| 1. |
- Watson, Hunna J., et al.
(författare)
-
Common Genetic Variation and Age of Onset of Anorexia Nervosa
- 2022
-
Ingår i: BIOLOGICAL PSYCHIATRY: GLOBAL OPEN SCIENCE. - : Elsevier BV. - 2667-1743. ; 2:4, s. 368-378
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Genetics and biology may influence the age of onset of anorexia nervosa (AN). The aims of this study were to determine whether common genetic variation contributes to age of onset of AN and to investigate the genetic associations between age of onset of AN and age at menarche.METHODS: A secondary analysis of the Psychiatric Genomics Consortium genome-wide association study (GWAS) of AN was performed, which included 9335 cases and 31,981 screened controls, all from European ancestries. We conducted GWASs of age of onset, early-onset AN (,13 years), and typical-onset AN, and genetic correlation, genetic risk score, and Mendelian randomization analyses.RESULTS: Two loci were genome-wide significant in the typical-onset AN GWAS. Heritability estimates (single nucleotide polymorphism-h2) were 0.01-0.04 for age of onset, 0.16-0.25 for early-onset AN, and 0.17-0.25 for typical-onset AN. Early-and typical-onset AN showed distinct genetic correlation patterns with putative risk factors for AN. Specifically, early-onset AN was significantly genetically correlated with younger age at menarche, and typical-onset AN was significantly negatively genetically correlated with anthropometric traits. Genetic risk scores for age of onset and early-onset AN estimated from independent GWASs significantly predicted age of onset. Mendelian randomization analysis suggested a causal link between younger age at menarche and early -onset AN.CONCLUSIONS: Our results provide evidence consistent with a common variant genetic basis for age of onset and implicate biological pathways regulating menarche and reproduction.
|
|
| 2. |
- Boushel, Robert, et al.
(författare)
-
Maintained peak leg and pulmonary VO2 despite substantial reduction in muscle mitochondrial capacity.
- 2015
-
Ingår i: Scandinavian Journal of Medicine and Science in Sports. - : Wiley. - 0905-7188 .- 1600-0838. ; 25:Suppl 4, s. 135-143
-
Tidskriftsartikel (refereegranskat)abstract
- We recently reported the circulatory and muscle oxidative capacities of the arm after prolonged low-intensity skiing in the arctic (Boushel et al., 2014). In the present study, leg VO2 was measured by the Fick method during leg cycling while muscle mitochondrial capacity was examined on a biopsy of the vastus lateralis in healthy volunteers (7 male, 2 female) before and after 42 days of skiing at 60% HR max. Peak pulmonary VO2 (3.52 ± 0.18 L.min(-1) pre vs 3.52 ± 0.19 post) and VO2 across the leg (2.8 ± 0.4L.min(-1) pre vs 3.0 ± 0.2 post) were unchanged after the ski journey. Peak leg O2 delivery (3.6 ± 0.2 L.min(-1) pre vs 3.8 ± 0.4 post), O2 extraction (82 ± 1% pre vs 83 ± 1 post), and muscle capillaries per mm(2) (576 ± 17 pre vs 612 ± 28 post) were also unchanged; however, leg muscle mitochondrial OXPHOS capacity was reduced (90 ± 3 pmol.sec(-1) .mg(-1) pre vs 70 ± 2 post, P < 0.05) as was citrate synthase activity (40 ± 3 μmol.min(-1) .g(-1) pre vs 34 ± 3 vs P < 0.05). These findings indicate that peak muscle VO2 can be sustained with a substantial reduction in mitochondrial OXPHOS capacity. This is achieved at a similar O2 delivery and a higher relative ADP-stimulated mitochondrial respiration at a higher mitochondrial p50. These findings support the concept that muscle mitochondrial respiration is submaximal at VO2max , and that mitochondrial volume can be downregulated by chronic energy demand.
|
|
| 3. |
- Blackwood, Sarah J, et al.
(författare)
-
Extreme Variations in Muscle Fiber Composition Enable Detection of Insulin Resistance and Excessive Insulin Secretion.
