| 1. |
- Adler, Dana, et al.
(author)
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Weak Electromagnetic Fields Accelerate Fusion of Myoblasts.
- 2021
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In: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 22:9
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Journal article (peer-reviewed)abstract
- Weak electromagnetic fields (WEF) alter Ca2+ handling in skeletal muscle myotubes. Owing to the involvement of Ca2+ in muscle development, we investigated whether WEF affects fusion of myoblasts in culture. Rat primary myoblast cultures were exposed to WEF (1.75 µT, 16 Hz) for up to six days. Under control conditions, cell fusion and creatine kinase (CK) activity increased in parallel and peaked at 4-6 days. WEF enhanced the extent of fusion after one and two days (by ~40%) vs. control, but not thereafter. Exposure to WEF also enhanced CK activity after two days (almost four-fold), but not afterwards. Incorporation of 3H-thymidine into DNA was enhanced by one-day exposure to WEF (~40%), indicating increased cell replication. Using the potentiometric fluorescent dye di-8-ANEPPS, we found that exposure of cells to 150 mM KCl resulted in depolarization of the cell membrane. However, prior exposure of cells to WEF for one day followed by addition of KCl resulted in hyperpolarization of the cell membrane. Acute exposure of cells to WEF also resulted in hyperpolarization of the cell membrane. Twenty-four hour incubation of myoblasts with gambogic acid, an inhibitor of the inward rectifying K+ channel 2.1 (Kir2.1), did not affect cell fusion, WEF-mediated acceleration of fusion or hyperpolarization. These data demonstrate that WEF accelerates fusion of myoblasts, resulting in myotube formation. The WEF effect is associated with hyperpolarization but WEF does not appear to mediate its effects on fusion by activating Kir2.1 channels.
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| 2. |
- Berthelson, Per, et al.
(author)
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Acute exercise and starvation induced insulin resistance
- 2012
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In: Medicine & Science In Sports & Exercise, 2012, S498 Vol. 44 No. 5 Supplement. 2661.. ; , s. 2661-
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Conference paper (other academic/artistic)abstract
- It is well known that starvation causes insulin resistance. The mechanism is unclear but may relate disturbances in lipid metabolism i.e. incomplete mitochondrial FA oxidation and/or accumulation of lipid intermediates. Exercise results in increased substrate oxidation and may thus remove interfering lipid metabolites and reverse starvation-induced insulin resistance. However, the effect of acute exercise and starvation on insulin sensitivity is not known.Purpose: The aim of this study was to investigate the effect of exercise on starvation-induced insulin resistance and to elucidate potential mechanisms.Methods: Nine healthy lean subjects underwent 84h starvation on two occasions separated by at least 2 weeks. The starvation period was followed by either exercise (EX; 5x10 min intervals with 2-4 min rest, starting at 70 %VO2 max) or an equal period of rest (NE). Before and after the starvation period (3h after exercise/rest) subjects were investigated with muscle biopsies, bloo samples and an intravenous glucose tolerance test. Muscle samples were used for measurement of mitochondrial respiration in permeabilized muscle fibers (Oroboros oxygraph), glycogen content and activation of signaling proteins.Results: Insulin sensitivity was significantly higher in the EX group compared to the NE group (p<0.05). After starvation mitochondrial respiration was lower in both groups with complex I substrates whereas respiration with complex I+II substrates was higher in EX (p<0.05 vs. basal and NE). Muscle glycogen was decreased to 73% (NE) and 31% (EX) of the basal values. The EX group had a significant increased activation of AS160. Plasma FA increased 3-4 fold to 1.39±0.32(NE) and 1.80±0.49 (EX) (mmol/l) after starvation and plasma beta-hydroxybutyrate increased about 50-fold to 6.43±2.01(NE) and 7.12±1.59 (EX)(mmol/l).Conclusion: Acute exercise reverses starvation-induced insulin resistance. Plasma FA and BOH were increased to similar extent after NE and EX and cannot explain the changes in insulin sensitivity. However, an increased substrate oxidation together with the observed increased capacity for mitochondrial FA oxidation after EX may be involved in the activation of AS160 and the reversal of starvation-induced insulin resistance.
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| 3. |
- Blackwood, Sarah J, et al.
(author)
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Elevated heart rate and decreased muscle endothelial nitric oxide synthase in early development of insulin resistance.
- 2024
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In: American Journal of Physiology. Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 327:2, s. E172-E182
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Journal article (peer-reviewed)abstract
- Insulin resistance (IR) is a risk factor for the development of several major metabolic diseases. Muscle fiber composition is established early in life and is associated with insulin sensitivity. Hence, muscle fiber composition was used to identify early defects in the development of IR in healthy young individuals in the absence of clinical manifestations. Biopsies were obtained from the thigh muscle, followed by an intravenous glucose tolerance test. Indices of insulin action were calculated and cardiovascular measurements, analyses of blood and muscle were performed. Whole-body insulin sensitivity (SIgalvin) was positively related to expression of type I muscle fibers (r=0.49; P<0.001) and negatively related to resting heart rate (HR, r=-0.39; P<0.001), which was also negatively related to expression of type I muscle fibers (r=-0.41; P<0.001). Muscle protein expression of endothelial nitric oxide synthase (eNOS), whose activation results in vasodilation, was measured in two subsets of subjects expressing a high percentage of type I fibers (59±6%; HR = 57±9 beats/min; SIgalvin = 1.8±0.7 units) or low percentage of type I fibers (30±6%; HR = 71±11; SIgalvin = 0.8±0.3 units; P<0.001 for all variables vs. first group). eNOS expression was: 1. higher in subjects with high type I expression; 2. almost two-fold higher in pools of type I vs. II fibers; 3. only detected in capillaries surrounding muscle fibers; and 4. linearly associated with SIgalvin. These data demonstrate that an altered function of the autonomic nervous system and a compromised capacity for vasodilation in the microvasculature occur early in the development of IR.
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| 4. |
- Blackwood, Sarah J, et al.
(author)
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Extreme Variations in Muscle Fiber Composition Enable Detection of Insulin Resistance and Excessive Insulin Secretion.
