| 1. |
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| 2. |
- 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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| 3. |
- Bruton, Joseph D., et al.
(author)
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Ryanodine receptors of pancreatic beta-cells mediate a distinct context-dependent signal for insulin secretion
- 2003
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In: The FASEB Journal. - : Wiley. - 0892-6638 .- 1530-6860. ; 17:2, s. 301-303
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Journal article (peer-reviewed)abstract
- The ryanodine (RY) receptors in beta-cells amplify signals by Ca2+-induced Ca2+ release (CICR). The role of CICR in insulin secretion remains unclear in spite of the fact that caffeine is known to stimulate secretion. This effect of caffeine is attributed solely to the inhibition of cAMP-phosphodiesterases (cAMP-PDEs). We demonstrate that stimulation of insulin secretion by caffeine is due to a sensitization of the RY receptors. The dose-response relationship of caffeine-induced inhibition of cAMP-PDEs was not correlated with the stimulation of insulin secretion. Sensitization of the RY receptors stimulated insulin secretion in a context-dependent manner, that is, only in the presence of a high concentration of glucose. This effect of caffeine depended on an increase in [Ca2+]i. Confocal images of beta-cells demonstrated an increase in [Ca2+]i induced by caffeine but not by forskolin. 9-Methyl-7-bromoeudistomin D (MBED), which sensitizes RY receptors, did not inhibit cAMP-PDEs, but it stimulated secretion in a glucose-dependent manner. The stimulation of secretion by caffeine and MBED involved both the first and the second phases of secretion. We conclude that the RY receptors of beta-cells mediate a distinct glucose-dependent signal for insulin secretion and may be a target for developing drugs that will stimulate insulin secretion only in a glucose-dependent manner.
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| 4. |
- Cheng, Arthur J., et al.
(author)
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Carbohydrates do not accelerate force recovery after glycogen-depleting followed by high-intensity exercise in humans
- 2020
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In: Scandinavian Journal of Medicine and Science in Sports. - : Blackwell Publishing. - 0905-7188 .- 1600-0838. ; 30:6, s. 998-1007
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Journal article (peer-reviewed)abstract
- Prolonged low-frequency force depression (PLFFD) induced by fatiguing exercise is characterized by a persistent depression in submaximal contractile force during the recovery period. Muscle glycogen depletion is known to limit physical performance during prolonged low- and moderate-intensity exercise, and accelerating glycogen re-synthesis with post-exercise carbohydrate intake can facilitate recovery and improve repeated bout exercise performance. Short-term, high-intensity exercise however, can cause PLFFD without any marked decrease in glycogen. Here we studied whether recovery from PLFFD was accelerated by carbohydrate ingestion after 60-min of moderate-intensity glycogen-depleting cycling exercise followed by six 30-s all-out cycling sprints. We used a randomized cross-over study design where nine recreationally-active males drank a beverage containing either carbohydrate or placebo after exercise. Blood glucose and muscle glycogen concentrations were determined at baseline, immediately post-exercise, and during the 3-h recovery period. Transcutaneous electrical stimulation of the quadriceps muscle was performed to determine the extent of PLFFD by eliciting low-frequency (20Hz) and high-frequency (100Hz) stimulations. Muscle glycogen was severely depleted after exercise, with a significantly higher rate of muscle glycogen re-synthesis during the 3-h recovery period in the carbohydrate than in the placebo trials (13.7 and 5.4 mmol glucosyl units/kg wet weight/h, respectively). Torque at 20Hz was significantly more depressed than 100 Hz torque during the recovery period in both conditions, and the extent of PLFFD (20/100Hz ratio) was not different between the two trials. In conclusion, carbohydrate supplementation enhances glycogen re-synthesis after glycogen-depleting exercise but does not improve force recovery when the exercise also involves all-out cycling sprints.
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| 5. |
- Cheng, Arthur J., et al.
