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

Training effects on skeletal muscle calcium handling in human chronic heart failure

I Brage finner du siste tekst-versjon av artikkelen, og den kan inneholde ubetydelige forskjeller fra forlagets pdf-versjon. Forlagets pdf-versjon finner du på www.ovid.com: http://dx.doi.org/10.1249/MSS.0b013e3181c29ec1 / In Brage you'll find the final text version of the article, and it may contain insignificant differences from the journal's pdf version. The definitive version is available at www.ovid.com: http://dx.doi.org/10.1249/MSS.0b013e3181c29ec1Purpose: 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

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

Definitions of calculated contractile parameters.

<p>Definitions of calculated contractile parameters.</p

Characteristic fatigue development during the first 100 s of exercise.

<p>Representative tracings of shortening (upper panel) and force (lower panel) assembled from the first 100 s. Tracings at start, 20 s and 100 s exercise are highlighted (black). Note the reduced shortening already at 20 s exercise. At 100 s exercise, there is a further reduction in shortening, and there is also a slowing of the remaining phases of the contraction cycle and especially a significant prolongation of the isometric relaxation phase (lower panel).</p

Overview of the three experimental protocols.

<p>Intermittent stimulation at 30 Hz for 1 s every 2 s. <i>A</i>) 20 s exercise (stimulation) followed by 2.5 min rest. <i>B</i>) 100 s exercise followed by 15 min rest. <i>C</i>) 15 min exercise (1^st bout) followed by 15 min rest before initiating another 15 min exercise (2^nd bout). In all protocols, muscles were harvested (arrows) at start and at end of exercise, as well as after rest. In <i>C</i>, there was an additional harvesting point at 100 s both in the 1^st and 2^nd bout.</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