Hans Kristian Stadheim

The effects of acute and chronic exercise on PGC‐1α, irisin and browning of subcutaneous adipose tissue in humans

Irisin was first identified as a peroxisome proliferator‐activated receptor γ co‐activator‐1α (PGC‐1α) dependent myokine with the potential to induce murine brown‐fat‐like development of white adipose tissue. In humans, the regulatory effect of training on muscle FNDC5mRNA expression and subsequently irisin levels in plasma is more controversial. We recruited 26 inactive men (13 normoglycaemic and normal weight, controls; and 13 slightly hyperglycaemic and overweight, pre‐diabetes group) aged 40–65 years for a 12‐week intervention of combined endurance and strength training with four sessions of training per week. Before and after the 12‐week intervention period, participants were exposed to an acute endurance workload of 45 min at 70% of VO2max, and muscle biopsies were taken prior to and after exercise. Skeletal muscle mRNA for PGC1A and FNDC5 correlated and both PGC1A and FNDC5mRNA levels increased after 12 weeks of training in both control and pre‐diabetes subjects. Circulating irisin was reduced in response to 12 weeks of training, and was increased acutely (~1.2‐fold) just after acute exercise. Plasma concentration of irisin was higher in pre‐diabetes subjects compared with controls. There was little effect of 12 weeks of training on selected browning genes in subcutaneous adipose tissue. UCP1mRNA did not correlate with FNDC5 expression in subcutaneous adipose tissue or skeletal muscle or with irisin levels in plasma. We observed no enhancing effect of long‐term training on circulating irisin levels, and little or no effect of training on browning of subcutaneous white adipose tissue in humans.

Caffeine Increases Performance in Cross-country Double-Poling Time Trial Exercise.

PURPOSE Caffeine (CAF) improves performance in both short- and long-duration running and cycling where performance relies on power output and endurance capacity of leg muscles. No studies have so far tested the effects of CAF while using the double-poling (DP) technique in cross-country skiing. When using the DP technique, arm muscles provide the speed-generating force and therefore play an important role in performance outcome. The metabolism of arm muscles differs from that of leg muscles. Thus, results from studies on leg muscles and CAF may not be directly applicable to exercises while using the DP technique in cross-country skiing. The purpose of our study was therefore to investigate the effects of CAF on exercise performance in DP. METHOD Ten highly trained male cross-country skiers (V·O 2max running, 69.3 ± 1.0 mL · kg · min(-1)) performed a placebo (PLA) and CAF trial using a randomized, double-blind, crossover design. Performance was assessed by measuring the time to complete an 8-km cross-country DP performance test (C-PT). CAF (6 mg · kg(-1)) or PLA was ingested 75 min before the C-PT. RESULTS CAF ingestion reduced the time to complete the 8-km C-PT from 34:26 ± 1:25 to 33:01 ± 1:24 min (P < 0.05). The subjects maintained higher speed and HR throughout the C-PT, and lactate was higher immediately after the C-PT with CAF exposure compared with PLA. Subjects reported lower RPE at submaximal intensities during CAF compared with PLA, although HR was similar. CONCLUSION CAF intake enhances endurance performance in an 8-km C-PT, where arm muscles limit performance. CAF ingestion allowed the participants to exercise with a higher HR and work intensity possibly by reducing perception of effort or facilitating motor unit recruitment.

The exercise-regulated myokine chitinase-3-like protein 1 stimulates human myocyte proliferation

Chitinase‐3‐like protein 1 (CHI3L1) is involved in tissue remodelling and inflammatory processes. Plasma levels are elevated in patients with insulin resistance and T2DM. We recently showed that CHI3L1 and its receptor protease‐activated receptor 2 (PAR‐2) are expressed in skeletal muscle. Activation of PAR‐2 by CHI3L1 protects against TNF‐α‐induced inflammation and insulin resistance. However, the effect of exercise on CHI3L1 and PAR‐2 signalling remains unknown. The aim of this work was to study the impact of exercise on CHI3L1 production and the effect of CHI3L1/PAR‐2 signalling on skeletal muscle growth and repair.

Subsarcolemmal lipid droplet responses to a combined endurance and strength exercise intervention