- 2022
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In: Journal of Clinical Endocrinology and Metabolism. - : Oxford University Press. - 0021-972X .- 1945-7197. ; 107:7, s. e2729-e2737
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Journal article (peer-reviewed)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.
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| 5. |
- Blackwood, Sarah J, et al.
(author)
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Insulin resistance after a 3-day fast is associated with an increased capacity of skeletal muscle to oxidize lipids.
- 2023
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In: American Journal of Physiology. Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 324:5, s. E390-E401
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Journal article (peer-reviewed)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.
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| 6. |
- Blackwood, Sarah J, et al.
(author)
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Isoproterenol enhances force production in mouse glycolytic and oxidative muscle via separate mechanisms.
- 2019
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In: Pflügers Archiv. - : Springer. - 0031-6768 .- 1432-2013. ; 471:10, s. 1305-1316
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Journal article (peer-reviewed)abstract
- Fight or flight is a biologic phenomenon that involves activation of β-adrenoceptors in skeletal muscle. However, how force generation is enhanced through adrenergic activation in different muscle types is not fully understood. We studied the effects of isoproterenol (ISO, β-receptor agonist) on force generation and energy metabolism in isolated mouse soleus (SOL, oxidative) and extensor digitorum longus (EDL, glycolytic) muscles. Muscles were stimulated with isometric tetanic contractions and analyzed for metabolites and phosphorylase activity. Under conditions of maximal force production, ISO enhanced force generation markedly more in SOL (22%) than in EDL (8%). Similarly, during a prolonged tetanic contraction (30 s for SOL and 10 s for EDL), ISO-enhanced the force × time integral more in SOL (25%) than in EDL (3%). ISO induced marked activation of phosphorylase in both muscles in the basal state, which was associated with glycogenolysis (less in SOL than in EDL), and in EDL only, a significant decrease (16%) in inorganic phosphate (Pi). ATP turnover during sustained contractions (1 s EDL, 5 s SOL) was not affected by ISO in EDL, but essentially doubled in SOL. Under conditions of maximal stimulation, ISO has a minor effect on force generation in EDL that is associated with a decrease in Pi, whereas ISO has a marked effect on force generation in SOL that is associated with an increase in ATP turnover. Thus, phosphorylase functions as a phosphate trap in ISO-mediated force enhancement in EDL and as a catalyzer of ATP supply in SOL.
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| 7. |
- Blackwood, Sarah J, et al.
(author)
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Role of nitration in control of phosphorylase and glycogenolysis in mouse skeletal muscle.
- 2021
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In: American Journal of Physiology. Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 320:4, s. E691-E701
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Journal article (peer-reviewed)abstract
- Phosphorylase is one of the most carefully studied proteins in history, but knowledge of its regulation during intense muscle contraction is incomplete. Tyrosine nitration of purified preparations of skeletal muscle phosphorylase results in inactivation of the enzyme and this is prevented by antioxidants. Whether an altered redox state affects phosphorylase activity and glycogenolysis in contracting muscle is not known. Here, we investigate the role of redox state in control of phosphorylase and glycogenolysis in isolated mouse fast-twitch (extensor digitorum longus, EDL) and slow-twitch (soleus) muscle preparations during repeated contractions. Exposure of crude muscle extracts to H2O2 had little effect on phosphorylase activity. However, exposure of extracts to peroxynitrite (ONOO-), a nitrating/oxidizing agent, resulted in complete inactivation of phosphorylase (half maximal inhibition at ~200 µM ONOO-), which was fully reversed by the presence of an ONOO-scavanger, dithiothreitol (DTT). Incubation of isolated muscles with ONOO- resulted in nitration of phosphorylase and marked inhibition of glycogenolysis during repeated contractions. ONOO- also resulted in large decreases in high-energy phosphates (ATP and phosphocreatine) in the rested state and following repeated contractions. These metabolic changes were associated with decreased force production during repeated contractions (to ~60% of control). In contrast, repeated contractions did not result in nitration of phosphorylase, nor did DTT or the general antioxidant N-acetylcysteine alter glycogenolysis during repeated contractions. These findings demonstrate that ONOO- inhibits phosphorylase and glycogenolysis in living muscle under extreme conditions. However, nitration does not play a significant role in control of phosphorylase and glycogenolysis during repeated contractions.
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| 8. |
- Bruton, Joseph D., et al.
(author)
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Increased fatigue resistance linked to Ca(2+)-stimulated mitochondrial biogenesis in muscle fibres of cold-acclimated mice
- 2010
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In: Journal of Physiology. - : Wiley. - 0022-3751 .- 1469-7793. ; 588:21, s. 4275-4288
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Journal article (peer-reviewed)abstract
- Mammals exposed to a cold environment initially generate heat by repetitive muscle activity (shivering). Shivering is successively replaced by the recruitment of uncoupling protein-1 (UCP1)-dependent heat production in brown adipose tissue. Interestingly, adaptations observed in skeletal muscles of cold-exposed animals are similar to those observed with endurance training. We hypothesized that increased myoplasmic free [Ca2+] ([Ca2+]i) is important for these adaptations. To test this hypothesis, experiments were performed on flexor digitorum brevis (FDB) muscles, which do not participate in the shivering response, of adult wild-type (WT) and UCP1-ablated (UCP1-KO) mice kept either at room temperature (24 ºC) or cold-acclimated (4 ºC) for 4-5 weeks. [Ca2+]i (measured with indo-1) and force were measured under control conditions and during fatigue induced by repeated tetanic stimulation in intact single fibres. The results show no differences between fibres from WT and UCP1-KO mice. However, muscle fibres from cold-acclimated mice showed significant increases in basal [Ca2+]i (~50%), tetanic [Ca2+]i (~40%), and sarcoplasmic reticulum (SR) Ca2+ leak (~four-fold) as compared to fibres from room-temperature mice. Muscles of cold-acclimated mice showed increased expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and increased citrate synthase activity (reflecting increased mitochondrial content). Fibres of cold-acclimated mice were more fatigue resistant with higher tetanic [Ca2+]i and less force loss during fatiguing stimulation. In conclusion, cold exposure induces changes in FDB muscles similar to those observed with endurance training and we propose that increased [Ca2+]i is a key factor underlying these adaptations.
