Lengthening contraction and interpretations of active state tension in the isometric twitch response of skeletal muscle

The plateau of tetanic tension in a lengthening contraction of muscle at any given length is always greater than that in an isometric contraction at the same given length. To account for this excess of tension, it is suggested that the contractile machinery is "locked" in a strained condition that might make the muscle capable of bearing a greater tension in a lengthening contraction than it can develop in an isometric contraction. It is proposed that this strained condition also occurs in a lengthening contraction of the twitch response. If this proposal is valid it seems certain that the plateu of tension in the lengthening contraction of the twitch response cannot be equated with the plateau of tension in the isometric contraction of tetanus. The design of the original concept, that the plateau of active state tension in the lengthening contraction of the twitch is equal to the plateau of tension (Po) in the isometric contraction of tetanus, is based upon the assumption that the contractile component is neither lengthening nor shortening during both of these plateaus. This assumption is made without considering the possibility that the plateau in the lengthening contraction might be due to concurrent lengthening of series elastic elements and shortening of the contractile component. To account for the plateau of tension observed after quick lengthening in the early phase of twitch contraction indirect evidence is presented favoring the view that the quick lengthening during stretch is followed by slow lengthening and stress relaxation (decrease of tension) in series elastic elements and simultaneous shortening and increase of tension in the contractile component. When the original concept of active state tension in the twitch response is interpreted in the light of lengthening contraction, it is concluded that the labeled or implied Po for the plateau of the active state tension is unwarranted and confusing. It seems that the primary source of confusion is the assumption that the tension a muscle is capable of bearing in a lengthening contraction is equatable with the tension it can develop in an isometric contraction.     

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.     

The effect of autografting on the myosin composition in skeletal muscle fibers

The purpose of the study was to investigate the changes in myosin heavy chain (MHC) and myosin light chain (MLC) isoforms following autotransplantation of extensor digitorum longus muscles. Muscles were grafted in "standard" and "nerve-intact" conditions. MHC and MLC isoforms were analyzed by sodium dodecyl sulphate gel electrophoresis. Changes in MHC isoforms 10, 30, and 60 days after grafting were similar in the "standard" and the "nerve-intact" grafts. In contrast to MHC, changes in MLC were different in the 10th day groups, but the same in the 30th day groups. Sixty days after grafting the content of MLC isoforms was the same as the control muscles. These data indicate that transient loss of functional innervation, even for a short time, has permanent effect on the composition of MHC but not MLC isoforms in regenerating skeletal muscle fibers.     

The effect of neostigmine on suxamethonium induced neuromuscular block in the dog

The effects of neostigmine on suxamethonium induced neuromuscular block were investigated in the intact, anaesthetised dog using the train-of-four twitch to record neuromuscular activity. Marked antagonism of the block was observed when the train-of-four ratio was 0.38 and less. To avoid potentiating the block, the use of neostigmine is not recommended without first determining the state of neuromuscular activity with a peripheral nerve stimulator using train-of-four stimulation.     

The effect of propionyl L-carnitine on skeletal muscle metabolism in renal failure

The effect of propionyl L-carnitine on skeletal muscle metabolism in chronic renal failure. Carnitine deficiency, resulting in defective oxidative ATP synthesis, has been implicated in the myopathy of chronic renal failure. Using 31P magnetic resonance spectroscopy we examined calf muscle metabolism in 10 dialysed patients before and after 8 weeks of propionyl L-carnitine (PLC) 2 g.p.o. daily. Resting phosphocreatine/ATP (4.41 +/- 0.20 [SEM]) decreased to normal control levels on PLC (3.98 +/- 0.14; controls 4.00 +/- 0.06). In contrast, there was no effect of PLC on aerobic and anaerobic metabolism of muscle during or following 2-10 min exercise. The maximal calculated oxidative capacity (Qmax) remained below normal (28 +/- 3 mM/min before and 24 +/- 3 mM/min after PLC; controls 49 +/- 3 mM/min). Qmax correlated positively with hemoglobin concentration ([Hb]) after PLC (p < 0.03). Oxidative capacity assessed by phosphocreatine recovery T significantly improved with PLC administration (0.93 +/- 0.1 to 0.74 +/- 0.08 min) in those patients (n = 6) with [Hb] > 10 g/dl. [Hb] was rate limiting to oxidative metabolism in recovery from exercise but only following treatment with PLC. Patients with anemia or those subjects who use relatively more non-oxidatively synthesized ATP during exercise, do not respond to PLC. Oxidative metabolism did not normalize on PLC suggesting that anemia and carnitine deficiency are not the only causes of mitochondrial dysfunction in renal failure.     

