Lene Simonsen

Effects of aging on human skeletal muscle after immobilization and retraining

Inactivity is a recognized compounding factor in sarcopenia and muscle weakness in old age. However, while the negative effects of unloading on skeletal muscle in young individuals are well elucidated, only little is known about the consequence of immobilization and the regenerative capacity in elderly individuals. Thus the aim of this study was to examine the effect of aging on changes in muscle contractile properties, specific force, and muscle mass characteristics in 9 old (61-74 yr) and 11 young men (21-27 yr) after 2 wk of immobilization and 4 wk of retraining. Both young and old experienced decreases in maximal muscle strength, resting twitch peak torque and twitch rate of force development, quadriceps muscle volume, pennation angle, and specific force after 2 wk of immobilization (P < 0.05). The decline in quadriceps volume and pennation angle was smaller in old compared with young (P < 0.05). In contrast, only old men experienced a decrease in quadriceps activation. After retraining, both young and old regained their initial muscle strength, but old had smaller gains in quadriceps volume compared with young, and pennation angle increased in young only (P < 0.05). The present study is the first to demonstrate that aging alters the neuromuscular response to short-term disuse and recovery in humans. Notably, immobilization had a greater impact on neuronal motor function in old individuals, while young individuals were more affected at the muscle level. In addition, old individuals showed an attenuated response to retraining after immobilization compared with young individuals.

Metabolic effects of interleukin‐6 in human splanchnic and adipose tissue

Interleukin‐6 (IL‐6) was infused intravenously for 2.5 h in seven healthy human volunteers at a dose giving rise to a circulating IL‐6 concentration of ≈35 ng l−1. The metabolic effects of this infusion were studied in subcutaneous adipose tissue on the anterior abdominal wall and in the splanchnic tissues by the Fick principle after catheterizations of an artery, a subcutaneous vein draining adipose tissue, and a hepatic vein, and measurements of regional adipose tissue and splanchnic blood flows. In control studies without IL‐6 infusion subcutaneous adipose tissue metabolism was studied by the same technique in eight healthy subjects. The net release of glycerol and fatty acids from the subcutaneous abdominal adipose tissue remained constant in the control experiment. IL‐6 infusion gave rise to increase in net glycerol release in subcutaneous adipose tissue while the net release of fatty acids did not change significantly. In the splanchnic region IL‐6 elicited a pronounced vasodilatation, and the uptake of fatty acids and the gluconeogenic precursors glycerol and lactate increased significantly. The splanchnic net output of glucose and triacylglycerol did not change during the IL‐6 infusion. It is concluded that IL‐6 elicits lipolytic effects in human adipose tissue in vivo, and that IL‐6 also has effects on the splanchnic lipid and carbohydrate metabolism.

Interleukin-6 production in human subcutaneous abdominal adipose tissue: the effect of exercise

The interleukin‐6 (IL‐6) output from subcutaneous, abdominal adipose tissue was studied in nine healthy subjects before, during and for 3 h after 1 h two‐legged bicycle exercise at 60 % maximal oxygen consumption. Seven subjects were studied in control experiments without exercise. The adipose tissue IL‐6 output was measured by direct Fick technique. An artery and a subcutaneous vein on the anterior abdominal wall were catheterized. Adipose tissue blood flow was measured using the 133Xe‐washout method. In both studies there was a significant IL‐6 output in the basal state and no significant change was observed during exercise. Post‐exercise the IL‐6 output began to increase after 30 min. Three hours post‐exercise it was 58.6 ± 22.2 pg (100 g)−1 min−1. In the control experiments the IL‐6 output also increased, but it only reached a level of 3.5 ± 0.8 pg (100 g)−1 min−1. The temporal profile of the post‐exercise change in the IL‐6 output closely resembles the changes in the outputs of glycerol and fatty acids, which we have described previously in the same adipose tissue depot. The difference is that it begins to increase ≈30 min before the glycerol and fatty acid outputs begin to increase. Thus, we suggest that the enhanced IL‐6 production post‐exercise in abdominal, subcutaneous adipose tissue may act locally via autocrine/paracrine mechanisms influencing lipolysis and fatty acid mobilization rate from this lipid depot.