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| 9. |
- Durrant, Christelle, et al.
(author)
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Defects in Galactose Metabolism and Glycoconjugate Biosynthesis in a UDP-Glucose Pyrophosphorylase-Deficient Cell Line Are Reversed by Adding Galactose to the Growth Medium.
- 2020
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In: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 21:6
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Journal article (peer-reviewed)abstract
- UDP-glucose (UDP-Glc) is synthesized by UGP2-encoded UDP-Glc pyrophosphorylase (UGP) and is required for glycoconjugate biosynthesis and galactose metabolism because it is a uridyl donor for galactose-1-P (Gal1P) uridyltransferase. Chinese hamster lung fibroblasts harboring a hypomrphic UGP(G116D) variant display reduced UDP-Glc levels and cannot grow if galactose is the sole carbon source. Here, these cells were cultivated with glucose in either the absence or presence of galactose in order to investigate glycoconjugate biosynthesis and galactose metabolism. The UGP-deficient cells display < 5% control levels of UDP-Glc/UDP-Gal and > 100-fold reduction of [6-3H]galactose incorporation into UDP-[6-3H]galactose, as well as multiple deficits in glycoconjugate biosynthesis. Cultivation of these cells in the presence of galactose leads to partial restoration of UDP-Glc levels, galactose metabolism and glycoconjugate biosynthesis. The Vmax for recombinant human UGP(G116D) with Glc1P is 2000-fold less than that of the wild-type protein, and UGP(G116D) displayed a mildly elevated Km for Glc1P, but no activity of the mutant enzyme towards Gal1P was detectable. To conclude, although the mechanism behind UDP-Glc/Gal production in the UGP-deficient cells remains to be determined, the capacity of this cell line to change its glycosylation status as a function of extracellular galactose makes it a useful, reversible model with which to study different aspects of galactose metabolism and glycoconjugate biosynthesis.
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| 10. |
- Edman, Sebastian, et al.
(author)
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Pro-Brain-Derived Neurotrophic Factor (BDNF), but Not Mature BDNF, Is Expressed in Human Skeletal Muscle : Implications for Exercise-Induced Neuroplasticity.
- 2024
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In: Function. - : Oxford University Press. - 2633-8823. ; 5:3
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Journal article (peer-reviewed)abstract
- Exercise promotes brain plasticity partly by stimulating increases in mature brain-derived neurotrophic factor (mBDNF), but the role of the pro-BDNF isoform in the regulation of BDNF metabolism in humans is unknown. We quantified the expression of pro-BDNF and mBDNF in human skeletal muscle and plasma at rest, after acute exercise (+/- lactate infusion), and after fasting. Pro-BDNF and mBDNF were analyzed with immunoblotting, enzyme-linked immunosorbent assay, immunohistochemistry, and quantitative polymerase chain reaction. Pro-BDNF was consistently and clearly detected in skeletal muscle (40-250 pg mg-1 dry muscle), whereas mBDNF was not. All methods showed a 4-fold greater pro-BDNF expression in type I muscle fibers compared to type II fibers. Exercise resulted in elevated plasma levels of mBDNF (55%) and pro-BDNF (20%), as well as muscle levels of pro-BDNF (∼10%, all P < 0.05). Lactate infusion during exercise induced a significantly greater increase in plasma mBDNF (115%, P < 0.05) compared to control (saline infusion), with no effect on pro-BDNF levels in plasma or muscle. A 3-day fast resulted in a small increase in plasma pro-BDNF (∼10%, P < 0.05), with no effect on mBDNF. Pro-BDNF is highly expressed in human skeletal muscle, particularly in type I fibers, and is increased after exercise. While exercising with higher lactate augmented levels of plasma mBDNF, exercise-mediated increases in circulating mBDNF likely derive partly from release and cleavage of pro-BDNF from skeletal muscle, and partly from neural and other tissues. These findings have implications for preclinical and clinical work related to a wide range of neurological disorders such as Alzheimer's, clinical depression, and amyotrophic lateral sclerosis.
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| 11. |
- Edman, Sebastian, 1990-
(author)
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Skeletal muscle fiber types in man : With special reference to anabolic signaling and mitochondrial bioenergetics
- 2022
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Doctoral thesis (other academic/artistic)abstract
- Human skeletal muscle consists of a mixture of slow-twitch (type I) and fast-twitch (type II) fibers. The type I fibers are endurance-oriented, with a metabolic system and infrastructure that supports aerobic metabolism. This entails a well-developed capillary grid and a mitochondrial network proportioned to the number of contractile units within the fiber. These fibers generally have slower and less forceful contraction mechanics and more limited muscle growth as a resource-efficient metabolic energy system is prioritized over increasing the number of contractile units. By contrast, type II fibers prioritize contractile capabilities and force generation at the cost of resource efficiency. These fibers have a substantially lower mitochondrial volume but prioritize structures and organelles that benefit muscle contraction instead. It is well known that resistance exercise combined with dietary protein intake stimulates the growth of contractile proteins leading to an increased muscle mass over time. Muscle mass accumulation is primarily driven by the amplification of muscle protein synthesis, which in turn is largely governed by the mTORC1 signaling pathway within the muscle cell. Little is known about how mTORC1 signaling regulates growth in the different fiber types. Furthermore, it is unknown whether blunted anabolic signaling in type II fibers of the elderly may explain why losses of muscle mass occur primarily in these fibers with advancing age.Endurance exercise, on the other hand, primarily stimulates a prioritization to synthesize new mitochondria to support the high demand for sustainable aerobic energy output. However, it remains to be determined if mitochondria created within type I and type II fibers are equal, or whether they have adapted to their respective milieu in any way. Therefore, the aim of the current thesis was to investigate how the mTORC1 pathway in type I and type II fibers responds to resistance exercise and nutritional stimuli in the form of essential amino acids (EAA), and to determine if this response is influenced by age. Fiber type-specific mitochondrial populations, including their respiratory capacity, were also investigated. To facilitate these investigations, a new and improved method for muscle fiber type identification was developed.In paper I, the phosphorylation of mTORC1 in response to resistance exercise and EAA intake was examined in 684 individual muscle fibers. Unsurprisingly, a significant increase in mTORC1 signaling was seen following the combination of resistance exercise and EAA intake, whereas the rise following resistance exercise alone was more modest. However, no evidence of a discrete response in