratrol (n = 9) or placebo (n = 7). The group that trained with placebo showed a ~20% increase in the capillary-to-fiber ratio, an increase in muscle protein expression of VEGF, VEGF receptor-2, and tissue inhibitor of matrix metalloproteinase (TIMP-1) but unaltered thrombospodin-1 levels. Muscle interstitial VEGF and thrombospodin-1 protein levels were unchanged after the training period. The group that trained with resveratrol supplementation did not show an increase in the capillary-to-fiber ratio or an increase in muscle VEGF protein. Muscle TIMP-1 protein levels were lower in the training and resveratrol group than in the training and placebo group. Both training groups showed an increase in forkhead box O1 protein. In nontraining groups, TIMP-1 protein was lower in the resveratrol-treated group than the placebo-treated group after 8 wk. In conclusion, these data show that exercise training has a strong angiogenic effect, whereas resveratrol supplementation may limit basal and training-induced angiogenesis.

Resveratrol blunts the positive effects of exercise training on cardiovascular health in aged men.

Ageing is thought to be associated with decreased vascular function partly due to oxidative stress. Resveratrol is a polyphenol, which in animal studies has been shown to decrease atherosclerosis, and improve cardiovascular health and physical capacity, in part through its effects on Sirtuin 1 signalling and through an improved antioxidant capacity. We tested the hypothesis that resveratrol supplementation enhances training-induced improvements in cardiovascular health parameters in aged men. Twenty-seven healthy physically inactive aged men (age: 65 ± 1 years; body mass index: 25.4 ± 0.7 kg m(-2); mean arterial pressure (MAP): 95.8 ± 2.2 mmHg; maximal oxygen uptake: 2488 ± 72 ml O2 min(-1)) were randomized into 8 weeks of either daily intake of either 250 mg trans-resveratrol (n = 14) or of placebo (n = 13) concomitant with high-intensity exercise training. Exercise training led to a 45% greater (P < 0.05) increase in maximal oxygen uptake in the placebo group than in the resveratrol group and to a decrease in MAP in the placebo group only (-4.8 ± 1.7 mmHg; P < 0.05). The interstitial level of vasodilator prostacyclin was lower in the resveratrol than in the placebo group after training (980 ± 90 vs. 1174 ± 121 pg ml(-1); P < 0.02) and muscle thromboxane synthase was higher in the resveratrol group after training (P < 0.05). Resveratrol administration also abolished the positive effects of exercise on low-density lipoprotein, total cholesterol/high-density lipoprotein ratio and triglyceride concentrations in blood (P < 0.05). Resveratrol did not alter the effect of exercise training on the atherosclerosis marker vascular cell adhesion molecule 1 (VCAM-1). Sirtuin 1 protein levels were not affected by resveratrol supplementation. These findings indicate that, whereas exercise training effectively improves several cardiovascular health parameters in aged men, concomitant resveratrol supplementation can blunt these effects.

Exercise-induced liver chemokine CXCL-1 expression is linked to muscle-derived interleukin-6 expression.

The chemokine CXC ligand-1 (CXCL-1) is a small cytokine that elicits effects by signalling through the chemokine receptor CXCR2. CXCL-1 has neutrophil chemoattractant activity, is involved in the processes of angiogenesis, inflammation and wound healing, and may possess neuroprotective effects. The aim of this study was to unravel the mechanisms whereby CXCL-1 is regulated by exercise inmice. After a single bout of exercise, CXCL-1 protein increased in serum(2.4-fold), and CXCL-1 mRNA in muscle (6.5-fold) and liver (41-fold). These increases in CXCL-1 were preceded by increases in serum interleukin-6 (IL-6) and muscle IL-6 mRNA. In contrast, exercise-induced regulation of liver CXCL-1 mRNA expression was completely blunted in IL-6 knockout mice. Based on these findings, we examined the possible existence of a muscle-to-liver axis by overexpressing IL-6 in muscles. This resulted in increases in serum CXCL-1 (5-fold) and liver CXCL-1 mRNA expression (24-fold) compared with control. Because IL-6 expression and release are known to be augmented during exercise in glycogen-depleted animals, CXCL-1 and IL-6 expression were examined after exercise in overnight-fasted mice.We found that fasting significantly augmented serum CXCL-1, and CXCL-1 expression in liver and muscle. Taken together, these data indicate that liver is the main source of serum CXCL-1 during exercise in mice, and that the CXCL-1 expression in the liver is regulated by muscle-derived IL-6.

PGC-1alpha-mediated adaptations in skeletal muscle.