Effects of a physiological GH pulse on interstitial glycerol in abdominal and femoral adipose tissue

Physiologically, growth hormone (GH) is secreted in pulses with episodic bursts shortly after the onset of sleep and postprandially. Such pulses increase circulating levels of free fatty acid and glycerol. We tested whether small GH pulses have detectable effects on intercellular glycerol concentrations in adipose tissue, and whether there would be regional differences between femoral and abdominal subcutaneous fat, by employing microdialysis for 6 h after administration of GH (200 μg) or saline intravenously. Subcutaneous adipose tissue blood flow (ATBF) was measured by the local Xenon washout method. Baseline of interstitial glycerol was higher in adipose tissue than in blood [220 ± 12 (abdominal) vs. 38 ± 2 (blood) μmol/l, P < 0.0005; 149 ± 9 (femoral) vs. 38 ± 2 (blood) μmol/l, P < 0.0005] and higher in abdominal adipose tissue compared with femoral adipose tissue ( P < 0.0005). Administration of GH induced an increase in interstitial glycerol in both abdominal and femoral adipose tissue (ANOVA: abdominal, P = 0.04; femoral, P = 0.03). There was no overall difference in the response to GH in the two regions during the study period as a whole (ANOVA: P = 0.5), but during peak stimulation of lipolysis abdominal adipose tissue was, in absolute but not in relative terms, stimulated more markedly than femoral adipose tissue (ANOVA: P = 0.03 from 45 to 225 min). Peak interstitial glycerol values of 253 ± 37 and 336 ± 74 μmol/l were seen after 135 and 165 min in femoral and abdominal adipose tissue, respectively. ATBF was not statistically different in the two situations (ANOVA: P = 0.7). In conclusion, we have shown that a physiological pulse of GH increases interstitial glycerol concentrations in both femoral and abdominal adipose tissue, indicating activated lipolysis. The peak glycerol increments after GH were higher in abdominal adipose tissue, perhaps due to a higher basal rate of lipolysis in this region.Physiologically, growth hormone (GH) is secreted in pulses with episodic bursts shortly after the onset of sleep and postprandially. Such pulses increase circulating levels of free fatty acid and glycerol. We tested whether small GH pulses have detectable effects on intercellular glycerol concentrations in adipose tissue, and whether there would be regional differences between femoral and abdominal subcutaneous fat, by employing microdialysis for 6 h after administration of GH (200 microgram) or saline intravenously. Subcutaneous adipose tissue blood flow (ATBF) was measured by the local Xenon washout method. Baseline of interstitial glycerol was higher in adipose tissue than in blood [220 +/- 12 (abdominal) vs. 38 +/- 2 (blood) micromol/l, P < 0.0005; 149 +/- 9 (femoral) vs. 38 +/- 2 (blood) micromol/l, P < 0.0005] and higher in abdominal adipose tissue compared with femoral adipose tissue (P < 0.0005). Administration of GH induced an increase in interstitial glycerol in both abdominal and femoral adipose tissue (ANOVA: abdominal, P = 0. 04; femoral, P = 0.03). There was no overall difference in the response to GH in the two regions during the study period as a whole (ANOVA: P = 0.5), but during peak stimulation of lipolysis abdominal adipose tissue was, in absolute but not in relative terms, stimulated more markedly than femoral adipose tissue (ANOVA: P = 0. 03 from 45 to 225 min). Peak interstitial glycerol values of 253 +/- 37 and 336 +/- 74 micromol/l were seen after 135 and 165 min in femoral and abdominal adipose tissue, respectively. ATBF was not statistically different in the two situations (ANOVA: P = 0.7). In conclusion, we have shown that a physiological pulse of GH increases interstitial glycerol concentrations in both femoral and abdominal adipose tissue, indicating activated lipolysis. The peak glycerol increments after GH were higher in abdominal adipose tissue, perhaps due to a higher basal rate of lipolysis in this region.