the different fiber types was found. In paper II, a new method was developed to facilitate the work surrounding fiber type-specific muscle physiology by limiting the extreme time requirements of fiber type identification of large sample sets of muscle fibers. The novel method, which was named THRIFTY, allows an experienced technician to classify over 800 fibers in under 11h.Paper III utilizes the high throughput of the THRIFTY method described in paper II to create the most extensive study to date on individually dissected muscle fibers with 27 602 included fibers. Here, the aim was to investigate whether the fiber type-specific muscle atrophy of the type II fibers in aging could be explained by an onset of anabolic resistance in these fibers. For this investigation, ten young and ten elderly men were recruited to perform a unilateral resistance exercise session followed by ingestion of EAA. This paper showed a slightly elevated mTORC1 signaling response in type I fibers. However, there were no signs of blunted mTORC1 signaling in the elderly. In paper IV, the high speed of the THRIFTY method was utilized to analyze the mitochondrial respiratory function of permeabilized type I and type II muscle fibers. In addition, the intrinsic protein expression of mitochondria in the type I and type II muscle fibers was analyzed. As expected, a higher volume of mitochondria and a greater respiratory rate in the type I fibers were found. However, on a per mitochondria basis, a higher maximal respiratory rate was observed in type II fibers together with increased levels of proteins in the electron transport chain. Likewise, proteins regulating mitochondrial fission and fusion were more highly expressed in the type II fiber mitochondria, which may be a compensatory mechanism for the low volume. In conclusion, both fiber types show robust increases in mTORC1 signaling in response to exercise and EAA ingestion. The results indicate that the response is slightly stronger in the type I fibers, which is contrary to what was predicted. Moreover, the highly specific type II fiber atrophy seen with aging cannot be explained by a blunted anabolic response in these fibers. Surprisingly, the mitochondria of type II fibers possess a higher respiratory capacity. However, this discrepancy is concealed by the vast difference in mitochondrial volume favoring type I fibers, ultimately leading to an overall greater respiratory rate in the type I fibers.
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| 12. |
- Einstein, Ofira, et al.
(author)
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Physical exercise therapy for autoimmune neuroinflammation : Application of knowledge from animal models to patient care.
- 2022
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In: Autoimmunity Reviews. - : Elsevier. - 1568-9972 .- 1873-0183. ; 21:4
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Journal article (peer-reviewed)abstract
- Physical exercise (PE) impacts various autoimmune diseases. Accordingly, clinical trials demonstrated the safety of PE in multiple sclerosis (MS) patients and indicated beneficial outcomes. There is also an increasing body of research on the beneficial effects of exercise on experimental autoimmune encephalomyelitis (EAE), the animal model of MS, and various mechanisms underlying these effects were suggested. However, despite the documented favorable impact of PE on our health, we still lack a thorough understanding of its effects on autoimmune neuroinflammation and specific guidelines of PE therapy for MS patients are lacking. To that end, current findings on the impact of PE on autoimmune neuroinflammation, both in human MS and animal models are reviewed. The concept of personalized PE therapy for autoimmune neuroinflammation is discussed, and future research for providing biological rationale for clinical trials to pave the road for precise PE therapy in MS patients is described.
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| 13. |
- Fainstein, Nina, et al.
(author)
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Exercise intensity-dependent immunomodulatory effects on encephalomyelitis.
- 2019
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In: Annals of Clinical & Translational Neurology. - : John Wiley & Sons. - 2328-9503. ; 6:9, s. 1647-1658
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Journal article (peer-reviewed)abstract
- BACKGROUND: Exercise training (ET) has beneficial effects on multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE). However, the intensity-dependent effects of ET on the systemic immune system in EAE remain undefined.OBJECTIVE: (1) To compare the systemic immune modulatory effects of moderate versus high-intensity ET protocols in protecting against development of EAE; (2) To investigate whether ET affects autoimmunity selectively, or causes general immunosuppression.METHODS: Healthy mice performed moderate or high-intensity treadmill running programs. Proteolipid protein (PLP)-induced transfer EAE was utilized to examine ET effects specifically on the systemic immune system. Lymph node (LN)-T cells from trained versus sedentary donor mice were transferred to naïve recipients and EAE severity was assessed, by clinical assessment and histopathological analysis. LN-T cells derived from donor trained versus sedentary PLP-immunized mice were analyzed in vitro for proliferation assays by flow cytometry analysis and cytokine and chemokine receptor gene expression using real-time PCR. T cell-dependent immune responses of trained versus sedentary mice to the nonautoantigen ovalbumin and susceptibility to Escherichia coli-induced acute peritonitis were examined.RESULTS: High-intensity training in healthy donor mice induced significantly greater inhibition than moderate-intensity training on proliferation and generation of encephalitogenic T cells in response to PLP-immunization, and on EAE severity upon their transfer into recipient mice. High-intensity training also inhibited LN-T cell proliferation in response to ovalbumin immunization. E. coli bacterial counts and dissemination were not affected by training.INTERPRETATION: High-intensity training induces superior effects in preventing autoimmunity in EAE, but does not alter immune responses to E. coli infection.
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| 14. |
- Flockhart, Mikael, et al.
(author)
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Reduced glucose tolerance and insulin sensitivity after prolonged exercise in endurance athletes.
- 2023
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In: Acta Physiologica. - : John Wiley & Sons. - 1748-1708 .- 1748-1716. ; 238:4
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Journal article (peer-reviewed)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.
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| 15. |
- Flockhart, Mikael, et al.
(author)
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THREE HOURS OF MODERATE INTENSITY EXERCISE TRAINING REDUCES GLUCOSE TOLERANCE IN ENDURANCE TRAINED ATHLETES
- 2022
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Conference paper (other academic/artistic)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.
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| 16. |
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| 17. |
- Frank, Per, et al.
