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It has been proposed that exercise capacity during whole body exercise in post-infarction congestive heart failure (CHF) patients is limited by skeletal muscle function. We therefore investigated the balance between cardiopulmonary and muscular metabolic capacity. CHF patients ( n=8) and healthy subjects (HS, n=12) were included. Patients with coronary artery disease (CAD, n=8) were included as a control for medication. All subjects performed a stepwise incremental load test during bicycling (∼24 kg muscle mass), two-legged knee extensor (2-KE) exercise (∼4 kg muscle mass) and one-legged knee extensor (1-KE) exercise (∼2 kg muscle mass). Peak power and peak pulmonary oxygen uptake (VO2peak) increased and muscle-specific VO2peak decreased with an increasing muscle mass involved in the exercise. Peak power and VO2peak were lower for CHF patients than HS, with values for CAD patients falling between CHF patients and HS. During bicycling, all groups utilized 24-29% of the muscle-specific VO2peak as measured during 1-KE exercise, with no difference between the groups. Hence, the muscle metabolic reserve capacity during whole body exercise is not different between CHF patients and HS, indicating that appropriately medicated and stable post-infarction CHF patients are not more limited by intrinsic skeletal muscle properties during whole body exercise than HS. [ABSTRACT FROM AUTHOR]

Objectives: We aimed to describe the quality improvement measures made by Norwegian general practice (GP) during the COVID-19 pandemic, evaluate the differences in quality improvements based on region and assess the combinations of actions taken., Design: Descriptive study., Setting: Participants were included after taking part in an online quality improvement COVID-19 course for Norwegian GPs in April 2020. The participants reported whether internal and external measures were in place: COVID-19 sign on entrance, updated home page, access to video consultations and/or electronic written consultations, home office solutions, separate working teams, preparedness for home visits, isolation rooms, knowledge on decontamination, access to sufficient supplies of personal protective equipment (PPE) and COVID-19 clinics., Participants: One hundred GP offices were included. The mean number of general practitioners per office was 5.63., Results: More than 80% of practices had the following preparedness measures: COVID-19 sign on entrance, updated home page, COVID-19 clinic in the municipality, video and written electronic consultations, knowledge on how to use PPE, and home office solutions for general practitioners. Less than 50% had both PPE and knowledge of decontamination. Lack of PPE was reported by 37%, and 34% reported neither sufficient PPE nor a dedicated COVID-19 clinic. 15% reported that they had an isolation room, but not enough PPE. There were no geographical differences., Conclusions: Norwegian GPs in this study implemented many quality improvements to adapt to the COVID-19 pandemic. Overall, the largest potentials for improvement seem to be securing sufficient supply of PPE and establishing an isolation room at their practices., Competing Interests: Competing interests: WDF owns a company, Epidemiologic Research & Methods, which does consulting work. He knows of no conflicts of interest with this work., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Protein O-GlcNAcylation has emerged as an important intracellular signaling system with both physiological and pathophysiological functions, but the role of protein O-GlcNAcylation in skeletal muscle remains elusive. In this study, we tested the hypothesis that protein O-GlcNAcylation is a dynamic signaling system in skeletal muscle in exercise and disease. Immunoblotting showed different protein O-GlcNAcylation pattern in the prototypical slow twitch soleus muscle compared to fast twitch EDL from rats, with greater O-GlcNAcylation level in soleus associated with higher expression of the modulating enzymes O-GlcNAc transferase (OGT), O-GlcNAcase (OGA), and glutamine fructose-6-phosphate amidotransferase isoforms 1 and 2 (GFAT1, GFAT2). Six weeks of exercise training by treadmill running, but not an acute exercise bout, increased protein O-GlcNAcylation in rat soleus and EDL There was a striking increase in O-GlcNAcylation of cytoplasmic proteins ~50 kDa in size that judged from mass spectrometry analysis could represent O-GlcNAcylation of one or more key metabolic enzymes. This suggests that cytoplasmic O-GlcNAc signaling is part of the training response. In contrast to exercise training, postinfarction heart failure (HF) in rats and humans did not affect skeletal muscle O-GlcNAcylation level, indicating that aberrant O-GlcNAcylation cannot explain the skeletal muscle dysfunction in HF Human skeletal muscle displayed extensive protein O-GlcNAcylation that by large mirrored the fiber-type-related O-GlcNAcylation pattern in rats, suggesting O-GlcNAcylation as an important signaling system also in human skeletal muscle., (© 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.)