(author)
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Doublet discharge stimulation increases sarcoplasmic reticulum Ca2+ release and improves performance during fatiguing contractions in mouse muscle fibres
- 2013
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In: Journal of Physiology. - : Wiley. - 0022-3751 .- 1469-7793. ; 591:15, s. 3739-3748
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Journal article (peer-reviewed)abstract
- Double discharges (doublets) of motor neurones at the onset of contractions increase both force and rate of force development during voluntary submaximal contractions. The purpose of this study was to examine the role of doublet discharges on force and myoplasmic free [Ca2+] ([Ca2+](i)) during repeated fatiguing contractions, using a stimulation protocol mimicking the in vivo activation pattern during running. Individual intact fibres from the flexor digitorum brevis muscle of mice were stimulated at 33 degrees C to undergo 150 constant-frequency (five pulses at 70 Hz) or doublet (an initial, extra pulse at 200 Hz) contractions at 300 ms intervals. In the unfatigued state, doublet stimulation resulted in a transient (approximate to 10 ms) approximate doubling of [Ca2+](i), which was accompanied by a greater force-time integral (approximate to 70%) and peak force (approximate to 40%) compared to constant frequency contractions. Moreover, doublets markedly increased force-time integral and peak force during the first 25 contractions of the fatiguing stimulation. In later stages of fatigue, addition of doublets increased force production but the increase in force production corresponded to only a minor portion of the fatigue-induced reduction in force. In conclusion, double discharges at the onset of contractions effectively increase force production, especially in early stages of fatigue. This beneficial effect occurs without additional force loss in later stages of fatigue, indicating that the additional energy cost induced by doublet discharges to skeletal muscle is limited.
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| 6. |
- Cheng, Arthur J., et al.
(author)
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Post-exercise recovery of contractile function and endurance in humans and mice is accelerated by heating and slowed by cooling skeletal muscle
- 2017
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In: Journal of Physiology. - : John Wiley & Sons. - 0022-3751 .- 1469-7793. ; 595:24, s. 7413-7426
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Journal article (peer-reviewed)abstract
- Key points: We investigated whether intramuscular temperature affects the acute recovery of exercise performance following fatigue-induced by endurance exercise. Mean power output was better preserved during an all-out arm-cycling exercise following a 2 h recovery period in which the upper arms were warmed to an intramuscular temperature of ˜ 38°C than when they were cooled to as low as 15°C, which suggested that recovery of exercise performance in humans is dependent on muscle temperature. Mechanisms underlying the temperature-dependent effect on recovery were studied in intact single mouse muscle fibres where we found that recovery of submaximal force and restoration of fatigue resistance was worsened by cooling (16-26°C) and improved by heating (36°C). Isolated whole mouse muscle experiments confirmed that cooling impaired muscle glycogen resynthesis. We conclude that skeletal muscle recovery from fatigue-induced by endurance exercise is impaired by cooling and improved by heating, due to changes in glycogen resynthesis rate.Manipulation of muscle temperature is believed to improve post-exercise recovery, with cooling being especially popular among athletes. However, it is unclear whether such temperature manipulations actually have positive effects. Accordingly, we studied the effect of muscle temperature on the acute recovery of force and fatigue resistance after endurance exercise. One hour of moderate-intensity arm cycling exercise in humans was followed by 2 h recovery in which the upper arms were either heated to 38°C, not treated (33°C), or cooled to ∼15°C. Fatigue resistance after the recovery period was assessed by performing 3 × 5 min sessions of all-out arm cycling at physiological temperature for all conditions (i.e. not heated or cooled). Power output during the all-out exercise was better maintained when muscles were heated during recovery, whereas cooling had the opposite effect. Mechanisms underlying the temperature-dependent effect on recovery were tested in mouse intact single muscle fibres, which were exposed to ∼12 min of glycogen-depleting fatiguing stimulation (350 ms tetani given at 10 s interval until force decreased to 30% of the starting force). Fibres were subsequently exposed to the same fatiguing stimulation protocol after 1-2 h of recovery at 16-36°C. Recovery of submaximal force (30 Hz), the tetanic myoplasmic free [Ca2+] (measured with the fluorescent indicator indo-1), and fatigue resistance were all impaired by cooling (16-26°C) and improved by heating (36°C). In addition, glycogen resynthesis was faster at 36°C than 26°C in whole flexor digitorum brevis muscles. We conclude that recovery from exhaustive endurance exercise is accelerated by raising and slowed by lowering muscle temperature.