(author)
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Acute exercise during starvation improves insulin sensitivity and increases mitochondrial FA oxidation
- 2012
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Conference paper (other academic/artistic)abstract
- Aim: To investigate if exercise can reverse starvation-induced insulin resistance and to elucidate the mechanism. Methods: Nine subjects underwent 87 h of starvation with (EX) or without (NE) one exercise session at the end. Before and after starvation (3 h post-exercise) subjects underwent an intravenous glucose tolerance test and muscle biopsy. Results: Insulin sensitivity decreased after starvation (NE) but increased after exercise (EX). Glycogen stores were reduced and plasma FA and β-Hydroxybutyrate increased in both conditions. Mitochondrial respiration with FA substrate increased in EX but was unchanged in NE. RCR and mitochondrial ROS production decreased in both conditions. Phosphorylation of Acetyl-CoA carboxylase (ACC) and Akt substrate of 160 kDA (AS160) proteins increased in EX. Conclusion: Exercise improves starvation induced insulin resistance, probably by increased mitochondrial FA oxidation, reduced glycogen stores and alterations in signaling proteins involved in glucose uptake and FA metabolism.
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| 18. |
- Frank, Per, et al.
(author)
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Acute exercise reverses starvation-mediated insulin resistance in humans.
- 2013
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In: American Journal of Physiology. Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 304:4, s. E436-43
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Journal article (peer-reviewed)abstract
- Within 2-3 days of starvation, pronounced insulin resistance develops, possibly mediated by increased lipid load. Here, we show that one exercise bout increases mitochondrial fatty acid (FA) oxidation and reverses starvation-induced insulin resistance. Nine healthy subjects underwent 75-h starvation on two occasions: with no exercise (NE) or with one exercise session at the end of the starvation period (EX). Muscle biopsies were analyzed for mitochondrial function, contents of glycogen, and phosphorylation of regulatory proteins. Glucose tolerance and insulin sensitivity, measured with an intravenous glucose tolerance test (IVGTT), were impaired after starvation, but in EX the response was attenuated or abolished. Glycogen stores were reduced, and plasma FA was increased in both conditions, with a more pronounced effect in EX. After starvation, mitochondrial respiration decreased with complex I substrate (NE and EX), but in EX there was an increased respiration with complex I + II substrate. EX altered regulatory proteins associated with increases in glucose disposal (decreased phosphorylation of glycogen synthase), glucose transport (increased phosphorylation of Akt substrate of 160 kDa), and FA oxidation (increased phosphorylation of acetyl-CoA carboxylase). In conclusion, exercise reversed starvation-induced insulin resistance and was accompanied by reduced glycogen stores, increased lipid oxidation capacity, and activation of signaling proteins involved in glucose transport and FA metabolism.
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| 19. |
- Goldberg, Yehuda, et al.
(author)
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Continuous and interval training attenuate encephalomyelitis by separate immunomodulatory mechanisms.
- 2021
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In: Annals of Clinical and Translational Neurology. - : Wiley-Blackwell. - 2328-9503. ; 8:1, s. 190-200
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Journal article (peer-reviewed)abstract
- BACKGROUND: Studies have reported beneficial effects of exercise training on autoimmunity, and specifically on multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). However, it is unknown whether different training paradigms affect disease course via shared or separate mechanisms.OBJECTIVE: To compare the effects and mechanism of immune modulation of high intensity continuous training (HICT) versus high intensity interval training (HIIT) on systemic autoimmunity in EAE.METHODS: We used the proteolipid protein (PLP)-induced transfer EAE model to examine training effects on the systemic autoimmune response. Healthy mice performed HICT or HIIT by running on a treadmill. Lymph-node (LN)-T cells from PLP-immunized trained- versus sedentary donor mice were transferred to naïve recipients and EAE clinical and pathological severity were assessed. LN cells derived from donor trained and sedentary PLP-immunized mice were analyzed in vitro for T-cell activation and proliferation, immune cell profiling, and cytokine mRNA levels and cytokine secretion measurements.RESULTS: Both HICT and HIIT attenuated the encephalitogenicity of PLP-reactive T cells, as indicated by reduced EAE clinical severity and inflammation and tissue pathology in the central nervous system, following their transfer into recipient mice. HICT caused a marked inhibition of PLP-induced T-cell proliferation without affecting the T-cell profile. In contrast, HIIT did not alter T-cell proliferation, but rather inhibited polarization of T cells into T-helper 1 and T-helper 17 autoreactive populations.INTERPRETATION: HICT and HIIT attenuate systemic autoimmunity and T cell encephalitogenicity by distinct immunomodulatory mechanisms.
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| 20. |
- Goldberg, Yehuda, et al.
(author)
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High-intensity interval training attenuates development of autoimmune encephalomyelitis solely by systemic immunomodulation.
- 2023
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In: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 13:1
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Journal article (peer-reviewed)abstract
- The impact of high-intensity interval training (HIIT) on the central nervous system (CNS) in autoimmune neuroinflammation is not known. The aim of this study was to determine the direct effects of HIIT on the CNS and development of experimental autoimmune encephalomyelitis (EAE). Healthy mice were subjected to HIIT by treadmill running and the proteolipid protein (PLP) transfer EAE model was utilized. To examine neuroprotection, PLP-reactive lymph-node cells (LNCs) were transferred to HIIT and sedentary (SED) mice. To examine immunomodulation, PLP-reactive LNCs from HIIT and SED donor mice were transferred to naïve recipients and analyzed in vitro. HIIT in recipient mice did not affect the development of EAE following exposure to PLP-reactive LNCs. HIIT mice exhibited enhanced migration of systemic autoimmune cells into the CNS and increased demyelination. In contrast, EAE severity in recipient mice injected with PLP-reactive LNCs from HIIT donor mice was significantly diminished. The latter positive effect was associated with decreased migration of autoimmune cells into the CNS and inhibition of very late antigen (VLA)-4 expression in LNCs. Thus, the beneficial effect of HIIT on EAE development is attributed solely to systemic immunomodulatory effects, likely because of systemic inhibition of autoreactive cell migration and reduced VLA-4 integrin expression.
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| 21. |
- Hamdi, Liel, et al.
