inosinic-acid and Fatigue

The force produced by muscles declines during prolonged activity and this decline arises largely from processes within the muscle. At a cellular level the reduced force could be caused by: (a) reduced intracellular calcium release during activity; (b) reduced sensitivity of the myofilaments to calcium; or (c) reduced maximal force development. Experiments involving intracellular calcium measurements in isolated single fibres show that all 3 of the above contribute to the decline of force during fatigue. Metabolic changes associated with fatigue are probably involved in each of the 3 factors. Thus the accumulation of phosphate and protons which occur during fatigue cause a reduction in calcium sensitivity and a decline in maximal force. The cause of the reduced intracellular calcium during contractions in fatigue is less clear. During prolonged tetani the conduction of the action potential in the T-tubules appears to fail leading to reduced intracellular calcium in the central part of the muscle fibre. However, during repeated tetani there is a uniform decline of intracellular calcium across the fibre and this remains one of the least understood processes which contribute to fatigue.

Topics: Action Potentials; Adenosine Monophosphate; Adenosine Triphosphate; Animals; Calcium; Calcium Channels; Fatigue; Humans; Inosine Monophosphate; Mice; Muscle Contraction; Spasm

The supply of energy is of fundamental importance for the ability to sustain exercise. The maximal duration of exercise is negatively related to the relative intensity both during dynamic and static exercise. Since exercise intensity is linearly related to the rate of energy utilisation this suggests that energetic deficiency plays a major role in the aetiology of muscle fatigue. Characteristic metabolic changes in the muscle are generally observed at fatigue--the pattern being different after short term exercise (lactate accumulation and phosphocreatine depletion) from after prolonged exercise at moderate intensity (glycogen depletion). A common metabolic denominator at fatigue during these and many other conditions is a reduced capacity to generate ATP and is expressed by an increased catabolism of the adenine nucleotide pool in the muscle fibre. Transient increases in ADP are suggested to occur during energetic deficiency and may be the cause of fatigue. Experimental evidence from human studies demonstrate that near maximal power output can be attained during acidotic conditions. Decreases in muscle pH is therefore unlikely to affect the contractile machinery by a direct effect. However, acidosis may interfere with the energy supply possibly by reducing the glycolytic rate, and could by this mechanism be related to muscle fatigue.

Topics: Adenosine Diphosphate; Adenosine Triphosphate; AMP Deaminase; Exercise; Fatigue; Humans; Inosine Monophosphate; Maximal Voluntary Ventilation; Muscle Contraction

The hypothesis that fatigue during prolonged exercise arises from insufficient intramuscular glycogen, which limits tricarboxylic acid cycle (TCA) activity due to reduced TCA cycle intermediates (TCAI), was tested in this experiment. Seven endurance-trained men cycled at approximately 70% of peak O(2) uptake (Vo(2 peak)) until exhaustion with low (LG) or high (HG) preexercise intramuscular glycogen content. Muscle glycogen content was lower (P < 0.05) at fatigue than at rest in both trials. However, the increase in the sum of four measured TCAI (>70% of the total TCAI pool) from rest to 15 min of exercise was not different between trials, and TCAI content was similar after 103 +/- 15 min of exercise (2.62 +/- 0.31 and 2.59 +/- 0.28 mmol/kg dry wt for LG and HG, respectively), which was the point of volitional fatigue during LG. Subjects cycled for an additional 52 +/- 9 min during HG, and although glycogen was markedly reduced (P < 0.05) during this period, no further change in the TCAI pool was observed, thus demonstrating a clear dissociation between exercise duration and the size of the TCAI pool. Neither the total adenine nucleotide pool (TAN = ATP + ADP + AMP) nor IMP was altered compared with rest in either trial, whereas creatine phosphate levels were not different when values measured at fatigue were compared with those measured after 15 min of exercise. These data demonstrate that altered glycogen availability neither compromises TCAI pool expansion nor affects the TAN pool or creatine phosphate or IMP content during prolonged exercise to fatigue. Therefore, our data do not support the concept that a decrease in muscle TCAI during prolonged exercise in humans compromises aerobic energy provision or is the cause of fatigue.