- 2022
-
Ingår i: Journal of Clinical Endocrinology and Metabolism. - : Oxford University Press. - 0021-972X .- 1945-7197. ; 107:7, s. e2729-e2737
-
Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: Muscle fiber composition is associated with peripheral insulin action.OBJECTIVE: We investigated whether extreme differences in muscle fiber composition are associated with alterations in peripheral insulin action and secretion in young, healthy subjects who exhibit normal fasting glycemia and insulinemia.METHODS: Relaxation time following a tetanic contraction was used to identify subjects with a high or low expression of type I muscle fibers: group I (n=11), area occupied by type I muscle fibers = 61.0 ± 11.8%; group II (n=8), type I area = 36.0 ± 4.9% (P<0.001). Biopsies were obtained from the vastus lateralis muscle and analyzed for mitochondrial respiration on permeabilized fibers, muscle fiber composition and capillary density. An intravenous glucose tolerance test was performed and indices of glucose tolerance, insulin sensitivity and secretion were determined.RESULTS: Glucose tolerance was similar between groups, whereas whole-body insulin sensitivity was decreased by ~50% in group II vs group I (P=0.019). First phase insulin release (area under the insulin curve during 10 min after glucose infusion) was increased by almost 4-fold in group II vs I (P=0.01). Whole-body insulin sensitivity was correlated with % area occupied by type I fibers (r=0.54; P=0.018) and capillary density in muscle (r=0.61; P=0.005), but not with mitochondrial respiration. Insulin release was strongly related to % area occupied by type II fibers (r=0.93; P<0.001).CONCLUSIONS: Assessment of muscle contractile function in young healthy subjects may prove useful in identifying individuals with insulin resistance and enhanced glucose stimulated insulin secretion prior to onset of clinical manifestations.
|
|
| 4. |
- Blackwood, Sarah J, et al.
(författare)
-
Insulin resistance after a 3-day fast is associated with an increased capacity of skeletal muscle to oxidize lipids.
- 2023
-
Ingår i: American Journal of Physiology. Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 324:5, s. E390-E401
-
Tidskriftsartikel (refereegranskat)abstract
- There is a debate on whether lipid-mediated insulin resistance derives from an increased or decreased capacity of muscle to oxidize fats. Here we examine the involvement of muscle fiber composition in the metabolic responses to a 3-day fast (starvation, which results in increases in plasma lipids and insulin resistance) in two groups of healthy young subjects: 1, area occupied by type I fibers = 61.0 ± 11.8%; 2, type I area = 36.0 ± 4.9% (P<0.001). Muscle biopsies and intravenous glucose tolerance tests were performed after an overnight fast and after starvation. Biopsies were analyzed for muscle fiber composition and mitochondrial respiration. Indices of glucose tolerance and insulin sensitivity were determined. Glucose tolerance was similar in both groups after an overnight fast and deteriorated to a similar degree in both groups after starvation. In contrast, whole-body insulin sensitivity decreased markedly after starvation in group 1 (P<0.01), whereas the decrease in group 2 was substantially smaller (P=0.06). Non-esterified fatty acids and β-hydroxybutyrate levels in plasma after an overnight fast were similar between groups and increased markedly and comparably in both groups after starvation, demonstrating similar degrees of lipid load. The capacity of permeabilized muscle fibers to oxidize lipids was significantly higher in group 1 vs. 2, whereas there was no significant difference in pyruvate oxidation between groups. The data demonstrate that loss of whole-body insulin sensitivity after short-term starvation is a function of muscle fiber composition and is associated with an elevated rather than a diminished capacity of muscle to oxidize lipids.
|
|
| 5. |
- Cardinale, Daniele A., 1982-, et al.
(författare)
-
Muscle mass and inspired oxygen influence oxygen extraction at maximal exercise : role of mitochondrial oxygen affinity.
- 2019
-
Ingår i: Acta Physiologica. - : Wiley-Blackwell. - 1748-1708 .- 1748-1716. ; 225:1
-
Tidskriftsartikel (refereegranskat)abstract
- AIM:We examined the Fick components together with mitochondrial O2 affinity (p50mito ) in defining O2 extraction and O2 uptake during exercise with large and small muscle mass during normoxia (NORM) and hyperoxia (HYPER).METHODS:Seven individuals performed two incremental exercise tests to exhaustion on a bicycle ergometer (BIKE) and two on a one-legged knee extension ergometer (KE) in NORM or HYPER. Leg blood flow and VO2 were determined by thermodilution and the Fick method. Maximal ADP-stimulated mitochondrial respiration (OXPHOS) and p50mito were measured ex vivo in isolated mitochondria. Mitochondrial excess capacity in the leg was determined from OXPHOS in permeabilized fibers and muscle mass measured with magnetic resonance imaging in relation to peak leg O2 delivery.RESULTS:The ex vivo p50mito increased from 0.06±0.02 to 0.17±0.04 kPa with varying substrate supply and O2 flux rates from 9.84±2.91 to 16.34±4.07 pmol O2 ·s-1 ·μg-1 respectively. O2 extraction decreased from 83% in BIKE to 67% in KE as a function of a higher O2 delivery, and lower mitochondrial excess capacity. There was a significant relationship between O2 extraction and mitochondrial excess capacity and p50mito that was unrelated to blood flow and mean transit time.CONCLUSION:O2 extraction varies with mitochondrial respiration rate, p50mito and O2 delivery. Mitochondrial excess capacity maintains a low p50mito which enhances O2 diffusion from microvessels to mitochondria during exercise. This article is protected by copyright. All rights reserved.