(author)
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Exercise training alters autoimmune cell invasion into the brain in autoimmune encephalomyelitis.
- 2022
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In: Annals of Clinical and Translational Neurology. - : Wiley-Blackwell. - 2328-9503. ; 9:11, s. 1792-1806
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Journal article (peer-reviewed)abstract
- BACKGROUND: The mechanisms by which exercise training (ET) elicits beneficial effects on the systemic immune system and the central nervous system (CNS) in autoimmune neuroinflammation are not fully understood.OBJECTIVES: To investigate (1) the systemic effects of high-intensity continuous training (HICT) on the migratory potential of autoimmune cells; (2) the direct effects of HICT on blood-brain-barrier (BBB) properties.METHODS: Healthy mice were subjected to high-intensity continuous training (HICT) by treadmill running. The proteolipid protein (PLP) transfer EAE model was utilized to examine the immunomodulatory effects of training, where PLP-reactive lymph-node cells (LNCs) from HICT and sedentary donor mice were analyzed in vitro and transferred to naïve recipients that developed EAE. To examine neuroprotection, encephalitogenic LNCs from donor mice were transferred into HICT or sedentary recipient mice and the BBB was analyzed.RESULTS: Transfer of PLP-reactive LNCs obtained from HICT donor mice attenuated EAE severity and inflammation in recipient mice. HICT markedly inhibited very late antigen (VLA)-4 and lymphocyte function-associated antigen (LFA)-1 expression in LNCs. Transfer of encephalitogenic LNCs into HICT recipients resulted in milder EAE and attenuated CNS inflammation. HICT reduced BBB permeability and the expression of intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 in CNS blood vessels.INTERPRETATION: HICT attenuates EAE development by both immunomodulatory and neuroprotective effects. The reduction in destructive CNS inflammation in EAE is attributed to systemic inhibition of autoreactive cell migratory potential, as well as reduction in BBB permeability, which are associated with reduced VLA-4/VCAM-1 and LFA-1/ICAM-1 interactions.
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| 22. |
- Katz, Abram
(author)
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A century of exercise physiology : key concepts in regulation of glycogen metabolism in skeletal muscle.
- 2022
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In: European Journal of Applied Physiology. - : Springer. - 1439-6319 .- 1439-6327. ; 122:8, s. 1751-1772
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Journal article (peer-reviewed)abstract
- Glycogen is a branched, glucose polymer and the storage form of glucose in cells. Glycogen has traditionally been viewed as a key substrate for muscle ATP production during conditions of high energy demand and considered to be limiting for work capacity and force generation under defined conditions. Glycogenolysis is catalyzed by phosphorylase, while glycogenesis is catalyzed by glycogen synthase. For many years, it was believed that a primer was required for de novo glycogen synthesis and the protein considered responsible for this process was ultimately discovered and named glycogenin. However, the subsequent observation of glycogen storage in the absence of functional glycogenin raises questions about the true role of the protein. In resting muscle, phosphorylase is generally considered to be present in two forms: non-phosphorylated and inactive (phosphorylase b) and phosphorylated and constitutively active (phosphorylase a). Initially, it was believed that activation of phosphorylase during intense muscle contraction was primarily accounted for by phosphorylation of phosphorylase b (activated by increases in AMP) to a, and that glycogen synthesis during recovery from exercise occurred solely through mechanisms controlled by glucose transport and glycogen synthase. However, it now appears that these views require modifications. Moreover, the traditional roles of glycogen in muscle function have been extended in recent years and in some instances, the original concepts have undergone revision. Thus, despite the extensive amount of knowledge accrued during the past 100 years, several critical questions remain regarding the regulation of glycogen metabolism and its role in living muscle.
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| 23. |
- Katz, Abram, et al.
(author)
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Effects of N-acetylcysteine on isolated mouse skeletal muscle : contractile properties, temperature dependence, and metabolism
- 2014
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In: Pflügers Archiv. - : Springer Science and Business Media LLC. - 0031-6768 .- 1432-2013. ; 466:3, s. 577-585
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Journal article (peer-reviewed)abstract
- The effects of the general antioxidant N-acetylcysteine (NAC) on muscle function and metabolism were examined. Isolated paired mouse extensor digitorum longus muscles were studied in the absence or presence of 20 mM NAC. Muscles were electrically stimulated to perform 100 isometric tetanic contractions (300 ms duration) at frequencies resulting in similar to 85 % of maximal force (70-150 Hz at 25-40 A degrees C). NAC did not significantly affect peak force in the unfatigued state at any temperature but significantly slowed tetanic force development in a temperature-dependent fashion (e.g., time to 50 % of peak tension averaged 35 A +/- 2 ms [control] and 37 A +/- 1 ms [NAC] at 25 A degrees C vs. 21 A +/- 1 ms [control] and 52 A +/- 6 ms [NAC, P < 0.01] at 40 A degrees C). During repeated contractions, NAC maximally enhanced peak force by the fifth tetanus at all temperatures (by similar to 30 %). Thereafter, the effect of NAC disappeared rapidly at high temperatures (35-40 A degrees C) and more slowly at the lower temperatures (25-30 A degrees C). At all temperatures, the enhancing effect of NAC on peak force was associated with a slowing of relaxation. NAC did not significantly affect myosin light chain phosphorylation at rest or after five contractions (similar to 50 % increase vs. rest). After five tetani, lactate and inorganic phosphate increased about 20-fold and 2-fold, respectively, both in control and NAC-treated muscles. Interestingly, after five tetani, the increase in glucose 6-P was similar to 2-fold greater, whereas the increase in malate was inhibited by similar to 75 % with NAC vs. control, illustrating the metabolic effects of NAC. NAC slightly decreased the maximum shortening velocity in early fatigue (five to seven repeated tetani). These data demonstrate that the antioxidant NAC transiently enhances muscle force generation by a mechanism that is independent of changes in myosin light chain phosphorylation and inorganic phosphate. The slowing of relaxation suggests that NAC enhances isometric force by facilitating fusion (i.e., delaying force decline between pulses). The initial slowing of tension development and subsequent slowing of relaxation suggest that NAC would result in impaired performance during a high-intensity dynamic exercise.