Muscle lipid stores and insulin sensitivity have a recognized association although the mechanism remains unclear. We investigated how a 12‐week supervised combined endurance and strength exercise intervention influenced muscle lipid stores in sedentary overweight dysglycemic subjects and normal weight control subjects (n = 18). Muscle lipid stores were measured by magnetic resonance spectroscopy (MRS), electron microscopy (EM) point counting, and direct EM lipid droplet measurements of subsarcolemmal (SS) and intramyofibrillar (IMF) regions, and indirectly, by deep sequencing and real‐time PCR of mRNA of lipid droplet‐associated proteins. Insulin sensitivity and VO2max increased significantly in both groups after 12 weeks of training. Muscle lipid stores were reduced according to MRS at baseline before and after the intervention, whereas EM point counting showed no change in LD stores post exercise, indicating a reduction in muscle adipocytes. Large‐scale EM quantification of LD parameters of the subsarcolemmal LD population demonstrated reductions in LD density and LD diameters. Lipid droplet volume in the subsarcolemmal LD population was reduced by ~80%, in both groups, while IMF LD volume was unchanged. Interestingly, the lipid droplet diameter (n = 10 958) distribution was skewed, with a lack of small diameter lipid droplets (smaller than ~200 nm), both in the SS and IMF regions. Our results show that the SS LD lipid store was sensitive to training, whereas the dominant IMF LD lipid store was not. Thus, net muscle lipid stores can be an insufficient measure for the effects of training.

Regulation of angiopoietin‐like protein 4 production during and after exercise

Angiopoietin‐like protein 4 (ANGPTL4) may regulate lipoprotein lipase‐dependent plasma clearance of triacylglycerol from skeletal muscle during exercise. The aim of this study was to examine the importance of muscle in regulating ANGPTL4 in response to exercise. We sampled muscle biopsies and serum before, immediately after, and 2 h after 45 min of ergometer cycling. Sampling was done before and after a 12‐week training intervention in controls and dysglycemic subjects. Moreover, fat biopsies were taken before and after the training intervention. The regulation of ANGPTL4 was also investigated in several tissues of exercising mice, and in cultured myotubes. ANGPTL4 levels in serum and expression in muscle were highest 2 h after exercise in both groups. Whereas ANGPTL4 was higher in muscle of exercising controls as compared to dysglycemic subjects, the opposite was observed in serum. In exercising mice, Angptl4 mRNA showed both higher basal expression and induction in liver compared to muscle. Angptl4 mRNA was much higher in adipose tissue than muscle and was also induced by exercise. We observed two mRNA isoforms of ANGPTL4 in muscle and fat in humans. Both were induced by exercise in muscle; one isoform was expressed 5‐ to 10‐fold higher than the other. Studies in mice and cultured myotubes showed that both fatty acids and cortisol have the potential to increase ANGPTL4 expression in muscle during exercise. In conclusion, ANGPTL4 is markedly induced in muscle in response to exercise. However, liver and adipose tissue may contribute more than muscle to the exercise‐induced increase in circulating ANGPTL4.

Insulin sensitivity, body composition and adipose depots following 12 w combined endurance and strength training in dysglycemic and normoglycemic sedentary men

Abstract Context: Insulin resistance and dysglycemia are associated with physical inactivity and adiposity, and may be improved by exercise. Objective: Investigate the effect of exercise on insulin sensitivity, body composition and adipose depots in sedentary men with (n = 11) or without (n = 11) overweight and dysglycemia. Material and methods: Euglycemic-hyperinsulinemic clamp, ankle-to-neck MRI, MRS, muscle and adipose tissue biopsies before and after 12 weeks combined strength and endurance exercise. Results: Insulin sensitivity, VO2max, strength, whole-body and muscle fat content, and abdominal adipose depots were improved without obvious differences between normo- and dysglycemic men. Hepatic fat, waist circumference and subcutaneous adipose tissue were reduced in the dysglycemic group. For both groups plasma adiponectin was reduced, whereas IL-6 was unchanged. Visceral fat was preferentially lost compared with other adipose depots. Discussion and conclusion: Body composition, fat distribution and insulin sensitivity improved following training in sedentary middle-aged men with and without dysglycemia.

An acute bout of exercise modulate the inflammatory response in peripheral blood mononuclear cells in healthy young men

Abstract Context: Exercise increases the levels of circulating inflammatory mediators. Objective: Does an acute bout of exercise affect the mRNA gene expression level of inflammatory markers in peripheral blood mononuclear cells (PBMCs) and contribute to the circulating levels of inflammatory mediators? Materials and methods: Ten healthy, non-smoking men (22–28 years old) performed 1-hour cycling at 70% of VO2 max. Results: The gene transcripts of CXCL16, IL-1β, IL-8, COX-2, TXB21 and GATA3 were significantly up-regulated in PBMCs. Serum levels of CXCL16, IL-6, TNFα and IL-10 were also significantly increased after exercise. Discussion and conclusion: Increased mRNA transcription of inflammatory genes in PBMCs may contribute to increased level of inflammatory markers after an acute bout of exercise. The increased mRNA levels of GATA-3 and TXB21 may indicate that T cell lymphocytes are activated and secrete cytokines into the circulation. It needs to be further investigated if exercise changes the Th1/Th2 balance.