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| 7. |
- Evertsson, Kim
(author)
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Protein expression and modifications in denervated atrophic and hypertrophic skeletal muscle
- 2014
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Doctoral thesis (other academic/artistic)abstract
- Skeletal muscle comprises about 45% of the total body weight. It is the largest tissue in the body, vital for maintaining posture, produce locomotion, breathing but also functions as a large reservoir of proteins. Regulation and maintenance of muscle mass is a delicate process and is determined by the balance between protein synthesis and degradation. Following denervation skeletal muscles change their functional and structural properties. Most muscles start to lose weight due to the inactivity caused by denervation and become atrophic, whereas the hemidiaphragm initially increases in weight the first 6-10 days and becomes hypertrophic, followed by a decrease in weight. The aim of this thesis was to examine the expression and phosphorylation of factors potentially involved in the regulation of skeletal muscle mass in denervated atrophic hind-limb muscles and in denervated hypertrophic hemidiaphragm muscles in mice. Another aim was to identify markers that could be linked to lysosomal and autophagic activities in denervated muscle.Factors of the Akt/mTOR pathway were studied and results indicative of increased protein synthesis were obtained in both denervated atrophic and hypertrophic muscles. This suggests that skeletal muscle atrophy following denervation is more likely to depend on increased protein degradation rather than an overall decrease in protein synthesis (paper I). A differential response of MK2 Thr317 phosphorylation in denervated atrophic and hypertrophic muscles was confirmed, without corresponding changes in phosphorylation of p38, indicating that other factors than p38 are responsible for this differential response, possibly Hsp70. Factors other than MK2 may be responsible for the phosphorylation of Hsp25, since increased levels of phosphorylated Hsp25 were seen in all denervated muscles studied (paper II). Results also suggested FoxO1 and MuRF1 to have potential roles in tissue remodeling that occurs after denervation (paper III). Immunoreactivity for the lysosomal marker Lamp1 and for the autophagic marker protein Lc3 was observed in characteristic ring-like structures in transverse sections of denervated muscle fibers (paper IV).
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| 8. |
- Gineste, Charlotte, et al.
(author)
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Enzymatically dissociated muscle fibers display rapid dedifferentiation and impaired mitochondrial calcium control
- 2022
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In: iScience. - : Elsevier. - 2589-0042. ; 25:12
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Journal article (peer-reviewed)abstract
- Cells rapidly lose their physiological phenotype upon disruption of their extracellular matrix (ECM)-intracellular cytoskeleton interactions. By comparing adult mouse skeletal muscle fibers, isolated either by mechanical dissection or by collagenase-induced ECM digestion, we investigated acute effects of ECM disruption on cellular and mitochondrial morphology, transcriptomic signatures, and Ca2+ handling. RNA-sequencing showed striking differences in gene expression patterns between the two isolation methods with enzymatically dissociated fibers resembling myopathic phenotypes. Mitochondrial appearance was grossly similar in the two groups, but 3D electron microscopy revealed shorter and less branched mitochondria following enzymatic dissociation. Repeated contractions resulted in a prolonged mitochondrial Ca2+ accumulation in enzymatically dissociated fibers, which was partially prevented by cyclophilin inhibitors. Of importance, muscle fibers of mice with severe mitochondrial myopathy show pathognomonic mitochondrial Ca2+ accumulation during repeated contractions and this accumulation was concealed with enzymatic dissociation, making this an ambiguous method in studies of native intracellular Ca2+ fluxes.
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| 9. |
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| 10. |
- Islam, M. Shahidul, et al.