Lifestyle-related diseases are rapidly increasing at least in part due to less physical activity. The health beneficial effects of regular physical activity include metabolic adaptations in skeletal muscle, which are thought to be elicited by cumulative effects of transient gene responses to each single exercise, but how is this regulated? A potential candidate in this is the transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1alpha, which has been identified as a master regulator of mitochondrial biogenesis, but also been shown to regulate proteins involved in angiogenesis and the anti-oxidant defence as well as to affect expression of inflammatory markers. Exercise increases PGC-1alpha transcription and potentially PGC-1alpha activity through post-translational modifications, and concomitant PGC-1alpha-mediated gene regulation is suggested to be an underlying mechanism for adaptations in skeletal muscle, when exercise is repeated. The current review presents some of the key findings in PGC-1alpha-mediated regulation of metabolically related, anti-oxidant and inflammatory proteins in skeletal muscle in the basal state and in response to exercise training, and describes functional significance of PGC-1alpha-mediated effects in skeletal muscle. In addition, regulation of PGC-1alpha expression and activity in skeletal muscle is described. The impact of changes in PGC-1alpha expression in mouse skeletal muscle and the ability of PGC-1alpha to regulate multiple pathways and functions underline the potential importance of PGC-1alpha in skeletal muscle adaptations in humans. The absence of exercise-induced PGC-1alpha-mediated gene regulation during a physical inactive lifestyle is suggested to lead to reduced oxidative capacity of skeletal muscle and concomitant impaired metabolism.

Coverage rates of the children vaccination programme in Greenland.

In order to estimate the current coverage rate among all children in Greenland, we conducted an observational cross-sectional study identifying all children in Greenland eligible for a vaccination between 1 March 2018 and 16 June 2019. we found an overall national coverage of 85.4%. The national coverage for the vaccinations given at birth was 97.1%, dropping to 94.3%, 87.7% and 83.6% at ages 3, 5 and 12 months. Among children eligible for the Measles, Mumps and Rubella-vaccinations, the national coverage was 76.9% for children aged 15 months and 64.1% for children aged 4 years, but dropping to 40.9% in the districts. At preschool, the national coverage was 79.9%. Among the 12-year-old, the national coverages of the two vaccinations against Human Papilloma Virus were 88.4% and 71.6%, respectively, and for the three Hepatitis B-vaccinations 89.8%, 84.1% and 69.6%. A subgroup-analysis and test of an SMS-reminder system in Nuuk improved the coverage from 57.8% to 75.5% locally. Overall, we found a high national coverage rate among the newborn in Greenland. The national coverage rates of the remaining vaccinations were below the WHO-recommendations, however with great regional differences.Abbreviations: CVP: Children Vaccination Programme; BCG: Bacille Calmette-Guerin; EMR: Electronic medical Record system; DTPHiB: Diphtheria, Tetanus, Pertussis, Polio, Haemophilus influenza B; HBV: Hepatitis B; HPV: Human Papilloma Virus; MMR: Measles, Mumps, Rubella; SMS: Short Text Message; WHO: World Health Organization; GVAP: Global Vaccine Action Plan; EVAP: The WHO European Vaccine Action Plan.

Gestational diabetes and macrosomia among Greenlanders. Time to change diagnostic strategy?

Gestational diabetes mellitus (GDM) is a serious condition associated to both maternal and offspring complications. Yet, no globally accepted consensus exists on how to test and diagnose GDM. In Greenland, the clinical criteria for testing and diagnosing GDM are adapted from Danish guidelines. The aim of this study was to estimate the prevalence of GDM among Greenlanders using both the current clinical GDM criteria and the recent WHO 2013 criteria and, further, to study the association between GDM, pre-pregnant overweight or obesity and macrosomia. A cross-sectional study of all 450 Greenlandic women who gave birth to a singleton in Nuuk within 1 year was performed. Based on an oral glucose tolerance test measuring capillary whole blood glucose, 119 women were categorised as having clinical GDM, WHO 2013 GDM or not GDM. Macrosomia defined as birth weight above 4,000 g was used as outcome variable. The prevalence of clinical GDM and WHO 2013 GDM was 0.4% (95% CI; 0-1.1) and 6.9% (95% CI; 4.5-9.2). WHO 2013 GDM, fasting blood glucose, pre-pregnant maternal overweight and obesity were associated with macrosomia. WHO 2013 GDM criteria were superior to clinical criteria in predicting macrosomia indicating that it may be time to consider the diagnostic strategy used in Greenland. Pre-pregnant overweight may also need more intensified lifestyle-intervention. ABBREVIATIONS: GDM: Gestational diabetes mellitus; VP: venous plasma; CWB: capillary whole blood; OGTT: oral glucose tolerance test; WHO: World Health Organisation; FIGO: The International Federation of Gynaecology and Obstetrics; BMI: body mass index; GA: gestational age.

