| 1. |
- Arlock, Per, et al.
(författare)
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Excitation and contraction of cardiac muscle and coronary arteries of brain-dead pigs
- 2023
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Ingår i: FASEB BioAdvances. - : Wiley. - 2573-9832. ; 5:2, s. 71-84
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Tidskriftsartikel (refereegranskat)abstract
- Excitability and contraction of cardiac muscle from brain-dead donors critically influence the success of heart transplantation. Membrane physiology, Ca2+-handling, and force production of cardiac muscle and the contractile properties of coronary arteries were studied in hearts of brain-dead pigs. Cardiac muscle and vascular function after 12 h brain death (decapitation between C2 and C3) were compared with properties of fresh tissue. In both isolated cardiomyocytes (whole-cell patch clamp) and trabecular muscle (conventional microelectrodes), action potential duration was shorter in brain dead, compared to controls. Cellular shortening and Ca2+ transients were attenuated in the brain dead, and linked to lower mRNA expression of L-type calcium channels and a slightly lower ICa,L, current, as well as to a lower expression of phospholamban. The current–voltage relationship and the current above the equilibrium potential of the inward K+ (IK1) channel were altered in the brain-dead group, associated with lower mRNA expression of the Kir2.2 channel. Delayed K+ currents were detected (IKr, IKs) and were not different between groups. The transient outward K+ current (Ito) was not observed in the pig heart. Coronary arteries exhibited increased contractility and sensitivity to the thromboxane analogue (U46619), and unaltered endothelial relaxation. In conclusion, brain death involves changes in cardiac cellular excitation which might lower contractility after transplantation. Changes in the inward rectifier K+ channel can be associated with an increased risk for arrhythmia. Increased reactivity of coronary arteries may lead to increased risk of vascular spasm, although endothelial relaxant function was well preserved.
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| 2. |
- Bamberg, Krister, et al.
(författare)
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Electrolyte handling in the isolated perfused rat kidney : demonstration of vasopressin V2-receptor-dependent calcium reabsorption
- 2020
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Ingår i: Upsala Journal of Medical Sciences. - : TAYLOR & FRANCIS LTD. - 0300-9734 .- 2000-1967. ; 125:4, s. 274-280
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Tidskriftsartikel (refereegranskat)abstract
- Background The most profound effect of vasopressin on the kidney is to increase water reabsorption through V-2-receptor (V2R) stimulation, but there are also data suggesting effects on calcium transport. To address this issue, we have established an isolated perfused kidney model with accurate pressure control, to directly study the effects of V2R stimulation on kidney function, isolated from systemic effects. Methods The role of V2R in renal calcium handling was studied in isolated rat kidneys using a new pressure control system that uses a calibration curve to compensate for the internal pressure drop up to the tip of the perfusion cannula. Results Kidneys subjected to V2R stimulation using desmopressin (DDAVP) displayed stable osmolality and calcium reabsorption throughout the experiment, whereas kidneys not administered DDAVP exhibited a simultaneous fall in urine osmolality and calcium reabsorption. Epithelial sodium channel (ENaC) inhibition using amiloride resulted in a marked increase in potassium reabsorption along with decreased sodium reabsorption. Conclusions A stable isolated perfused kidney model with computer-controlled pressure regulation was developed, which retained key physiological functions. The preparation responds to pharmacological inhibition of ENaC channels and activation of V2R. Using the model, the dynamic effects of V2R stimulation on calcium handling and urine osmolality could be visualised. The study thereby provides evidence for a stimulatory role of V2R in renal calcium reabsorption.
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| 3. |
- Dennhag, Nils, 1989-, et al.