(author)
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In situ activation of the type 2 ryanodine receptor in pancreatic beta cells requires cAMP-dependent phosphorylation
- 1998
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In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 95:11, s. 6145-6150
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Journal article (peer-reviewed)abstract
- Molecular mechanisms that regulate in situ activation of ryanodine receptors (RY) in different cells are poorly understood. Here we demonstrate that caffeine (10 mM) released Ca2+ from the endoplasmic reticulum (ER) in the form of small spikes in only 14% of cultured fura-2 loaded beta cells from ob/ob mice. Surprisingly, when forskolin, an activator of adenylyl cyclase was present, caffeine induced larger Ca2+ spikes in as many as 60% of the cells. Forskolin or the phosphodiesterase-resistant PKA activator Sp-cAMPS alone did not release Ca2+ from ER. 4-Chloro-3-ethylphenol (4-CEP), an agent that activates RYs in other cell systems, released Ca2+ from ER, giving rise to a slow and small increase in [Ca2+]i in beta cells. Prior exposure of cells to forskolin or caffeine (5 mM) qualitatively altered Ca2+ release by 4-CEP, giving rise to Ca2+ spikes. In glucose-stimulated beta cells forskolin induced Ca2+ spikes that were enhanced by 3,9-dimethylxanthine, an activator of RYs. Analysis of RNA from islets and insulin-secreting betaTC-3-cells by RNase protection assay, using type-specific RY probes, revealed low-level expression of mRNA for the type 2 isoform of the receptor (RY2). We conclude that in situ activation of RY2 in beta cells requires cAMP-dependent phosphorylation, a process that recruits the receptor in a functionally operative form.
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| 11. |
- Ivarsson, Niklas, et al.
(author)
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SR Ca2+ leak in skeletal muscle fibers acts as an intracellular signal to increase fatigue resistance.
- 2019
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In: The Journal of General Physiology. - : Rockefeller University Press. - 0022-1295 .- 1540-7748. ; 151:4, s. 567-577
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Journal article (peer-reviewed)abstract
- Effective practices to improve skeletal muscle fatigue resistance are crucial for athletes as well as patients with dysfunctional muscles. To this end, it is important to identify the cellular signaling pathway that triggers mitochondrial biogenesis and thereby increases oxidative capacity and fatigue resistance in skeletal muscle fibers. Here, we test the hypothesis that the stress induced in skeletal muscle fibers by endurance exercise causes a reduction in the association of FK506-binding protein 12 (FKBP12) with ryanodine receptor 1 (RYR1). This will result in a mild Ca2+ leak from the sarcoplasmic reticulum (SR), which could trigger mitochondrial biogenesis and improved fatigue resistance. After giving mice access to an in-cage running wheel for three weeks, we observed decreased FKBP12 association to RYR1, increased baseline [Ca2+]i, and signaling associated with greater mitochondrial biogenesis in muscle, including PGC1α1. After six weeks of voluntary running, FKBP12 association is normalized, baseline [Ca2+]i returned to values below that of nonrunning controls, and signaling for increased mitochondrial biogenesis was no longer present. The adaptations toward improved endurance exercise performance that were observed with training could be mimicked by pharmacological agents that destabilize RYR1 and thereby induce a modest Ca2+ leak. We conclude that a mild RYR1 SR Ca2+ leak is a key trigger for the signaling pathway that increases muscle fatigue resistance.
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| 12. |
- 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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| 13. |
- Kosterina, Natalia, 1983-, et al.
(author)
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History effect and timing of force production introduced in a skeletal muscle model
- 2012
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In: Biomechanics and Modeling in Mechanobiology. - : Springer Science and Business Media LLC. - 1617-7959 .- 1617-7940. ; 11:7, s. 947-957
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Journal article (peer-reviewed)abstract
- Skeletal muscle modelling requires a detailed description of muscular force production. We have performed a series of experiments on mouse skeletal muscles to give a basis for an improved description of the muscular force production. Our previous work introduced a force modification in isometric phases, which was based on the work performed by or on the muscle during transient-length-varying contractions. Here, state-space diagrams were used to investigate the timing aspects of the force production. These show a dominant exponential nature of the force development in isometric phases of the contractions, reached after a non-exponential phase, assumed as an activation or deactivation stage and not further analysed here. The time constants of the exponential functions describing isometric force redevelopment after length variations appear to be related to the one for an initial isometric contraction, but depending on the previous history. The timing of force production calculated from the state-space diagrams was in agreement with the generally accepted muscle properties, thereby demonstrating the reliability of the method. A macroscopic muscular model consisting of a contractile element, parallel and series elastic elements was developed. The parameters from the experiment analysis, particularly the force modification after non-isometric contractions and the time constants, were reproduced by the simulations. The relationship between time constants introduced in a mechanistic model and the measured macroscale timings is discussed.
