Fatigue mechanisms and skeletal muscle function in experimental and human heart failure

Skeletal muscle fatigue, the decline in skeletal muscle performance with activity, is extensively reviewed in the literature. The common experimental setup is to stimulate a skeletal muscle preparation isometrically and meassure force. The decline in force serves as the fatigue parameter, and muscle from animals with heart failure typically has a greater fall in force than muscle from control animals. Also, skeletal muscle fatigue is a common symptom for the heart failure (chf) patient. This was the basis for the work presented in this thesis in muscle physiology. In spite the great amount of research on skeletel muscle fatigue, only rarely is fatigue studied using shortening contractions. Also, although altered calcium cycling could contribute to the development of fatigue, the calcium handling properties in skeletal muscle from chf patients has not been evaluated. The aim of this thesis is to investigate the development of and the mechanisms contributing to fatigue following shortening contractions. Also, it aims to uncover wheather the increased fatiguability in the chf patient can be explained by altered calcium homeostasis compared to controls. The animals used in this thesis were either healthy or they suffered from chf induced by coronary infarction. All animals were used in an in situ stimulation protocol were the stimulated muscle were allowed to shorten. Muscle biopsies from the thigh were obtained from heart failure patients and healthy contols. The main results are that the ability to shorten seems to be more fatigue sensitive following shortening contractions compared to maximal isometric force capacity and that modification of key proteins in the contractile apparatus could be of importance to the fatigue development. Further, skeletal muscle from chf patients have altered calcium handling properties compared to healthy controls although this seem unrelated to the increased fatiguability in human heart failure

How well did Norwegian general practice prepare to address the COVID-19 pandemic?

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.publishedVersio

Attenuated Fatigue in Slow Twitch Skeletal Muscle during Isotonic Exercise in Rats with Chronic Heart Failure

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 >15mmHg. During isoflurane anaesthesia, SOL with intact blood supply was stimulated (1s on 1s off) at 30Hz 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 (Fmax) and the concentrations of ATP and CrP were not different in the two groups. During stimulation, Fmax 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

Multiple Causes of Fatigue during Shortening Contractions in Rat Slow Twitch Skeletal Muscle

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. Copyright 2013 Hortemo et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License

How well did Norwegian general practice prepare to address the COVID-19 pandemic?

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

Time course of fatigue and recovery during 20 s and 100 s exercise.

<p>The panels show development of contraction (panels <i>A</i>, <i>B</i> and <i>C</i>) and relaxation (panels <i>D</i>, <i>E</i> and <i>F</i>) parameters during fatigue development (black symbols, solid line) and recovery (white symbols, dotted line). Exercise times are given at bottom x-axis and recovery times at top x-axis. <i>A)</i> Maximal rate of isometric force development, dF/dt. <i>B</i>) Maximal isotonic shortening velocity, dL/dt. C) Maximal shortening, S_max. D) Maximal isotonic relengthening velocity, −dL/dt. E) Maximal isometric relaxation rate, −dF/dt. <i>F</i>) Time to resting length, TTL₀ (squares) and tau2 (circles). Symbols are averages ± SEM. * p<0.05 <i>vs.</i> initial value. † p<0.05 <i>vs.</i> 20 s. <i>N</i> start<i>24</i>; 20 s = <i>12</i>; 100 s = <i>12</i>; 20 s +2.5 min recovery = <i>6</i>; 100 s +15 min recovery = <i>6</i>.</p

Contractile performance in the 1^st bout (open bars) <i>vs.</i> the 2^nd bout (black bars).

<p>Contraction (panels <i>A</i>, <i>B</i> and <i>C</i>) and relaxation (panels <i>D</i>, <i>E</i> and <i>F</i>) parameters at start (0 s), at 100 s and at 900 s of shortening contractions. <i>A</i>) Maximal rate of isometric force development, dF/dt. <i>B</i>) Maximal isotonic shortening velocity, dL/dt. <i>C</i>) Maximal shortening, S_max. <i>D</i>) Maximal isotonic relengthening velocity, −dL/dt. <i>E</i>) Maximal isometric relaxation rate, −dF/dt. <i>F</i>) Tau2 values. Bars are averages ± SEM. * p<0.05 <i>vs.</i> initial value. # p<0.05 <i>vs.</i> corresponding 1^st bout value. † p<0.05 <i>vs.</i> 100 s. <i>N</i> start 1^st = <i>20</i>; 100 s 1^st = <i>12</i>; 15 min 1^st = <i>6</i>; start 2^nd = <i>12</i>; 100 s 2^nd = <i>20</i>; 15 min 2^nd = <i>6</i>.</p

Isometric relaxation and lactate.

<p>Isometric relaxation rate (−dF/dt) was strongly correlated to muscle lactate throughout the exercise protocols. Data are obtained from all measured time points in the 1^st bout (black), after recovery (grey) and in the 2^nd bout (white), presented as a linear regression (r² = 0.81, p<0,01) based on group means ± SEM.</p

Effects of afterload and stimulation frequency on dephosphorylation of MLC-2s.

<p>Panel <i>A</i> and <i>B</i>: The effects of altered afterload of the exercising muscle. Stimulation frequency was 30 Hz as in the standard protocols. <i>A</i>) Shortening (S_max) at start was strongly correlated to the pre-set afterload (r² = 0.99). <i>B</i>) The phosphorylation level of MLC-2s (white bars) relative to resting control (100%) and the corresponding S_max (black bars) at 15 min exercise. Afterload was set to 10, 20 or 33% of F_max. Panel <i>C</i> and <i>D:</i> The effects of altered muscle stimulation frequency. Afterload was 33% of F_max as in the standard protocols. <i>C</i>) S_max (black circles) and force development (grey squares) in the unfatigued muscle at various stimulation frequencies. <i>D</i>) The phosphorylation level of MLC-2s (white bars) and S_max (black bars) at 15 min exercise with stimulation frequency 40, 30 or 20 Hz. Symbols are averages ± SEM. *p<0.05 <i>vs.</i> 33% afterload. †p<0.05 <i>vs.</i> 30 Hz. <i>N</i> 10% afterload = <i>6</i>; 20% afterload = <i>5</i>; 33% afterload = <i>8</i>; 20 Hz = <i>6</i>; 40 Hz = <i>6</i>.</p

Metabolites in soleus muscle at rest (Ctr) and at different exercise and recovery times.

<p>Values are in mmol kg wet weight^-1, average ± SEM.</p>*<p>p<0.05 <i>vs.</i> control,</p>†<p>p<0.05 <i>vs.</i> 20 s exercise,</p>#<p>p<0.05 <i>vs</i>. 100 s exercise in the 1^st bout. <i>Rec</i>. recovery.</p>1<p>i.e. at start of the 2^nd bout.</p