(författare)
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fhl2b mediates extraocular muscle protection in zebrafish models of muscular dystrophies and its ectopic expression ameliorates affected body muscles
- 2024
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- In muscular dystrophies, muscle fibers loose integrity and die, causing significant suffering and premature death. Strikingly, the extraocular muscles (EOMs) are spared, functioning well despite the disease progression. Although EOMs have been shown to differ from body musculature, the mechanisms underlying this inherent resistance to muscle dystrophies remain unknown. Here, we demonstrate important differences in gene expression as a response to muscle dystrophies between the EOMs and trunk muscles in zebrafish via transcriptomic profiling. We show that the LIM-protein Fhl2 is increased in response to the knockout of desmin, plectin and obscurin, cytoskeletal proteins whose knockout causes different muscle dystrophies, and contributes to disease protection of the EOMs. Moreover, we show that ectopic expression of fhl2b can partially rescue the muscle phenotype in the zebrafish Duchenne muscular dystrophy model sapje, significantly improving their survival. Therefore, Fhl2 is a protective agent and a candidate target gene for therapy of muscular dystrophies.
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| 4. |
- Dore, Riccardo, et al.
(författare)
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Resistance to thyroid hormone induced tachycardia in RTHα syndrome
- 2023
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Ingår i: Nature Communications. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Mutations in thyroid hormone receptor α1 (TRα1) cause Resistance to Thyroid Hormone α (RTHα), a disorder characterized by hypothyroidism in TRα1-expressing tissues including the heart. Surprisingly, we report that treatment of RTHα patients with thyroxine to overcome tissue hormone resistance does not elevate their heart rate. Cardiac telemetry in male, TRα1 mutant, mice indicates that such persistent bradycardia is caused by an intrinsic cardiac defect and not due to altered autonomic control. Transcriptomic analyses show preserved, thyroid hormone (T3)-dependent upregulation of pacemaker channels (Hcn2, Hcn4), but irreversibly reduced expression of several ion channel genes controlling heart rate. Exposure of TRα1 mutant male mice to higher maternal T3 concentrations in utero, restores altered expression and DNA methylation of ion channels, including Ryr2. Our findings indicate that target genes other than Hcn2 and Hcn4 mediate T3-induced tachycardia and suggest that treatment of RTHα patients with thyroxine in high dosage without concomitant tachycardia, is possible.
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| 5. |
- Li, Mei, et al.
(författare)
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Development and prevention of ischemic contracture (“stone heart”) in the pig heart
- 2023
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Ingår i: Frontiers in Cardiovascular Medicine. - : Frontiers Media SA. - 2297-055X. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Stone heart (ischemic contracture) is a rare and serious condition observed in the heart after periods of warm ischemia. The underlying mechanisms are largely unknown and treatment options are lacking. In view of the possibilities for cardiac donation after circulatory death (DCD), introducing risks for ischemic damage, we have investigated stone heart in pigs. Following cessation of ventilation, circulatory death (systolic pressure <8 mmHg) occurred within 13.1 ± 1.2 min; and a stone heart, manifested with asystole, increased left ventricular wall thickness and stiffness, established after a further 17 ± 6 min. Adenosine triphosphate and phosphocreatine levels decreased by about 50% in the stone heart. Electron microscopy showed deteriorated structure with contraction bands, Z-line streaming and swollen mitochondria. Synchrotron based small angle X-ray scattering of trabecular samples from stone hearts revealed attachment of myosin to actin, without volume changes in the sarcomeres. Ca2+ sensitivity, determined in permeabilized muscle, was increased in stone heart samples. An in vitro model for stone heart, using isolated trabecular muscle exposed to hypoxia/zero glucose, exhibited the main characteristics of stone heart in whole animals, with a fall in high-energy phosphates and development of muscle contracture. The stone heart condition in vitro was significantly attenuated by the myosin inhibitor MYK-461 (Mavacamten). In conclusion, the stone heart is a hypercontracted state associated with myosin binding to actin and increased Ca2+ sensitivity. The hypercontractile state, once developed, is poorly reversible. The myosin inhibitor MYK-461, which is clinically approved for other indications, could be a promising venue for prevention.
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| 6. |
- Liu, Jiao, et al.
