Temperature-dependent skeletal muscle dysfunction in rats with congestive heart failure.

Abnormalities in the excitation-contraction coupling of slow-twitch muscle seem to explain the slowing and increased fatigue observed in congestive heart failure (CHF). However, it is not known which elements of the excitation-contraction coupling might be affected. We hypothesize that the temperature sensitivity of contractile properties of the soleus muscle might be altered in CHF possibly because of alterations of the temperature sensitivity of intracellular Ca(2+) handling. We electrically stimulated the in situ soleus muscle of anesthetised rats that had 6-wk postinfarction CHF using 1 and 50 Hz and using a fatigue protocol (5-Hz stimulation for 30 min) at 35, 37, and 40 degrees C. Ca(2+) uptake and release were measured in sarcoplasmic reticulum vesicles at various temperatures. Contraction and relaxation rates of the soleus muscle were slower in CHF than in sham at 35 degrees C, but the difference was almost absent at 40 degrees C. The fatigue protocol revealed that force development was more temperature sensitive in CHF, whereas contraction and relaxation rates were less temperature sensitive in CHF than in sham. The Ca(2+) uptake and release rates did not correlate to the difference between CHF and sham regarding contractile properties or temperature sensitivity. In conclusion, the discrepant results regarding altered temperature sensitivity of contraction and relaxation rates in the soleus muscle of CHF rats compared with Ca(2+) release and uptake rates in vesicles indicate that the molecular cause of slow-twitch muscle dysfunction in CHF is not linked to the intracellular Ca(2+) cycling.

Muscle contractile properties during intermittent nontetanic stimulation in rat skeletal muscle.

To examine changes in contractile properties and mechanisms of fatigue during submaximal nontetanic skeletal muscle activity, in situ perfused soleus (60-min protocol) and extensor digitorum longus (EDL; 10-min protocol) muscles of the rat were electrically stimulated intermittently at low frequency. The partly fused trains of contractions showed a two-phase change in appearance. During the first phase, relaxation slowed, one-half relaxation time increased, and maximal relaxation first derivative of force (dF/dt) decreased. Developed force during the trains was reduced and was closely related to the rate of relaxation in this first phase. During the second phase, relaxation became faster again, one-half relaxation time decreased, and force returned to resting levels between contractions in a train. In contrast, developed force remained reduced, so that peak force of the contractions was 51% (soleus) and 30% (EDL) of control. In the soleus muscle, the changes in contractile properties were not related to ATP, creatine phosphate, or lactate content. The changes in contractile properties fit best with a mechanism of fatigue involving changes in Ca(2+) handling by the sarcoplasmic reticulum.

Loss of potassium from muscle during moderate exercise in humans: a result of insufficient activation of the Na+-K+-pump?

In this study, we have investigated whether the muscle net potassium (K+) loss, observed during two-legged intermittent static knee-extensions at 30% MVC (n = 9), is caused by an insufficient activation of the Na+-K+-pumps. Furthermore, we have investigated whether the changes in the K+ homeostasis can be causally related to fatigue. K+ loss was calculated from the arterio-venous concentration difference and plasma flow. In three subjects, femoral venous K+ concentration was measured continuously with a K+ selective electrode. Na+-K+-pump activity was estimated from the rate of removal of K+ from the blood during 30-s pauses inserted into the exercise protocol. A large net K+ loss took place during the first minutes of exercise, but diminished quickly and disappeared after 20 min. An increasing net K+ loss reappeared after 30 min. Only 10% of the lost K+ had been regained after the 20-min recovery. A lag in the activation of the Na+-K+-pumps may explain the K+ loss at the beginning of exercise, but gradual pump activation prevented a net K+ loss after 20 min of exercise. The reappearance of the net K+ loss in the later stage of exercise and the subsequent slow recovery of intracellular K+ seemed to be caused by an insufficient further activation of the pumps, rather than by the capacity of the pumps being surpassed. Fatigue was not related to the accumulation of K+ in the interstitium. However, during exercise, the decrease in intracellular K+ content was linearly related to the fall of maximal force. We conclude that during repeated isometric contractions, insufficient activation of the Na+-K+-pumps causes a continuous muscle K+ loss which was associated with fatigue.

Skeletal muscle fatigue in normal subjects and heart failure patients. Is there a common mechanism?