|
|
| 6. |
- Flockhart, Mikael, et al.
(författare)
-
Reduced glucose tolerance and insulin sensitivity after prolonged exercise in endurance athletes.
- 2023
-
Ingår i: Acta Physiologica. - : John Wiley & Sons. - 1748-1708 .- 1748-1716. ; 238:4
-
Tidskriftsartikel (refereegranskat)abstract
- AIM: The purpose of this study was to 1. investigate if glucose tolerance is affected after one acute bout of different types of exercise; 2. assess if potential differences between two exercise paradigms are related to changes in mitochondrial function; and 3. determine if endurance athletes differ from nonendurance-trained controls in their metabolic responses to the exercise paradigms.METHODS: Nine endurance athletes (END) and eight healthy nonendurance-trained controls (CON) were studied. Oral glucose tolerance tests (OGTT) and mitochondrial function were assessed on three occasions: in the morning, 14 h after an overnight fast without prior exercise (RE), as well as after 3 h of prolonged continuous exercise at 65% of VO2 max (PE) or 5 × 4 min at ~95% of VO2 max (HIIT) on a cycle ergometer.RESULTS: Glucose tolerance was markedly reduced in END after PE compared with RE. END also exhibited elevated fasting serum FFA and ketones levels, reduced insulin sensitivity and glucose oxidation, and increased fat oxidation during the OGTT. CON showed insignificant changes in glucose tolerance and the aforementioned measurements compared with RE. HIIT did not alter glucose tolerance in either group. Neither PE nor HIIT affected mitochondrial function in either group. END also exhibited increased activity of 3-hydroxyacyl-CoA dehydrogenase activity in muscle extracts vs. CON.CONCLUSION: Prolonged exercise reduces glucose tolerance and increases insulin resistance in endurance athletes the following day. These findings are associated with an increased lipid load, a high capacity to oxidize lipids, and increased fat oxidation.
|
|
| 7. |
- Flockhart, Mikael, et al.
(författare)
-
THREE HOURS OF MODERATE INTENSITY EXERCISE TRAINING REDUCES GLUCOSE TOLERANCE IN ENDURANCE TRAINED ATHLETES
- 2022
-
Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- BACKGROUNDIt is well accepted that exercise training improves glucose uptake and insulin sensitivity, and that endurance trained athletes in general show a high capacity for these parameters and excellent metabolic control. However, some studies fail to observe positive effects on glucose regulation in healthy, trained subjects the day after exercise. These, often unexpected, results have been postulated to be caused by excessive training loads, muscle damage, energy deficit, differences in glucose uptake in the exercised and non-exercised musculature and a metabolic interaction through increased fatty acid metabolism which suppresses glucose oxidation and uptake. The mode or volume of exercise that can lead to glucose intolerance in trained athletes as well as mechanistic insights and its relevance for health and performance are, however, not fully understood.AIMWe studied the metabolic response to a glucose load the day after a session of high intensity interval training (HIIT) or three hours of continuous exercise (3h) in endurance trained athletes and compared the results with measurements during rest.METHODNine endurance trained athletes (5 females, 4 males) underwent oral glucose tolerance tests (OGTT) after rest and ~14 hours after exercise on a cycle ergometer (HIIT 5x4 minutes at ~95% of VO2max or 3h at 65% of VO2max). Venous blood was sampled at 15-minute intervals for 120 minutes and concentrations of glucose, insulin, free fatty acids (FFA) and ketones (β-hydroxybutyrate) were measured. Statistical analysis was performed using a RM one-way ANOVA with the Giesser-Greenhouse correction and Dunnett’s test was used to compare the exercise conditions to the resting condition.RESULTSThe area under the curve (AUC) during the OGTT increased greatly after 3h (668±124 mM · min) (p<0.01) compared to rest (532±89) but was found to be unchanged after HIIT (541±96). Resting values of FFA and ketones were increased after 3h (p<0.01 and p<0.05, respectively) but not after HIIT. Insulin was found to be unaltered during all conditions.CONCLUSIONS AND RELEVANCEHere, we show manifestation of glucose intolerance in endurance trained athletes together with concomitant increases in plasma concentrations of FFA and ketones the day after a session of prolonged exercise training but not after HIIT. This could be a protective response for securing glucose delivery to the brain and therefore have a positive effect on endurance. It also has the potential to reduce the recovery of glycogen depots, glucose uptake during exercise and performance at higher work rates.