(författare)
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Altered Sarcomeric Structure and Function in Woody Breast Myopathy of Avian Pectoralis Major Muscle
- 2020
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Ingår i: Frontiers in Physiology. - : Frontiers Media SA. - 1664-042X. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- The “Woody” or “Wooden” breast disease is a severe myopathy of pectoralis major muscle recently identified within rapidly growing broiler lines all around the world with a prevalence rate around 20%, or even higher. Although of significant ethical and economic impact, little is known regarding the structural and functional aspects of the contractile apparatus in the woody breast muscle. The aim of the present study was to determine physiological properties of the contractile system in the morphologically intact muscle fibers of focally damaged woody breast in comparison with normal muscle fibers to gain insight into the muscle function of the animal and possibly mechanisms involved in the disease development. Muscle samples were taken from woody breast (non-lesioned areas) and normal breast muscles from broilers. Length-tension curves, maximal active stress, maximal shortening velocity, calcium sensitivity, rate of tension development, lattice spacing and muscle biochemical composition were investigated on single skinned fibers. Sarcomeres of woody breast fibers were more compliant, which is very likely related to the wider spacing (18% wider compared to controls) between thick and thin filament. No differences were found in optimal sarcomere length (2.68 ± 0.04 vs. 2.65 ± 0.05 μm) nor in maximal active stress (116 ± 17 vs. 125 ± 19 mN mm–2). However, woody breast fibers had less steep descending arm as shown in length-tension curve. Woody breast muscle fibers had 40% bigger sarcomeric volume compared to controls. Content of contractile proteins (myosin and actin), and maximal shortening velocity were unchanged indicating that the growth in woody breast muscle fiber was associated with synthesis of new contractile units with unaltered kinetics. Calcium sensitivity was decreased in woody breast muscle fibers significantly. In conclusion, the results show that the rapid growth of muscle in woody breast disease is associated with significant structural and functional changes in the pectoralis major musculature, associated with alterations in the mechanical anchoring of contractile filaments.
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| 7. |
- Liu, Jiao, et al.
(författare)
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Longitudinal vibration interferes with cross-bridge attachment and prevents muscle fibre shrinkage under PSE-like conditions
- 2021
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Ingår i: Meat Science. - : Elsevier BV. - 0309-1740. ; 179
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Tidskriftsartikel (refereegranskat)abstract
- The impact of longitudinal vibration on cross-bridge attachments between myofilaments was investigated in single fibres and intact muscle. Sinusoidal length vibration (frequency 50 Hz, amplitude 5% of fibre length) reduced active force by 40% when fibres were activated by elevation of [Ca2+], but did not alter the force when fibres were in rigor state. When vibrated for 30 min in rigor at pH 5.5 and 38 °C (PSE conditions), the lateral shrinkage of the fibres was significantly reduced, suggesting a potential positive influence of vibration on water-holding capacity. In whole muscle incubated at 38 °C until 8 h post mortem, the progress of rigor onset was accessed by measuring the increase in muscle stiffness. Vibration applied 3-5 h post mortem postponed rigor development, but did not have significant influence on water-holding capacity compared with non-vibrated conditions. In conclusion, the results suggest that muscle vibration can be a future technique to delay rigor development and prevent muscle fibre shrinkage and PSE development after slaughter.
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| 8. |
- Rohl, S., et al.
(författare)
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Lack of PCSK6 Increases Flow-Mediated Outward Arterial Remodeling in Mice
- 2020
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Ingår i: Cells. - : MDPI AG. - 2073-4409. ; 9:4
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Tidskriftsartikel (refereegranskat)abstract
- Proprotein convertases (PCSKs) process matrix metalloproteases and cytokines, but their function in the vasculature is largely unknown. Previously, we demonstrated upregulation of PCSK6 in atherosclerotic plaques from symptomatic patients, localization to smooth muscle cells (SMCs) in the fibrous cap and positive correlations with inflammation, extracellular matrix remodeling and cytokines. Here, we hypothesize that PCSK6 could be involved in flow-mediated vascular remodeling and aim to evaluate its role in the physiology of this process using knockout mice. Pcsk6(-/-) and wild type mice were randomized into control and increased blood flow groups and induced in the right common carotid artery (CCA) by ligation of the left CCA. The animals underwent repeated ultrasound biomicroscopy (UBM) examinations followed by euthanization with subsequent evaluation using wire myography, transmission electron microscopy or histology. The Pcsk6(-/-) mice displayed a flow-mediated increase in lumen circumference over time, assessed with UBM. Wire myography revealed differences in the flow-mediated remodeling response detected as an increase in lumen circumference at optimal stretch with concomitant reduction in active tension. Furthermore, a flow-mediated reduction in expression of SMC contractile markers SMA, MYH11 and LMOD1 was seen in the Pcsk6(-/-) media. Absence of PCSK6 increases outward remodeling and reduces medial contractility in response to increased blood flow.