The impact of exercise training and resveratrol supplementation on gut microbiota composition in high-fat diet fed mice.

The aim of this study was to examine the effect of exercise training and dietary supplementation of resveratrol on the composition of gut microbiota and to test the hypothesis that exercise training and resveratrol can prevent high-fat diet (HFD)-induced changes in the gut microbiota. Mice fed a HFD supplemented with resveratrol (4 g/kg food) were protected against diet-induced obesity, while exercise trained HFD-fed animals (running on average 50 km/week) were not. Dietary resveratrol supplementation induced changes predominantly in the low-abundant bacteria, while exercise training induced changes in the high-abundant bacteria in the gut as analyzed by ADONIS test with Weighted UniFrac distances. Interestingly, the two interventions affected the gut microbiome independently of the inflammatory state of the HFD-fed animals as assessed by the systemic serum amyloid A levels. These results suggest that both resveratrol supplementation and regular physical activity modulate the composition of murine microbiota independently of the systemic inflammatory state. Moreover, the effects of exercise training on the microbiota seem to occur without changes in adiposity, while resveratrol-mediated alterations may relate to adipose tissue mass.

Exercise training protects against aging-induced mitochondrial fragmentation in mouse skeletal muscle in a PGC-1α dependent manner.

Aging is associated with impaired mitochondrial function, whereas exercise training enhances mitochondrial content and function in part through activation of PGC-1α. Mitochondria form dynamic networks regulated by fission and fusion with profound effects on mitochondrial functions, yet the effects of aging and exercise training on mitochondrial network structure remain unclear. This study examined the effects of aging and exercise training on mitochondrial network structure using confocal microscopy on mitochondria-specific stains in single muscle fibers from PGC-1α KO and WT mice. Hyperfragmentation of mitochondrial networks was observed in aged relative to young animals while exercise training normalized mitochondrial network structure in WT, but not in PGC-1α KO. Mitochondrial fission protein content (FIS1 and DRP1) relative to mitochondrial content was increased with aging in both WT and PGC-1α KO mice, while exercise training lowered mitochondrial fission protein content relative to mitochondrial content only in WT. Mitochondrial fusion protein content (MFN1/2 and OPA1) was unaffected by aging and lifelong exercise training in both PGC-1α KO and WT mice. The present results provide evidence that exercise training rescues aging-induced mitochondrial fragmentation in skeletal muscle by suppressing mitochondrial fission protein expression in a PGC-1α dependent manner.

Gestational diabetes mellitus in Greenland: a national study of prevalence and testing efficacy.

BACKGROUND: Within the last 20 years, the prevalence of gestational diabetes mellitus (GDM) has been reported to be increasing worldwide in correlation with ethnic and geographic variations. The actual prevalence of GDM throughout all of Greenland remains unknown. OBJECTIVE: The aim of this study was to estimate the prevalence of GDM among Greenlanders and non-Greenlanders living in Greenland and to estimate the efficacy of testing for GDM. DESIGN: This study was performed as an observational, cross-sectional study including all women with permanent address in Greenland who had given birth to a singleton during 2014. The prevalence of GDM was calculated as the proportion of all pregnant women tested with a 75-g 2-h glucose tolerance test who had a 2-h capillary whole-blood glucose value of 8.5 mmol/l or above. Testing efficacy was calculated as the proportion of women who fulfilled the testing criteria who were actually tested in Greenland in 2014. RESULTS: A total of 794 women (727 Greenlanders and 67 non-Greenlanders) were included in the study. The prevalence of GDM among tested women was 3.3% (confidence interval, CI: 0.9-5.6) among Greenlanders and 12.5% (CI: 0-25.7) among non-Greenlanders, corresponding, respectively, to 1.0% (CI: 0.3-1.3) and 4.5% (CI: 0-9.4) of all singleton pregnancies in Greenland in 2014. The overall testing efficacy was 69.0% among all eligible residents of Greenland and 85.1% among eligible residents in the capital city, Nuuk. CONCLUSION: In conclusion, the prevalence of GDM seems quite low in Greenland. Although diagnostic testing activity has improved within the last 6 years, still around one-third of all pregnant women in all Greenland fulfilling the testing criteria were not tested. Universal testing for GDM may be needed to improve testing of GDM in Greenland.

Effects of Exercise Training on Regulation of Skeletal Muscle Glucose Metabolism in Elderly Men.