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| 14. |
- Kosterina, Natalia, et al.
(author)
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Mechanical work as predictor of force enhancement and force depression
- 2009
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In: Journal of Biomechanics. - : Elsevier BV. - 0021-9290 .- 1873-2380. ; 42:11, s. 1628-1634
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Journal article (peer-reviewed)abstract
- The steady-state force following active muscle shortening or stretch differs from the maximum isometric force associated with the final length. This phenomenon proves that the isometric force production is not only dependent on current muscle length and length time derivative, but depends on the preceding contraction history. Isolated extensor digitorum longus and soleus muscles from mice (NMRI strain) were used to investigate the force produced by a muscle, and some parameters hypothetically influencing this history-dependent force modification. The muscles were pre-stimulated at a fixed length, then different stretch/shortening episodes were introduced, whereafter changes of the active force were recorded while the muscles were held isometrically to approach a steady-state force before de-stimulation. The mechanical work during active stretch and shortening was evaluated by integrating the product of force and ramp velocity over the length-varying period. The results show a negative linear correlation between the force modification and the mechanical work produced on or by the muscle, continuous between shortening and stretch. A corresponding modification of the passive force component following each stimulation was also observed. The conclusion is that the isometric force attained after stretch or shortening is well described by an asymptotic force which is determined by the mechanical work.
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| 15. |
- Kosterina, Natalia, et al.
(author)
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Muscular force production after concentric contraction
- 2008
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In: Journal of Biomechanics. - : Elsevier BV. - 0021-9290 .- 1873-2380. ; 41:11, s. 2422-2429
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Journal article (peer-reviewed)abstract
- The steady-state force following active shortening does not reach the maximum isometric force associated with the final length. Isolated extensor digitorum longus and soleus muscles from mice (NMRI strain) were used to investigate the force produced by a muscle, and some parameters hypothetically influencing this shortening-induced force depression. The muscles were pre-stimulated at fixed length, shortened and then held isometrically to give maximum post-shortening forces, before de-stimulation. The shortening magnitude was 0.18. 0.36 or 0.72 mm (about 2-7% of optimal length), time of shortening was chosen as 0.03, 0.06 and 0.12 s, and final length as +0.72. 0 and -0.72mm, related to optimal length. The mechanical work during active shortening was evaluated by integrating the product of force and shortening velocity over the shortening period. The results show a positive correlation between the force depression and the mechanical work. whereas the force depression was not correlated to the velocity of shortening. Depression of the passive force component was also observed following all stimulations. Experiments show that the fully stimulated redevelopment of isometric force following concentric contraction follows a time function similar to the creation of force when isometric muscle is initially stimulated. The conclusion is that the isometric force development after active shortening can be well described by an asymptotic force which is decided by the produced work, and the initial isometric time constant.
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| 16. |
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| 17. |
- Nielsen, Joachim, et al.