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| 9. |
- Rydberg, Mattias, et al.
(författare)
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Patient Experiences after Open Trigger Finger Release in Patients with Type 1 and Type 2 Diabetes-A Retrospective Study Using Patient-reported Outcome Measures
- 2023
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Ingår i: Plastic and reconstructive surgery. Global open. - 2169-7574. ; 11:6
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Tidskriftsartikel (refereegranskat)abstract
- UNLABELLED: Trigger finger is overrepresented among patients with diabetes mellitus (DM). Whether DM affects the outcome after open trigger finger release (OTFR) in patients with DM is not known. Our aim was thus to explore outcomes after OTFR in patients with type 1 (T1D) and type 2 DM (T2D).METHODS: Data included patient-reported outcome measures (PROMs) from all OTFRs performed between 2010 and 2020 registered in the Swedish national registry for hand surgery in individuals over 18 years cross-linked with the Swedish National Diabetes Register (NDR). PROMs included QuickDASH and HQ8, a questionnaire designed for national registry for hand surgery, preoperative and at 3 and 12 months postoperative. HQ8 included pain on load, pain on motion without load, and stiffness. Outcome was calculated using linear-mixed models and presented as means adjusted for age and stratified by sex.RESULTS: In total, 6242 OTFRs were included, whereof 496 had T1D (332, 67% women) and 869 had T2D (451, 52% women). Women with T1D reported more symptoms of stiffness (P < 0.001), and women with T2D reported more pain on load (P < 0.05), motion without load (P < 0.01), and worse overall result at 3 months. At 12 months, however, no differences were found in any of the HQ-8 PROMs among men or women. Women with T2D had slightly higher QuickDASH scores at 3 and 12 months.CONCLUSION: Patients with T1D and T2D can expect the same results after OTFR as individuals without DM, although the improvement might take longer especially among women with T2D.
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| 10. |
- Rydén, Mikael, et al.
(författare)
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Lipolysis defect in people with obesity who undergo metabolic surgery
- 2022
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Ingår i: Journal of Internal Medicine. - : Wiley-Blackwell Publishing Inc.. - 0954-6820 .- 1365-2796. ; 292:4, s. 667-678
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Cross-sectional studies demonstrate that catecholamine stimulation of fat cell lipolysis is blunted in obesity. We investigated whether this defect persists after substantial weight loss has been induced by metabolic surgery, and whether it is related to the outcome.DESIGN/METHODS: Patients with obesity not able to successfully reduce body weight by conventional means (n = 126) were investigated before and 5 years after Roux-en-Y gastric bypass surgery (RYGB). They were compared with propensity-score matched subjects selected from a control group (n = 1017), and with the entire group after adjustment for age, sex, body mass index (BMI), fat cell volume and other clinical parameters. Catecholamine-stimulated lipolysis (glycerol release) was investigated in isolated fat cells using noradrenaline (natural hormone) or isoprenaline (synthetic beta-adrenoceptor agonist).RESULTS: Following RYGB, BMI was reduced from 39.9 (37.5-43.5) (median and interquartile range) to 29.5 (26.7-31.9) kg/m2 (p < 0.0001). The post-RYGB patients had about 50% lower lipolysis rates compared with the matched and total series of controls (p < 0.0005). Nordrenaline activation of lipolysis at baseline was associated with the RYGB effect; those with high lipolysis activation (upper tertile) lost 30%-45% more in body weight, BMI or fat mass than those with low (bottom tertile) initial lipolysis activation (p < 0.0007).CONCLUSION: Patients with obesity requiring metabolic surgery have impaired ability of catecholamines to stimulate lipolysis, which remains despite long-term normalization of body weight by RYGB. Furthermore, preoperative variations in the ability of catecholamines to activate lipolysis may predict the long-term reduction in body weight and fat mass.
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