BACKGROUND: The aim was to investigate the molecular mechanisms behind exercise training-induced improvements in glucose regulation in aged subjects. METHODS: Twelve elderly male subjects completed 8 weeks of exercise training. Before and after the training period, the subjects completed an oral glucose tolerance test (OGTT) and a muscle biopsy was obtained from the vastus lateralis before and 45 minutes into the OGTT. Blood samples were collected before and up to 120 minutes after glucose intake. RESULTS: Exercise training increased Hexokinase II, GLUT4, Akt2, glycogen synthase (GS), pyruvate dehydrogenase (PDH)-E1α, PDK2 protein, and glycogen content in skeletal muscle. Furthermore, in response to glucose, GS activity was increased and the dephosphorylation of GS site 2 + 2a and 3a was enhanced after the training intervention. The glucose-mediated insulin stimulation of TBC1D4 Thr(642) phosphorylation was increased after exercise training. In the trained state, the PDHa activity was reduced following glucose intake and without changes in phosphorylation level of PDH-E1α. CONCLUSIONS: The present results suggest that exercise training improves glucose regulation in elderly subjects by enhancing the capacity and acute regulation of glucose uptake and by enhancing intracellular glucose removal to glycogen synthesis rather than glucose oxidation.

Role of PGC-1α in exercise training- and resveratrol-induced prevention of age-associated inflammation.

BACKGROUND/AIM: Age-related metabolic diseases are often associated with low-grade inflammation. The aim of the present study was to investigate the role of the transcriptional co-activator PGC-1α in the potential beneficial effects of exercise training and/or resveratrol in the prevention of age-associated low-grade inflammation. To address this, a long-term voluntary exercise training and resveratrol supplementation study was conducted. EXPERIMENTAL SETUP: Three month old whole body PGC-1α KO and WT mice were randomly assigned to four groups: untrained chow-fed, untrained chow-fed supplemented with resveratrol, chow-fed voluntarily exercise trained and chow-fed supplemented with resveratrol and voluntarily exercise trained. The intervention lasted 12 months and three month old untrained chow-fed mice served as young controls. RESULTS: Voluntary exercise training prevented an age-associated increase (p<0.05) in systemic IL-6 and adiposity in WT mice. PGC-1α expression was required for a training-induced prevention of an age-associated increase (p<0.05) in skeletal muscle TNFα protein. Independently of PGC-1α, both exercise training and resveratrol prevented an age-associated increase (p<0.05) in skeletal muscle protein carbonylation. CONCLUSION: The present findings highlight that exercise training is a more effective intervention than resveratrol supplementation in reducing age-associated inflammation and that PGC-1α in part is required for the exercise training-induced anti-inflammatory effects.

Effect of lifelong resveratrol supplementation and exercise training on skeletal muscle oxidative capacity in aging mice; impact of PGC-1α.

BACKGROUND: The present study tested the hypothesis that lifelong resveratrol (RSV) supplementation counteracts an age-associated decrease in skeletal muscle oxidative capacity through peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α and that RSV combined with lifelong exercise training (EX) exerts additive effects through PGC-1α in mice. METHODS: 3 month old PGC-1α whole body knockout (KO) and wild type (WT) littermate mice were placed in cages with or without running wheel and fed either standard chow or standard chow with RSV supplementation (4 g/kg food) for 12 months. Young (3 months of age), sedentary mice on standard chow served as young controls. A graded running performance test and a glucose tolerance test were performed 2 and 1 week, respectively, before euthanization where quadriceps and extensor digitorum longus (EDL) muscles were removed. RESULTS: In PGC-1α KO mice, quadriceps citrate synthase (CS) activity, mitochondrial (mt)DNA content as well as pyruvate dehydrogenase (PDH)-E1α, cytochrome (Cyt) c and vascular endothelial growth factor (VEGF) protein content were 20-75% lower and, EDL capillary-to-fiber (C:F) ratio was 15-30% lower than in WT mice. RSV and/or EX had no effect on the C:F ratio in EDL. CS activity (P=0.063) and mtDNA content (P=0.013) decreased with age in WT mice, and CS activity, mtDNA content, PDH-E1α protein and VEGF protein increased ~1.5-1.8-fold with lifelong EX in WT, but not in PGC-1α KO mice, while RSV alone had no significant effect on these proteins. CONCLUSION: Lifelong EX increased activity/content of oxidative proteins, mtDNA and angiogenic proteins in skeletal muscle through PGC-1α, while RSV supplementation alone had no effect. Combining lifelong EX and RSV supplementation had no additional effect on skeletal muscle oxidative and angiogenic proteins.