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| 24. |
- Katz, Abram
(author)
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The role of glycogen phosphorylase in glycogen biogenesis in skeletal muscle after exercise
- 2023
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In: Sports Medicine and Health Science. - : Elsevier. - 2666-3376. ; 5:1, s. 29-33
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Journal article (peer-reviewed)abstract
- Initially it was believed that phosphorylase was responsible for both glycogen breakdown and synthesis in the living cell. The discovery of glycogen synthase and McArdle's disease (lack of phosphorylase activity), together with the high Pi/glucose 1-P ratio in skeletal muscle, demonstrated that glycogen synthesis could not be attributed to reversal of the phosphorylase reaction. Rather, glycogen synthesis was attributable solely to the activity of glycogen synthase, subsequent to the transport of glucose into the cell. However, the well-established observation that phosphorylase was inactivated (i.e., dephosphorylated) during the initial recovery period after prior exercise, when the rate of glycogen accumulation is highest and independent of insulin, suggested that phosphorylase could play an active role in glycogen accumulation. But the quantitative contribution of phosphorylase inactivation was not established until recently, when studying isolated murine muscle preparations during recovery from repeated contractions at temperatures ranging from 25 to 35 °C. Thus, in both slow-twitch, oxidative and fast-twitch, glycolytic muscles, inactivation of phosphorylase accounted for 45%–75% of glycogen accumulation during the initial hours of recovery following repeated contractions. Such data indicate that phosphorylase inactivation may be the most important mechanism for glycogen accumulation under defined conditions. These results support the initial belief that phosphorylase plays a quantitative role in glycogen formation in the living cell. However, the mechanism is not via activation of phosphorylase, but rather via inactivation of the enzyme.
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| 25. |
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| 26. |
- Lanner, Johanna T., et al.
(author)
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Knockdown of TRPC3 with siRNA coupled to carbon nanotubes results in decreased insulin-mediated glucose uptake in adult skeletal muscle cells
- 2009
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In: The FASEB Journal. - : Wiley. - 0892-6638 .- 1530-6860. ; 23:6, s. 1728-1738
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Journal article (peer-reviewed)abstract
- The involvement of Ca2+ in the insulin-mediated signaling cascade, resulting in glucose uptake in skeletal muscle, is uncertain. Here, we test the hypothesis that Ca2+ influx through canonical transient receptor potential 3 (TRPC3) channels modulates insulin-mediated glucose uptake in adult skeletal muscle. Experiments were performed on adult skeletal muscle cells of wild-type (WT) and obese, insulin-resistant ob/ob mice. Application of the diacylglycerol analog 1-oleyl-2-acetyl-sn-glycerol (OAG) induced a nonselective cation current, which was inhibited by the addition of anti-TRPC3 antibody in the patch pipette and smaller in ob/ob than in WT cells. Knockdown of TRPC3, using a novel technique based on small interfering RNA (siRNA) coupled to functionalized carbon nanotubes, resulted in pronounced (similar to 70%) decreases in OAG-induced Ca2+ influx and insulin-mediated glucose uptake. TRPC3 and the insulin-sensitive glucose transporter 4 (GLUT4) coimmunoprecipitated, and immunofluorescence staining showed that they were colocalized in the proximity of the transverse tubular system, which is the predominant site of insulin-mediated glucose transport in skeletal muscle. In conclusion, our results indicate that TRPC3 interacts functionally and physically with GLUT4, and Ca2+ influx through TRPC3 modulates insulin-mediated glucose uptake. Thus, TRPC3 is a potential target for treatment of insulin-resistant conditions.-Lanner, J. T., Bruton, J. D., Assefaw-Redda, Y., Andronache, Z., Zhang, S.- J., Severa, D., Zhang, Z.- B., Melzer, W., Zhang, S.-L., Katz, A., Westerblad, H. Knockdown of TRPC3 with siRNA coupled to carbon nanotubes results in decreased insulin-mediated glucose uptake in adult skeletal muscle cells. FASEB J. 23, 1728-1738 (2009)
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| 27. |
- Moberg, Marcus, 1986-, et al.
(author)
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Acute normobaric hypoxia blunts contraction-mediated mTORC1- and JNK-signaling in human skeletal muscle.
- 2022
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In: Acta Physiologica. - : John Wiley & Sons. - 1748-1708 .- 1748-1716. ; 234:2
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Journal article (peer-reviewed)abstract
- AIM: Hypoxia has been shown to reduce resistance exercise-induced stimulation of protein synthesis and long-term gains in muscle mass. However, the mechanism whereby hypoxia exerts its effect is not clear. Here we examine the effect of acute hypoxia on the activity of several signaling pathways involved in regulation of muscle growth following a bout of resistance exercise.METHODS: Eight men performed two sessions of leg resistance exercise in Normoxia or Hypoxia (12% O2 ) in a randomized crossover fashion. Muscle biopsies were obtained at rest and at 0, 90,180 min after exercise. Muscle analyses included levels of signaling proteins and metabolites associated with energy turnover.RESULTS: Exercise during Normoxia induced a 5-10-fold increase of S6K1Thr389 phosphorylation throughout the recovery period, but Hypoxia blunted the increases by ~50%. Phosphorylation of JNKThr183/Tyr185 and the JNK target SMAD2Ser245/250/255 was increased by 30-40-fold immediately after exercise in Normoxia, but Hypoxia blocked almost 70% of the activation. Throughout recovery, phosphorylation of JNK and SMAD2 remained elevated following exercise in Normoxia, but the effect of Hypoxia was lost at 90-180 min post-exercise. Hypoxia had no effect on exercise induced Hippo- or autophagy-signaling and ubiquitin-proteasome related protein levels. Nor did Hypoxia alter the changes induced by exercise in high energy phosphates, glucose 6-P, lactate, or phosphorylation of AMPK or ACC.CONCLUSION: We conclude that acute severe hypoxia inhibits resistance exercise induced mTORC1- and JNK signaling in human skeletal muscle, effects that do not appear to be mediated by changes in the degree of metabolic stress in the muscle.
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| 28. |
- Munters, Li Alemo, et al.