Skeletal muscle fatigue develops gradually during all forms of exercise, and develops more rapidly in heart failure patients. The fatigue mechanism is still not known, but is most likely localized to the muscle cells themselves. During high intensity exercise the perturbations of the Na+ and K+ balance in the exercising muscle favour depolarization, smaller action potentials and inexcitability. The Na+, K+ pump becomes strongly activated and limits, but does not prevent the rise in extracellular Na+, K+ pump concentration and intracellular Na+ concentration. However, by virtue of its electrogenic property the pump may contribute in maintaining excitability and contractility by keeping the cells more polarized than the ion gradients predict. With prolonged exercise perturbations of Na+ and K+ are smaller and fatigue may be associated with altered cellular handling of Ca2+ and Mg2+. Release of Ca2+ from the sarcoplasmic reticulum (SR) is reduced in the absence of changes of the cellular content of Ca2+ and Mg2+. In heart failure several clinical reports indicate severe electrolyte perturbations in skeletal muscle. However, in well controlled studies small or insignificant changes are found. We conclude that with high intensity exercise perturbations of Na+ and K+ in muscle cells may contribute to fatigue, whereas with endurance type of exercise and in heart failure patients the skeletal muscle fatigue is more likely to reside in the intracellular control of Ca2+ release and reuptake.

Atrial contractile dysfunction after short-term atrial fibrillation is reduced by verapamil but increased by BAY K8644.

BACKGROUND: Reduced atrial contractility occurs after cessation of atrial fibrillation. Its mechanism is unknown, and no pharmacological treatment exists. It has been hypothesized that this atrial contractile dysfunction results from intracellular calcium overload due to rapid depolarizations during fibrillation. Accordingly, we examined the effects of drugs that reduce or increase transsarcolemmal calcium influx on postfibrillation atrial dysfunction. Furthermore, we examined whether the dysfunction could be attributed to atrial ischemia. METHODS AND RESULTS: Atrial contractility after atrial fibrillation was examined in open-chest pigs paced with a constant ventricular rate after complete AV block. Atrial contractility was computed as systolic shortening of left atrial diameter divided by atrial preload. Three groups of six pigs each were subjected to two 5-minute periods of atrial fibrillation separated by 1 hour of AV pacing. Verapamil or the calcium channel agonist BAY K8644 was administered intravenously before the second fibrillation period. The degree and duration of postfibrillation atrial contractile dysfunction were reduced with verapamil but increased with BAY K8644. In a control group, parallel changes occurred after the first and second fibrillation periods. Atrial tissue content of creatine phosphate declined slightly during fibrillation, whereas the tissue content of ATP and lactate remained unchanged. CONCLUSIONS: Atrial contractile dysfunction after short-term atrial fibrillation is reduced by the calcium antagonist verapamil, which suggests that transsarcolemmal calcium influx contributed to this dysfunction. The calcium agonist BAY K8644 increased postfibrillation atrial contractile dysfunction. Atrial ischemia was not observed during fibrillation.

Muscular function, metabolism and electrolyte shifts during prolonged repetitive exercise in humans.

Marked functional changes occur in human skeletal muscle during prolonged repetitive exercise. The maximum voluntary contraction force (MVC) falls gradually and may reach 50% of control within 30-60 min. The twitch tension declines faster and to a larger extent. During repetitive submaximal isometric contractions the rate of relaxation increase progressively, in parallel with an increased energy cost of contraction. These functional changes are all slowly reversed in the post-exercise period, as indicated by only minor changes over the first 30 min of recovery. Minor changes in substrates and metabolites, together with the slow rate of recovery, indicate that the alterations in contractile properties and energetics are independent of these metabolic factors. Alternative explanations may be related to electrolyte shifts over the sarcolemma or between cellular compartments. The total loss of K+ is small, and could not be detected by analysis of muscle biopsies. Only a slight initial rise in muscle content of calcium was found. The available data indicate that the increased energy cost of contraction is not connected to mitochondrial dysfunction, which might be caused by calcium accumulation. Rather, it seems that the ratio of ATP utilization to force is increased and this could possibly be connected to this faster relaxation rate. Considering the low excitation rates during submaximal voluntary contractions, each motor unit generates an oscillating force closely associated with Ca2+ fluctuations between SR and cytosol. Increased relaxation rats might be caused by faster reuptake of Ca2+ into the SR, and this could contribute to the faster ATP turnover.

Absence of an effect of fatigue on muscle efficiency during high-intensity exercise in rat skeletal muscle.

The effect of fatigue was studied on rat skeletal muscle efficiency during maximal dynamic exercise of 10s duration. After the initial 4s of exercise, power output decreased rapidly to 46.2 +/- 6.7% (mean +/- SD; n = 6) after 6s of stimulation and further to 17.5 +/- 5.8% in the last contraction. Both the rates of total work output and high-energy phosphate consumption decreased with increasing exercise duration. As a result muscle efficiency was not affected by exercise time in the present experiments. This result indicates that fatigue in severe maximal exercise is induced by a feed-back mechanism, which in the case of high ATP utilisation rates will reduce ATP splitting probably by reducing Ca(2+)-release from the sarcoplasmic reticulum.