(author)
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Subcellular distribution of glycogen and decreased tetanic Ca2+ in fatigued single intact mouse muscle fibres
- 2014
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In: Journal of Physiology. - : Wiley. - 0022-3751 .- 1469-7793. ; 592:9, s. 2003-2012
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Journal article (peer-reviewed)abstract
- Key points Muscle glycogen (the storage form of glucose) is consumed during muscle work and the depletion of glycogen is thought to be a main contributor to muscle fatigue. In this study, we used a novel approach to first measure fatigue-induced reductions in force and tetanic Ca2+ in isolated single mouse muscle fibres following repeated contractions and subsequently quantify the subcellular distribution of glycogen in the same fibre. Using this approach, we investigated whether the decreased tetanic Ca2+ induced by repeated contractions was associated with glycogen depletion in certain subcellular regions. The results show a positive correlation between depletion of glycogen located within the myofibrils and low tetanic Ca2+ after repetitive stimulation. We conclude that subcellular glycogen depletion has a central role in the decrease in tetanic Ca2+ that occurs during repetitive contractions. In skeletal muscle fibres, glycogen has been shown to be stored at different subcellular locations: (i) between the myofibrils (intermyofibrillar); (ii) within the myofibrils (intramyofibrillar); and (iii) subsarcolemmal. Of these, intramyofibrillar glycogen has been implied as a critical regulator of sarcoplasmic reticulum Ca2+ release. The aim of the present study was to test directly how the decrease in cytoplasmic free Ca2+ ([Ca2+](i)) during repeated tetanic contractions relates to the subcellular glycogen distribution. Single fibres of mouse flexor digitorum brevis muscles were fatigued with 70Hz, 350ms tetani given at 2s (high-intensity fatigue, HIF) or 10s (low-intensity fatigue, LIF) intervals, while force and [Ca2+](i) were measured. Stimulation continued until force decreased to 30% of its initial value. Fibres were then prepared for analyses of subcellular glycogen distribution by transmission electron microscopy. At fatigue, tetanic [Ca2+](i) was reduced to 70 +/- 4% and 54 +/- 4% of the initial in HIF (P<0.01, n=9) and LIF (P<0.01, n=5) fibres, respectively. At fatigue, the mean inter- and intramyofibrillar glycogen content was 60-75% lower than in rested control fibres (P<0.05), whereas subsarcolemmal glycogen was similar to control. Individual fibres showed a good correlation between the fatigue-induced decrease in tetanic [Ca2+](i) and the reduction in intermyofibrillar (P=0.051) and intramyofibrillar (P=0.0008) glycogen. In conclusion, the fatigue-induced decrease in tetanic [Ca2+](i), and hence force, is accompanied by major reductions in inter- and intramyofibrillar glycogen. The stronger correlation between decreased tetanic [Ca2+](i) and reduced intramyofibrillar glycogen implies that sarcoplasmic reticulum Ca2+ release critically depends on energy supply from the intramyofibrillar glycogen pool.
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| 18. |
- Persson, Malin, 1983-, et al.
(author)
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Force generated by myosin cross-bridges is reduced in myofibrils exposed to ROS/RNS
- 2019
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In: American Journal of Physiology - Cell Physiology. - : American Physiological Society. - 0363-6143 .- 1522-1563. ; 317:6, s. C1304-C1312
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Journal article (peer-reviewed)abstract
- Skeletal muscle weakness is associated with oxidative stress and oxidative posttranslational modifications on contractile proteins. There is indirect evidence that reactive oxygen/nitrogen species (ROS/RNS) affect skeletal muscle myofibrillar function, although the details of the acute effects of ROS/RNS on myosin-actin interactions are not known. In this study. we examined the effects of peroxynitrite (ONOO-) on the contractile properties of individual skeletal muscle myofibrils by monitoring myofibril-induced displacements of an atomic force cantilever upon activation and relaxation. The isometric force decreased by similar to 50% in myofibrils treated with the ONOO- donor (SIN-1) or directly with ONOO-. which was independent of the cross-bridge abundancy condition (i.e., rigor or relaxing condition) during SIN-1 or ONOO- treatment. The force decrease was attributed to an increase in the cross-bridge detachment rate (g(app)) in combination with a conservation of the force redevelopment rate (k(Tr)) and hence, an increase in the population of cross-bridges transitioning from force-generating to non-force-generating cross-bridges during steady-state. Taken together, the results of this study provide important information on how ROS/RNS affect myofibrillar force production which may be of importance for conditions where increased oxidative stress is part of the pathophysiology.
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| 19. |
- Trepci, Ada, et al.
(author)
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Quantification of Plasma Kynurenine Metabolites Following One Bout of Sprint Interval Exercise
- 2020
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In: International Journal of Tryptophan Research. - : SAGE Publications. - 1178-6469. ; 13
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Journal article (peer-reviewed)abstract
- The kynurenine pathway of tryptophan degradation produces several neuroactive metabolites suggested to be involved in a wide variety of diseases and disorders, however, technical challenges in reliably detecting these metabolites hampers cross-comparisons. The main objective of this study was to develop an accurate, robust and precise bioanalytical method for simultaneous quantification of ten plasma kynurenine metabolites. As a secondary aim, we applied this method on blood samples taken from healthy subjects conducting 1 session of sprint interval exercise (SIE). It is well accepted that physical exercise is associated with health benefits and reduces risks of psychiatric illness, diabetes, cancer and cardiovascular disease, but also influences the peripheral and central concentrations of kynurenines. In line with this, we found that in healthy old adults (n = 10; mean age 64 years), levels of kynurenine increased 1 hour (P =.03) after SIE, while kynurenic acid (KYNA) concentrations were elevated after 24 hours (P =.02). In contrast, no significant changes after exercise were seen in young adults (n = 10; mean age 24 years). In conclusion, the described method performs well in reliably detecting all the analyzed metabolites in plasma samples. Furthermore, we also detected an age-dependent effect on the degree by which a single intense training session affects kynurenine metabolite levels.