Topics: Adenine Nucleotides; Adult; Amino Acids; Blood Glucose; Citric Acid Cycle; Exercise; Fatigue; Glycogen; Heart Rate; Humans; Hypoxanthine; Inosine Monophosphate; Lactic Acid; Male; Muscle, Skeletal; Oxygen Consumption; Pyruvates; Time Factors

Reductions in work output during repeated contractions of rat medial gastrocnemius muscles (37 degrees C) were compared with changes in muscle metabolite concentrations. Three different exercise protocols were used in which the total number of stimuli and the length excursion were the same. The muscles performed a series of either 10, 25 or 40 repeated contractions at velocities of 20, 50 and 80 mm/s for groups A, B and C, respectively. In group A work output decreased steadily to 66% of the output in the first contraction. In groups B and C work output decreased to less than 10% of the first contraction. Changes in phosphocreatine and lactate concentrations were similar for all groups. However, very low ATP concentrations (approximately 35% of the resting value) were observed in groups B and C, compared with approximately 65% in group A. Inosine 5'-monophosphate (IMP) production was 9.9 mumol/g dry wt in group A and approximately 18 mumol/g dry wt in groups B and C. The results suggest fatigue does not depend on changes in intracellular inorganic phosphate and pH but possibly on changes in nucleotide metabolism.

Topics: Adenosine Triphosphate; Animals; Fatigue; Inosine Monophosphate; Lactates; Male; Muscle Contraction; Muscles; Organophosphorus Compounds; Phosphocreatine; Physical Exertion; Rats; Rats, Inbred Strains

Force-velocity, power-velocity and unloaded shortening data were obtained from in situ medial gastrocnemius muscle-tendon complexes (stimulated at 60 Hz) with intact circulation of mature male rats (approximately 125 days old). Measurements were carried out at the end of a long (15 s) contraction (fatigued muscles) or with a short (1 s) contraction either in the fresh state (fresh muscles) or in muscles which had recovered for 15 min after a long contraction. Compared to the fresh state fatigue reduced isometric force by 57%, maximal shortening velocity by approximately 40% and maximal power output by 81%. These reductions were similar to data previously obtained with younger rats (40 days old). However, the velocity data of the muscles which had recovered for 15 min after a long contraction showed a greater reduction in the mature rats. This difference between the two age groups together with a difference in the changes in the initial parts of the isometric force time curves suggest an age-dependent response of the fast-fatigable fibre population of these mixed muscles. In a separate series of experiments the underlying mechanism of the recovery from fatigue was studied in a group of young rats. Fatigue was induced with five long (15 s) contractions (each at 5 min intervals). The recovery of isometric force and power output was monitored with short contractions which indicated a plateau of recovery but the absolute values were still reduced after 60 min (85 and 71% of prefatigue values, respectively). Phosphocreatine concentration recovered rapidly, whereas the ATP concentration was still markedly reduced after 1 h of recovery. The time courses of recovery of inosine-5'-monophosphate (IMP) and lactate concentrations resembled those of force and power output. Thus it is possible that age-dependent differences in IMP and/or lactate production may play a role in fatigue and recovery from fatigue.

Topics: Adenosine Monophosphate; Animals; Fatigue; Inosine Monophosphate; Isometric Contraction; Lactates; Lactic Acid; Male; Muscle Contraction; Phosphocreatine; Rats; Rats, Inbred Strains; Time Factors

To study changes in muscle energy state during prolonged exercise, especially in relation to fatigue, muscle biopsies were obtained from seven healthy males working until exhaustion on a cycle ergometer at 68% (63-74%) of their maximal oxygen uptake. Biopsies were taken at rest, after 15 and 45 min of exercise and at exhaustion, and analysed for ATP, ADP, AMP, inosine monophosphate (IMP) and hypoxanthine content by high performance liquid chromatography (HPLC), and for creatine phosphate (CP), lactate and glycogen by enzymatic fluorometric techniques. Glycogen content at exhaustion was approximately 30% of the pre-exercise level. The CP content decreased steeply during the first 15 min of exercise (P less than 0.01) and continued to decrease during the rest of the exercise period (P less than 0.05). Pronounced increases in contents of IMP (64% P less than 0.001) and hypoxanthine (69%, P less than 0.05) were found when exhaustion was approaching. Furthermore, energy charge [EC; (ATP + 0.5 ADP)/(ATP + ADP + AMP)] was decreased at exhaustion (P less than 0.05). The increases in IMP and hypoxanthine which occurred when exhaustion was approaching during prolonged submaximal exercise together with the decrease in EC during this phase of exercise suggest a failure of the exercising skeletal muscle to regenerate ATP at exhaustion.

Topics: Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Adult; Fatigue; Glycogen; Humans; Hypoxanthine; Hypoxanthines; Inosine Monophosphate; Male; Muscles; Phosphocreatine; Physical Exertion