Fatigue in muscles that shorten might have other causes than fatigue during isometric contractions, since both cross-bridge cycling and energy demand are different in the two exercise modes. While isometric contractions are extensively studied, the causes of fatigue in shortening contractions are poorly mapped. Here, we investigate fatigue mechanisms during shortening contractions in slow twitch skeletal muscle in near physiological conditions. Fatigue was induced in rat soleus muscles with maintained blood supply by in situ shortening contractions at 37°C. Muscles were stimulated repeatedly (1 s on/off at 30 Hz) for 15 min against a constant load, allowing the muscle to shorten and perform work. Fatigue and subsequent recovery was examined at 20 s, 100 s and 15 min exercise. The effects of prior exercise were investigated in a second exercise bout. Fatigue developed in three distinct phases. During the first 20 s the regulatory protein Myosin Light Chain-2 (slow isoform, MLC-2s) was rapidly dephosphorylated in parallel with reduced rate of force development and reduced shortening. In the second phase there was degradation of high-energy phosphates and accumulation of lactate, and these changes were related to slowing of muscle relengthening and relaxation, culminating at 100 s exercise. Slowing of relaxation was also associated with increased leak of calcium from the SR. During the third phase of exercise there was restoration of high-energy phosphates and elimination of lactate, and the slowing of relaxation disappeared, whereas dephosphorylation of MLC-2s and reduced shortening prevailed. Prior exercise improved relaxation parameters in a subsequent exercise bout, and we propose that this effect is a result of less accumulation of lactate due to more rapid onset of oxidative metabolism. The correlation between dephosphorylation of MLC-2s and reduced shortening was confirmed in various experimental settings, and we suggest MLC-2s as an important regulator of muscle shortening.

Sarcoplasmic reticulum Ca(2+) ATPases (SERCAs) play a major role in muscle contractility by pumping Ca(2+) from the cytosol into the sarcoplasmic reticulum (SR) Ca(2+) store, allowing muscle relaxation and refilling of the SR with releasable Ca(2+). Decreased SERCA function has been shown to result in impaired muscle function and disease in human and animal models. In this study, we present a new mouse model with targeted disruption of the Serca2 gene in skeletal muscle (skKO) to investigate the functional consequences of reduced SERCA2 expression in skeletal muscle. SkKO mice were viable and basic muscle structure was intact. SERCA2 abundance was reduced in multiple muscles, and by as much as 95% in soleus muscle, having the highest content of slow-twitch fibres (40%). The Ca(2+) uptake rate was significantly reduced in SR vesicles in total homogenates. We did not find any compensatory increase in SERCA1 or SERCA3 abundance, or altered expression of several other Ca(2+)-handling proteins. Ultrastructural analysis revealed generally well-preserved muscle morphology, but a reduced volume of the longitudinal SR. In contracting soleus muscle in vitro preparations, skKO muscles were able to fully relax, but with a significantly slowed relaxation time compared to controls. Surprisingly, the maximal force and contraction rate were preserved, suggesting that skKO slow-twitch fibres may be able to contribute to the total muscle force despite loss of SERCA2 protein. Thus it is possible that SERCA-independent mechanisms can contribute to muscle contractile function.

During isometric contractions, slow twitch soleus muscles (SOL) from rats with chronic heart failure (chf) are more fatigable than those of sham animals. However, a muscle normally shortens during activity and fatigue development is highly task dependent. Therefore, we examined the development of skeletal muscle fatigue during shortening (isotonic) contractions in chf and sham-operated rats. Six weeks following coronary artery ligation, infarcted animals were classified as failing (chf) if left ventricle end diastolic pressure was >15 mmHg. During isoflurane anaesthesia, SOL with intact blood supply was stimulated (1s on 1s off) at 30 Hz for 15 min and allowed to shorten isotonically against a constant afterload. Muscle temperature was maintained at 37°C. In resting muscle, maximum isometric force (F(max)) and the concentrations of ATP and CrP were not different in the two groups. During stimulation, F(max) and the concentrations declined in parallel sham and chf. Fatigue, which was evident as reduced shortening during stimulation, was also not different in the two groups. The isometric force decline was fitted to a bi-exponential decay equation. Both time constants increased transiently and returned to initial values after approximately 200 s of the fatigue protocol. This resulted in a transient rise in baseline tension between stimulations, although this effect which was less prominent in chf than sham. Myosin light chain 2s phosphorylation declined in both groups after 100 s of isotonic contractions, and remained at this level throughout 15 min of stimulation. In spite of higher energy demand during isotonic than isometric contractions, both shortening capacity and rate of isometric force decline were as well or better preserved in fatigued SOL from chf rats than in sham. This observation is in striking contrast to previous reports which have employed isometric contractions to induce fatigue.