Skeletal muscle PGC-1α is required for maintaining an acute LPS-induced TNFα response.

Many lifestyle-related diseases are associated with low-grade inflammation and peroxisome proliferator activated receptor γ coactivator (PGC)-1α has been suggested to be protective against low-grade inflammation. However, whether these anti-inflammatory properties affect acute inflammation is not known. The aim of the present study was therefore to investigate the role of muscle PGC-1α in acute inflammation. Quadriceps muscles were removed from 10-week old whole body PGC-1α knockout (KO), muscle specific PGC-1α KO (MKO) and muscle-specific PGC-1α overexpression mice (TG), 2 hours after an intraperitoneal injection of either 0.8 µg LPS/g body weight or saline. Basal TNFα mRNA content was lower in skeletal muscle of whole body PGC-1α KO mice and in accordance TG mice showed increased TNFα mRNA and protein level relative to WT, indicating a possible PGC-1α mediated regulation of TNFα. Basal p65 phosphorylation was increased in TG mice possibly explaining the elevated TNFα expression in these mice. Systemically, TG mice had reduced basal plasma TNFα levels compared with WT suggesting a protective effect against systemic low-grade inflammation in these animals. While TG mice reached similar TNFα levels as WT and showed more marked induction in plasma TNFα than WT after LPS injection, MKO PGC-1α mice had a reduced plasma TNFα and skeletal muscle TNFα mRNA response to LPS. In conclusion, the present findings suggest that PGC-1α enhances basal TNFα expression in skeletal muscle and indicate that PGC-1α does not exert anti-inflammatory effects during acute inflammation. Lack of skeletal muscle PGC-1α seems however to impair the acute TNFα response, which may reflect a phenotype more susceptible to infections as also observed in type 2 diabetes patients.

Functional characterization of water transport and cellular localization of three aquaporin paralogs in the salmonid intestine.

Intestinal water absorption is greatly enhanced in salmonids upon acclimation from freshwater (FW) to seawater (SW); however, the molecular mechanism for water transport is unknown. We conducted a pharmacological characterization of water absorption in the rainbow trout intestine along with an investigation of the distribution and cellular localization of three aquaporins (Aqp1aa, -1ab, and -8ab) in pyloric caeca, middle (M), and posterior (P) intestine of the Atlantic salmon. In vitro iso-osmotic water absorption (J(v)) was higher in SW than FW-trout and was inhibited by (mmol L(-1)): 0.1 KCN (41%), 0.1 ouabain (72%), and 0.1 bumetanide (82%) suggesting that active transport, Na(+), K(+)-ATPase and Na(+), K(+), 2Cl(-)-co-transport are involved in establishing the driving gradient for water transport. J(v) was also inhibited by 1 mmol L(-1) HgCl(2), serosally (23% in M and 44% in P), mucosally (27% in M), or both (61% in M and 58% in P), suggesting involvement of both apical and basolateral aquaporins in water transport. The inhibition was antagonized by 5 mmol L(-1) mercaptoethanol. By comparison, 10 mmol L(-1) mucosal tetraethylammonium, an inhibitor of certain aquaporins, inhibited J(v) by 20%. In the presence of glucose, mucosal addition of phloridzin inhibited water transport by 20%, suggesting that water transport is partially linked to the Na(+)-glucose co-transporter. Using polyclonal antibodies against salmon Aqp1aa, -1ab, and -8ab, we detected Aqp1aa, and -1ab immunoreactivity in the brush border and sub-apical region of enterocytes in all intestinal segments. The Aqp8ab antibody showed a particularly strong immunoreaction in the brush border and sub-apical region of enterocytes throughout the intestine and also stained lateral membranes and peri-nuclear regions though at lower intensity. The present localization of three aquaporins in both apical and lateral membranes of salmonid enterocytes facilitates a model for transcellular water transport in the intestine of SW-acclimated salmonids.

[Necrosis of the tongue triggered by ergotamine in unrecognized temporal arteritis]. / Tungenekrose udløst af ergotamin ved uerkendt arteritis temporalis.

Tongue necrosis is a rare complication in arteritis temporalis. Our case is a 74-year-old patient who presented with weight loss, tiredness and fever during a 2-3-month period after ingestion of 2 mg ergotamine to treat her migraine. Tongue necrosis then occurred after ingestion of another 2 mg of ergotamine. Our patient had no preexisting diagnosis of arteritis temporalis. We reviewed possible clinical manifestations of temporal arteritis and cases of tongue necrosis in the world literature. It is possible that ergotamine can cause necrosis due to vasoconstriction of blood vessels which have an unstable blood flow.