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| 20. |
- Wallis, Karin, et al.
(author)
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Locomotor deficiencies and aberrant development of subtype-specific GABAergic interneuros caused by a unlignded thyroid hormopne receptor alpha-1
- 2008
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In: Journal of Neuroscience. - 0270-6474 .- 1529-2401. ; 28:8, s. 1904-1915
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Journal article (peer-reviewed)abstract
- Thyroid hormone (TH) deficiency during development causes severe and permanent neuronal damage, but the primary insult at the tissue level has remained unsolved. We have defined locomotor deficiencies in mice caused by a mutant thyroid hormone receptor alpha 1 (TR alpha 1) with potent aporeceptor activity attributable to reduced affinity to TH. This allowed identification of distinct functions that required either maternal supply of TH during early embryonic development or sufficient innate levels of hormone during late fetal development. In both instances, continued exposure to high levels of TH after birth and throughout life was needed. The hormonal dependencies correlated with severely delayed appearance of parvalbumin-immunoreactive GABAergic interneurons and increased numbers of calretinin-immunoreactive cells in the neocortex. This resulted in reduced numbers of fast spiking interneurons and defects in cortical network activity. The identification of locomotor deficiencies caused by insufficient supply of TH during fetal/perinatal development and their correlation with subtype-specific interneurons suggest a previously unknown basis for the neuronal consequences of endemic cretinism and untreated congenital hypothyroidism, and specifies TR alpha 1 as the receptor isoform mediating these effects.
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| 21. |
- Yamada, Takashi, et al.
(author)
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Nitrosative modifications of the Ca2+ release complex and actin underlie arthritis-induced muscle weakness.
- 2015
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In: Annals of the Rheumatic Diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 74:10, s. 1907-1914
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Journal article (peer-reviewed)abstract
- Skeletal muscle weakness is a prominent clinical feature in patients with rheumatoid arthritis (RA), but the underlying mechanism(s) is unknown. Here we investigate the mechanisms behind arthritis-induced skeletal muscle weakness with special focus on the role of nitrosative stress on intracellular Ca(2+) handling and specific force production.
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| 22. |
- Ørtenblad, Niels, et al.
(author)
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Muscle glycogen stores and fatigue
- 2013
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In: Journal of Physiology. - : Wiley. - 0022-3751 .- 1469-7793. ; 591:18, s. 4405-4413
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Research review (peer-reviewed)abstract
- Studies performed at the beginning of the last century revealed the importance of carbohydrate as a fuel during exercise, and the importance of muscle glycogen on performance has subsequently been confirmed in numerous studies. However, the link between glycogen depletion and impaired muscle function during fatigue is not well understood and a direct cause-and-effect relationship between glycogen and muscle function remains to be established. The use of electron microscopy has revealed that glycogen is not homogeneously distributed in skeletal muscle fibres, but rather localized in distinct pools. Furthermore, each glycogen granule has its own metabolic machinery with glycolytic enzymes and regulating proteins. One pool of such glycogenolytic complexes is localized within the myofibrils in close contact with key proteins involved in the excitation-contraction coupling and Ca2+ release from the sarcoplasmic reticulum (SR). We and others have provided experimental evidence in favour of a direct role of decreased glycogen, localized within the myofibrils, for the reduction in SR Ca2+ release during fatigue. This is consistent with compartmentalized energy turnover and distinctly localized glycogen pools being of key importance for SR Ca2+ release and thereby affecting muscle contractility and fatigability.
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