Purpose: Patients with chronic heart failure (CHF) typically complain about skeletal muscle fatigue. In rat experiments, reduced intracellular calcium release seems to be related to fatigue development in normal skeletal muscle but not in muscle from rats with CHF. We therefore hypothesize that training may not improve intracellular calcium cycling to the same extent in muscles from patients with CHF compared with healthy controls (HC)., Methods: Thirteen HC and 11 CHF patients performed 6 wk of unilateral knee extensor endurance training. Computed tomographic examinations of the thigh and biopsies of vastus lateralis were obtained bilaterally before and after the training period., Results: Peak power of the trained leg was 10% and 14% greater than that in the untrained leg in HC and CHF, respectively. For the HC, training resulted in a higher Ca2+ release rate and a lower leak in the trained leg associated with a tendency of increased ryanodine receptor (RyR) content with reduced phosphorylation level. In the trained leg of CHF patients, RyR content was reduced without associated changes of either Ca2+ leak or release rate., Conclusions: Training in HC has an effect on Ca2+ leak and release of the sarcoplasmic reticulum, but in CHF patients, training is achieved without such changes. Thus, calcium handling seems not to be the site of decreased exercise tolerance in CHF.

Skeletal muscle fatigue is most often studied in vitro at room temperature and is classically defined as a decline in maximum force production or power output, exclusively linked to repeated isometric contractions. However, most muscles shorten during normal use, and we propose that both the functional correlate of fatigue, as well as the fatigue mechanism, will be different during dynamic contractions compared with static contractions. Under isoflurane anesthesia, fatigue was induced in rat soleus muscles in situ by isotonic shortening contractions at 37 degrees C. Muscles were stimulated repeatedly for 1 s at 30 Hz every 2 s for a total of 15 min. The muscles were allowed to shorten isotonically against a load corresponding to one-third of maximal isometric force. Maximal unloaded shortening velocity (V(0)), maximum force production (F(max)), and isometric relaxation rate (-dF/dt) was reduced after 100 s but returned to almost initial values at the end of the stimulation protocol. Likewise, ATP and creatine phosphate (CrP) were reduced after 100 s, but the level of CrP was partially restored to initial values after 15 min. The rate of isometric force development, the velocity of shortening, and isotonic shortening were also reduced at 100 s, but in striking contrast, did not recover during the remainder of the stimulation protocol. The regulatory myosin light chain (MLC2s) was dephosphorylated after 100 s and did not recover. Although metabolic changes may account for the changes of F(max), -dF/dt, and V(0), dephosphorylation of MLC2s may be involved in the fatigue seen as sustained slower contraction velocities and decreased muscle shortening.

Patients with congestive heart failure (CHF) experience increased skeletal muscle fatigue. The mechanism underlying this phenomenon is unknown, but a deranged extracellular matrix (ECM) might be a contributing factor. Hence, we examined ECM components and regulators in a rat postinfarction model of CHF. At various time points during a 3.5 mo-period after induction of CHF in rats by left coronary artery ligation, blood, interstitial fluid (IF), and muscles were sampled. Isoflurane anesthesia was employed during all surgical procedures. IF was extracted by wicks inserted intermuscularly in a hind limb. We measured cytokines in plasma and IF, whereas matrix metalloproteinase (MMP) activity and collagen content, as well as the level of glycosaminoglycans and hyaluronan were determined in hind limb muscle. In vivo fatigue protocols of the soleus muscle were performed at 42 and 112 days after induction of heart failure. We found that the MMP activity and collagen content in the skeletal muscles increased significantly at 42 days after induction of CHF, and these changes were time related to increased skeletal muscle fatigability. These parameters returned to sham levels at 112 days. VEGF in IF was significantly lower in CHF compared with sham-operated rats at 3 and 10 days, but no difference was observed at 112 days. We conclude that temporary alterations in the ECM, possibly triggered by VEGF, are related to a transient development of skeletal muscle fatigue in CHF.

Background: MRCP has replaced ERCP as the diagnostic tool in diseases in the biliary and pancreatic ducts. Secretin increases the secretion to ducts, and this has been reported to improve MRCP image quality., Material and Methods: We report our experience with S-MRCP in our first 20 patients. Secretin was given intravenously and images were obtained every minute for 10 minutes. These images were compared with MRCP images taken before and after secretin stimulation., Results: New information was yielded in 18 cases, i.e. information not observed in previous radiological examinations., Interpretation: In diagnostics of dysfunction of the sphincter of Oddi, the method may be useful, given the functional aspect of the procedure where increased pressure in the ducts may lead to pain. It may further improve the diagnostics of pancreatic cancer versus pancreatitis, in pancreas divisum and sclerosing cholangitis. The method is also valuable for clarifying whether there is injury to the pancreatic duct after blunt abdominal trauma. Surgical common bile duct injuries may be better assessed than with any other method. In difficult pancreatic and biliary investigations, S-MRCP seems to be a useful and complication-free supplement to existing diagnostic methods.