Caffeine improves performance in double poling during acute exposure to 2,000 m altitude

There is limited research on the physiological effects of caffeine (CAF) ingestion on exercise performance during acute hypoxia. The aim of the present study was therefore to test the effect of placebo (PLA) and CAF (4.5 mg/kg) on double poling (DP) performance during acute hypoxia. Thirteen male subelite cross-country skiers (V̇o2max 72.6 ± 5.68 ml·kg(-1)·min(-1)) were included. Performance was assessed as 1) an 8-km cross-country DP time-trial (C-PT), and 2) time until task failure at a set workload equal to ∼90% of DP V̇o2max. Testing was carried out in a hypobaric chamber, at 800 mbar (Pio2: ∼125 mmHg) corresponding to ∼2,000 m above sea level in a randomized double-blinded, placebo-controlled, cross-over design. CAF improved time to task failure from 6.10 ± 1.40 to 7.22 ± 1.30 min (P < 0.05) and velocity the first 4 km (P < 0.05) but not overall time usage for the 8-km C-PT. During submaximal exercise subjects reported lower pain in arms and rate of perceived exertion (RPE) following CAF ingestion. Throughout C-PTs similar RPE and pain was shown between treatments. However, higher heart rate was observed during the CAF 8 km (187 ± 7 vs. 185 ± 7; P < 0.05) and 90% C-PT (185 ± 7 vs. 181 ± 9) associated with increased ventilation, blood lactate, glucose, adrenaline, decreased pH, and bicarbonate. The present study demonstrates for the first time that CAF ingestion improves DP time to task failure although not consistently time trial performance during acute exposure to altitude. Mechanisms underpinning improvements seem related to reduced pain RPE and increased heart rate during CAF C-PTs.

Exercise in vivo marks human myotubes in vitro: Training-induced increase in lipid metabolism

Background and aims Physical activity has preventive as well as therapeutic benefits for overweight subjects. In this study we aimed to examine effects of in vivo exercise on in vitro metabolic adaptations by studying energy metabolism in cultured myotubes isolated from biopsies taken before and after 12 weeks of extensive endurance and strength training, from healthy sedentary normal weight and overweight men. Methods Healthy sedentary men, aged 40–62 years, with normal weight (body mass index (BMI) < 25 kg/m2) or overweight (BMI ≥ 25 kg/m2) were included. Fatty acid and glucose metabolism were studied in myotubes using [14C]oleic acid and [14C]glucose, respectively. Gene and protein expressions, as well as DNA methylation were measured for selected genes. Results The 12-week training intervention improved endurance, strength and insulin sensitivity in vivo, and reduced the participants’ body weight. Biopsy-derived cultured human myotubes after exercise showed increased total cellular oleic acid uptake (30%), oxidation (46%) and lipid accumulation (34%), as well as increased fractional glucose oxidation (14%) compared to cultures established prior to exercise. Most of these exercise-induced increases were significant in the overweight group, whereas the normal weight group showed no change in oleic acid or glucose metabolism. Conclusions 12 weeks of combined endurance and strength training promoted increased lipid and glucose metabolism in biopsy-derived cultured human myotubes, showing that training in vivo are able to induce changes in human myotubes that are discernible in vitro.

Caffeine and Performance over Consecutive Days of Simulated Competition.

PURPOSE Performance improvements after caffeine (CAF) ingestion are well documented when using a 1-d protocol. In numerous competitions such as the Tour de France, Tour de Ski, world championships, and National College Athletic Association championships, athletes compete for several days in a row. To date, no studies have investigated the effects of CAF when competing for consecutive days in a row. This study aimed to investigate the effects of placebo (PLA) and two different CAF doses (3 and 4.5 mg·kg body mass) on performance in a 10-min all-out, cross-country, double poling ergometer test (C-PT) 2 d in a row. METHOD Eight highly trained male cross-country skiers (V˙O2max-run, 78.5 ± 1.6 mL·kg·min) participated in the study, which was a randomized, double-blind, PLA-controlled, crossover design. Performance was assessed as distance covered during a 10-min all-out C-PT. Oral ingestion of CAF or PLA was consumed 75 min before the all-out C-PT. RESULTS Poling distance was improved after CAF ingestions compared with that after PLA on both days. The improvements on day 1 were 4.0% (90% confidence limits, ±3.3) and 4.0% ± 2.9% for both CAF doses, respectively (P < 0.05), whereas improvements on day 2 were 5.0% ± 3.6% and 5.1% ± 2.8% for CAF3 and CAF4.5, respectively, compared with those for PLA. Improved performance was associated with increased HR, adrenaline concentration, blood lactate concentration, and V˙O2 consumption after CAF ingestion. Furthermore, performance was elevated despite higher creatine kinase concentration and muscular pain at arrival on day 2 for both CAF doses. CONCLUSIONS Both CAF doses improved performance in the 10-min all-out C-PT compared with PLA over two consecutive days. Therefore, CAF seems useful for athletes competing over consecutive days despite higher muscle damage occurring after enhanced performance on the first day.