(author)
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Improved exercise performance and increased aerobic capacity after endurance training of patients with stable polymyositis and dermatomyositis
- 2013
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In: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 15:4, s. R83-
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Journal article (peer-reviewed)abstract
- Introduction: This randomized, controlled study on patients with polymyositis or dermatomyositis was based on three hypotheses: patients display impaired endurance due to reduced aerobic capacity and muscle weakness, endurance training improves their exercise performance by increasing the aerobic capacity, and endurance training has general beneficial effects on their health status. Methods: In the first part of this study, we compared 23 patients with polymyositis or dermatomyositis with 12 age-and gender-matched healthy controls. A subgroup of patients were randomized to perform a 12-week endurance training program (exercise group, n = 9) or to a non-exercising control group (n = 6). We measured maximal oxygen uptake (VO2 max) and the associated power output during a progressive cycling test. Endurance was assessed as the cycling time to exhaustion at 65% of VO2 max. Lactate levels in the vastus lateralis muscle were measured with microdialysis. Mitochondrial function was assessed by measuring citrate synthase (CS) and beta-hydroxyacyl-CoA dehydrogenase (beta-HAD) activities in muscle biopsies. Clinical improvement was assessed according to the International Myositis Assessment and Clinical Studies Group (IMACS) improvement criteria. All assessors were blinded to the type of intervention (that is, training or control). Results: Exercise performance and aerobic capacity were lower in patients than in healthy controls, whereas lactate levels at exhaustion were similar. Patients in the exercise group increased their cycling time, aerobic capacity and CS and beta-HAD activities, whereas lactate levels at exhaustion decreased. Six of nine patients in the exercise group met the IMACS improvement criteria. Patients in the control group did not show any consistent changes during the 12-week study. Conclusions: Polymyositis and dermatomyositis patients have impaired endurance, which could be improved by 12 weeks of endurance training. The clinical improvement corresponds to increases in aerobic capacity and muscle mitochondrial enzyme activities. The results emphasize the importance of endurance exercise in addition to immunosuppressive treatment of patients with polymyositis or dermatomyositis.
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| 29. |
- Nordström, Fabian, et al.
(author)
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The lactate receptor GPR81 is predominantly expressed in type II human skeletal muscle fibers : potential for lactate autocrine signaling.
- 2023
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In: American Journal of Physiology - Cell Physiology. - : American Physiological Society. - 0363-6143 .- 1522-1563. ; 324:2, s. C477-C487
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Journal article (peer-reviewed)abstract
- GPR81 was first identified in adipocytes as a receptor for L-lactate, which upon binding inhibits cAMP-PKA-CREB signaling. Moreover, incubation of myotubes with lactate augments expression of GPR81 and genes and proteins involved in lactate- and energy metabolism. However, characterization of GPR81 expression and investigation of related signaling in human skeletal muscle under conditions of elevated circulating lactate levels are lacking. Muscle biopsies were obtained from healthy men and women at rest, after leg extension exercise, with or without venous infusion of sodium lactate, and 90 and 180 min after exercise (8 men and 8 women). Analyses included protein and mRNA levels of GPR81, as well as GPR81-dependent signaling molecules. GPR81 expression was 2.5-fold higher in type II glycolytic compared with type I oxidative muscle fibers, and the expression was inversely related to the percentage of type I muscle fibers. Muscle from women expressed about 25% more GPR81 protein than from men. Global PKA-activity increased by 5-8% after exercise, with no differences between trials. CREBS133 phosphorylation was reduced by 30% after exercise and remained repressed during the entire trials, with no influence of the lactate infusion. The mRNA expression of VEGF and PGC-1α were increased by 2.5 - 6-fold during recovery, and that of LDH reduced by 15% with no differences between trials for any gene at any time point. The high expression of GPR81-protein in type II fibers suggests that lactate functions as an autocrine signaling molecule in muscle; however, lactate does not appear to regulate CREB signaling during exercise.
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| 30. |
- Zaychik, Yifat, et al.
(author)
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High-Intensity Exercise Training Protects the Brain Against Autoimmune Neuroinflammation : Regulation of Microglial Redox and Pro-inflammatory Functions.
- 2021
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In: Frontiers in Cellular Neuroscience. - : Frontiers Media S.A.. - 1662-5102. ; 15
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Journal article (peer-reviewed)abstract
- Background: Exercise training induces beneficial effects on neurodegenerative diseases, and specifically on multiple sclerosis (MS) and it's model experimental autoimmune encephalomyelitis (EAE). However, it is unclear whether exercise training exerts direct protective effects on the central nervous system (CNS), nor are the mechanisms of neuroprotection fully understood. In this study, we investigated the direct neuroprotective effects of high-intensity continuous training (HICT) against the development of autoimmune neuroinflammation and the role of resident microglia. Methods: We used the transfer EAE model to examine the direct effects of training on the CNS. Healthy mice performed HICT by treadmill running, followed by injection of encephalitogenic proteolipid (PLP)-reactive T-cells to induce EAE. EAE severity was assessed clinically and pathologically. Brain microglia from sedentary (SED) and HICT healthy mice, as well as 5-days post EAE induction (before the onset of disease), were analyzed ex vivo for reactive oxygen species (ROS) and nitric oxide (NO) formation, mRNA expression of M1/M2 markers and neurotrophic factors, and secretion of cytokines and chemokines. Results: Transfer of encephalitogenic T-cells into HICT mice resulted in milder EAE, compared to sedentary mice, as indicated by reduced clinical severity, attenuated T-cell, and neurotoxic macrophage/microglial infiltration, and reduced loss of myelin and axons. In healthy mice, HICT reduced the number of resident microglia without affecting their profile. Isolated microglia from HICT mice after transfer of encephalitogenic T-cells exhibited reduced ROS formation and released less IL-6 and monocyte chemoattractant protein (MCP) in response to PLP-stimulation. Conclusions: These findings point to the critical role of training intensity in neuroprotection. HICT protects the CNS against autoimmune neuroinflammation by reducing microglial-derived ROS formation, neurotoxicity, and pro-inflammatory responses involved in the propagation of autoimmune neuroinflammation.
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