Post-exercise adipose tissue and skeletal muscle lipid metabolism in humans: the effects of exercise intensity

1 One purpose of the present experiments was to examine whether the relative workload or the absolute work performed is the major determinant of the lipid mobilization from adipose tissue during exercise. A second purpose was to determine the co‐ordination of skeletal muscle and adipose tissue lipid metabolism during a 3 h post‐exercise period. 2 Six subjects were studied twice. In one experiment, they exercised for 90 min at 40 % of maximal O2 consumption (V̇O2, max) and in the other experiment they exercised at 60 %V̇O2, max for 60 min. For both experiments, catheters were inserted in an artery, a subcutaneous abdominal vein and a femoral vein. Adipose tissue metabolism and skeletal muscle (leg) metabolism were measured using Ficks principle. 3 The results show that the lipolytic rate in adipose tissue during exercise was the same in each experiment. Post‐exercise, there was a very fast decrease in lipolysis, but it began to increase about 1 h post‐exercise and remained elevated for the following 2 h. The increase in post‐exercise non‐esterified fatty acid (NEFA) mobilization was greater after 60 % exercise than after 40 % exercise. 4 It is concluded that the lipolytic rate in abdominal subcutaneous adipose tissue during exercise is the same whether the relative workload is 40 % or 60 % of maximum. Post‐exercise, there is a substantial lipid mobilization from adipose tissue and only a small fraction of this is taken up in the lower extremities. This leaves a substantial amount of NEFAs for either NEFA/TAG (triacylglycerol) recirculation post‐exercise or immediate oxidation.

Regional Fat Metabolism in Human Splanchnic and Adipose Tissues; The Effect of Exercise

This study was conducted to investigate the role of splanchnic and adipose tissue in the regulation of fatty acid (FA) metabolism at rest, during 1 h of semi‐recumbent cycle exercise at 60 % of maximal power output and 3 h of recovery. In six post‐absorptive healthy volunteers catheters were placed in a radial artery, hepatic vein and a subcutaneous vein on the anterior abdominal wall. Whole body, and regional splanchnic and adipose tissue FA metabolism were measured by a constant infusion of the stable isotopes [U‐13C] palmitate and [2H5] glycerol and according to Ficks principle. The whole body rate of extracellular FA reesterification was similar at rest and during exercise (≈290 μmol min−1) and increased during recovery to a plateau of 390 μmol min−1. FA and triacylglycerol (TAG) uptake by adipose tissue was undetectable, but a constant but small glycerol uptake of ≈25 nmol (100 g)−1 min−1 was observed. From the FA taken up by the splanchnic area, 13 % was oxidized, 5–11 % converted to ketone bodies, and ≈35 % incorporated in TAG released both at rest and at the third hour of recovery from exercise. Splanchnic FA reesterification could account for 51 % and 58 % of whole body extracellular FA reesterification, of which half was accounted for by TAG released from the splanchnic area, at rest and in recovery, respectively. In conclusion, in the post‐absorptive state, adipose tissue contributes very little to extracellular FA reesterification and splanchnic reesterification can account for 50–60 %, implying that FA reesterification in other tissues is important. The extracellular FA reesterification rate does not change with exercise but is higher during recovery. Furthermore, the uptake of glycerol by adipose tissue indicates that adipose tissue can metabolize glycerol.

Glucose-Dependent Insulinotropic Polypeptide May Enhance Fatty Acid Re-esterification in Subcutaneous Abdominal Adipose Tissue in Lean Humans

OBJECTIVE Glucose-dependent insulinotropic polypeptide (GIP) has been implicated in lipid metabolism in animals. In humans, however, there is no clear evidence of GIP effecting lipid metabolism. The present experiments were performed in order to elucidate the effects of GIP on regional adipose tissue metabolism. RESEARCH DESIGN AND METHODS Eight healthy subjects were studied on four different occasions. Abdominal subcutaneous adipose tissue metabolism was assessed by measuring arterio-venous concentration differences and regional adipose tissue blood flow during GIP (1.5 pmol/kg/min) or saline infused intravenously alone or in combination with a hyperinsulinemic-hyperglycemic (HI-HG) clamp. RESULTS During GIP and HI-HG clamp, abdominal subcutaneous adipose tissue blood flow, hydrolysis of circulating triacylglycerol (TAG) (P = 0.009), and glucose uptake (P = 0.03) increased significantly while free fatty acid (FFA) output (P = 0.04) and FFA/glycerol release ratio (P = 0.02) decreased compared with saline and HI-HG clamp. CONCLUSIONS In conclusion, GIP in combination with hyperinsulinemia and slight hyperglycemia increased adipose tissue blood flow, glucose uptake, and FFA re-esterification, thus resulting in increased TAG deposition in abdominal subcutaneous adipose tissue.