|
|
| 8. |
|
|
| 9. |
- Larsen, Filip J, et al.
(författare)
-
High-intensity sprint training inhibits mitochondrial respiration through aconitase inactivation
- 2016
-
Ingår i: The FASEB Journal. - : Wiley. - 0892-6638 .- 1530-6860. ; 30:1, s. 417-427
-
Tidskriftsartikel (refereegranskat)abstract
- Intense exercise training is a powerful stimulus that activates mitochondrial biogenesis pathways and thus increases mitochondrial density and oxidative capacity. Moderate levels of reactive oxygen species (ROS) during exercise are considered vital in the adaptive response, but high ROS production is a serious threat to cellular homeostasis. Although biochemical markers of the transition from adaptive to maladaptive ROS stress are lacking, it is likely mediated by redox sensitive enzymes involved in oxidative metabolism. One potential enzyme mediating such redox sensitivity is the citric acid cycle enzyme aconitase. In this study, we examined biopsy specimens of vastus lateralis and triceps brachii in healthy volunteers, together with primary human myotubes. An intense exercise regimen inactivated aconitase by 55-72%, resulting in inhibition of mitochondrial respiration by 50-65%. In the vastus, the mitochondrial dysfunction was compensated for by a 15-72% increase in mitochondrial proteins, whereas H2O2 emission was unchanged. In parallel with the inactivation of aconitase, the intermediary metabolite citrate accumulated and played an integral part in cellular protection against oxidative stress. In contrast, the triceps failed to increase mitochondrial density, and citrate did not accumulate. Instead, mitochondrial H2O2 emission was decreased to 40% of the pretraining levels, together with a 6-fold increase in protein abundance of catalase. In this study, a novel mitochondrial stress response was highlighted where accumulation of citrate acted to preserve the redox status of the cell during periods of intense exercise.
|
|
| 10. |
- Larsen, Filip J, 1977-, et al.
(författare)
-
Mitochondrial oxygen affinity increases after sprint interval training and is related to the improvement in peak oxygen uptake.
- 2020
-
Ingår i: Acta Physiologica. - : John Wiley & Sons. - 1748-1708 .- 1748-1716. ; 229:3
-
Tidskriftsartikel (refereegranskat)abstract
- AIMS: The body responds to exercise training by profound adaptations throughout the cardiorespiratory and muscular systems, which may result in improvements in maximal oxygen consumption (VO2 peak) and mitochondrial capacity. By convenience, mitochondrial respiration is often measured at supra-physiological oxygen levels, an approach that ignores any potential regulatory role of mitochondrial affinity for oxygen (p50mito ) at physiological oxygen levels.METHODS: In this study, we examined the p50mito of mitochondria isolated from the Vastus lateralis and Triceps brachii in 12 healthy volunteers before and after a training intervention with 7 sessions of sprint interval training using both leg cycling and arm cranking. The changes in p50mito were compared to changes in whole-body VO2 peak.RESULTS: We here show that p50mito is similar in isolated mitochondria from the Vastus (40 ± 3.8 Pa) compared to Triceps (39 ± 3.3) but decreases (mitochondrial oxygen affinity increases) after 7 sessions of sprint interval training (to 26 ± 2.2 Pa in Vastus and 22 ± 2.7 Pa in Triceps, both p<0.01). The change in VO2 peak modeled from changes in p50mito was correlated to actual measured changes in VO2 peak (R2 =0.41, p=0.002).CONCLUSION: Together with mitochondrial respiratory capacity, p50mito is a critical factor when measuring mitochondrial function, it can decrease with sprint interval training and should be considered in the integrative analysis of the oxygen cascade from lung to mitochondria.
|
|