The effect of 0.5% ropivacaine on epidural blood flow.

Twenty patients scheduled for elective abdominal surgery received epidural analgesia with 20 ml 0.5% ropivacaine or 0.5% bupivacaine. Epidural blood flow was measured by an epidural 133Xe clearance technique on the day before surgery (no local anaesthetic) and again 1 h before surgery, 30 min after injection of the local anaesthetic during continuous infusion (8 ml/h). Median initial blood flow was 5.0 ml/min and 6.0 ml/ min per 100 g tissue in patients receiving ropivacaine and bupivacaine, respectively. After epidural bupivacaine, blood flow increased in 8 of 10 patients to 6.9 ml/min per 100 g tissue (P<0.05) in contrast to a decrease in 9 of 10 patients to 3.3 ml/min per 100 g tissue after ropivacaine (P<0.05), (P<0.01 between groups). The median level of sensory analgesia was T3.5 and T4.5 in the ropivacaine and bupivacaine group, respectively (P>0.05). The demonstrated vasoconstrictor effect of epidural ropivacaine may influence the duration of its local anaesthetic effect.

DEXTRAN HYDROGELS FOR COLON-SPECIFIC DRUG DELIVERY. V. DEGRADATION IN HUMAN INTESTINAL INCUBATION MODELS

Abstract In the present study degradation of dextran hydrogels, potential drug carriers for colon-specific drug delivery, was studied in simulated small intestinal juices as well as in a human colonic fermentation model. Dextran hydrogels were shown to be stable when incubated at 37°C with the small intestinal enzymes amyloglucosidase, invertase and pancreatin. After a 24 h incubation, less than 3.3% of free glucose was released. However, the hydrogels were still intact as measured by the dry weight remaining. The fermentation of dextran hydrogels and several mono- and polysaccharides to short-chain fatty acids (SCFA) was investigated after anaerobic incubation in a human colonic fermentation model at 37°C for 0–72 h. In addition, the dextranase activity of the incubations was determined. The amounts and ratios of SCFA formed varied considerably in relation to the type of substrate fermented (glucose, maize starch, potato starch, cellulose, soluble dextran and dextran hydrogels). Detailed SCFA analysis demonstrated that fermentable saccharides resulted in an increased SCFA production, in contrast to the metabolic inert polysaccharide, cellulose. The hydrogels were found to be completely degraded in the human colonic fermentation model. An increased crosslinking density or a decreased degree of hydration resulted in a lower degradability. The pH of the incubations were found to be inversely proportional to the SCFA production as a result of the increased acid formation.

Home-based cardiac rehabilitation is as effective as centre-based cardiac rehabilitation among elderly with coronary heart disease: results from a randomised clinical trial

BACKGROUND participation in centre-based cardiac rehabilitation (CR) is known to reduce morbidity and mortality but participation rates among the elderly are low. Establishing alternative programmes is important, and home-based CR is the predominant alternative. However, no studies have investigated the effect of home-based CR among a group of elderly patients with coronary heart disease with a long-term follow-up. METHODS randomised clinical trial comparing home-based CR with comprehensive centre-based CR among patients ≥ 65 years with coronary heart disease. RESULTS seventy-five patients participated. There were no significant differences in exercise capacity after the intervention between home and centre-based CR. Adjusted mean differences of peak VO₂ = 0.9 ml/kg/min (95% CI -0.7, 2.4) and of 6 min walk test = -18.7 m (95% CI -56.4, 18.9). In addition, no differences were found in the secondary outcomes of systolic blood pressure (-0.6 mmHg, 95% CI -11.3, 10.0), LDL cholesterol (0.3 mmol/l, 95% CI -0.04, 0.7), HDL cholesterol (0.2 mmol/l, 95% CI -0.01, 0.3), body composition, proportion of smokers and health-related quality of life. A group of patients who did not have an effect of either programmes were characterised by higher age, living alone and having COPD. At 12 months of follow-up, both groups had a significant decline in exercise capacity. CONCLUSIONS home-based CR is as effective as centre-based CR in improving exercise capacity, risk factor control and health-related quality of life. However, a group of patients did not improve regardless of the type of intervention. Continued follow-up is essential in order to maintain the gained improvements.