The effect of beta-adrenergic blockade on non-esterified fatty acid uptake of exercising skeletal muscle during arm cranking

A case of 62-year-old male patient with tuberculosis in the lower lung field of right side was reported. The case showed a solitary lesion in S8b of 2.5 x 2.0 cm in size and was detected by the mass survey. The case was complicated with chronic renal failure and was treated by lobectomy because of suspicion of lung cancer, as there was a marked pleural indentation on CT. By examining the resected specimen, the following findings were revealed. The solitary exudative tuberculous lesion located in the margin of the basal segment extended both to the costal and diaphragmatic pleura, and a small triangular shaped normal lung parenchyma located at the periphery of the lesion was isolated, and the air flow from the lower lobar bronchus was cut. As a result, hyperinflation of the isolated normal lung took place through collateral air leak and check-valve mechanism (The Culiner Theory), finally the pleural constriction was formed at the boundary between the lesion where the elasticity was lost and the hyperinflated parenchyma.     

Acid-base state of cerebrospinal fluid during pregnancy and its effect on spread of spinal anaesthesia

To assess the possible relationship between changes in acid-base state of cerebrospinal fluid (CSF) and enhanced spread of spinal anaesthesia during pregnancy, we have measured CSF pH, carbon dioxide tension (PCO2) and HCO3- values in 73 women undergoing spinal anaesthesia with hyperbaric amethocaine 8 mg. Patients were allocated to one of four groups according to gestational period: non-pregnant group (n = 13), first trimester group (8-13 weeks, n = 19), second trimester group (14-26 weeks, n = 11) and third trimester group (27-39 weeks, n = 30). The pH of the CSF was greater in the second and third trimester groups than in the non-pregnant group. CSF PCO2 decreased by 0.53-0.8 kPa throughout pregnancy. CSF HCO3- was decreased throughout pregnancy. Overall, no clinically significant correlation was found between maximum cephalad spread of analgesia and CSF pH, PCO2 or HCO3-. We conclude that pregnancy-induced changes in acid-base state of CSF have little effect on the spread of spinal anaesthesia, although there is a clinically different spread of spinal anaesthesia between non-pregnant and pregnant states.     

The effect of ischemic preconditioning on the recovery of skeletal muscle following tourniquet ischemia

It has been well documented that ischemic preconditioning limits ischemic-reperfusion injury in cardiac muscle, but the ability of ischemic preconditioning to limit skeletal muscle injury is less clear. Previous reports have emphasized the beneficial effects of ischemic preconditioning on skeletal muscle structure and capillary perfusion but have not evaluated muscle function. We investigated the morphologic and functional consequences of ischemic preconditioning, followed by a 2-hour period of tourniquet ischemia on muscles in the rat hindlimb. The 2-hour ischemia was imposed without preconditioning, or was preceded by three brief (10 minutes on/10 minutes off) preischemic conditioning intervals. We compared muscle morphology, isometric contractile function, and muscle fatigue properties in predominantly fast-twitch, tibialis anterior muscles 3 (n = 8) and 7 (n = 8) days after ischemia-reperfusion. Two hours of ischemia, followed by reperfusion, results in a 20 percent reduction of muscle mass (p < 0.05) and a 33 percent reduction in tetanic tension (p < 0.05) when compared with controls (n = 8) at 3 days. The same protocol, when preceded by ischemic preconditioning, results in similar decreases in muscle mass and contractile function. Neuromuscular transmission was also impaired in both ischemic groups 7 days after ischemia. Nerve-evoked maximum tetanic tension was 69 percent of the tension produced by direct muscle stimulation in the ischemia group and 65 percent of direct tension in the ischemic preconditioning/ischemia group. In summary, ischemic preconditioning, using the same protocol reported to be effective in limiting infarct size in porcine muscle, had no significant benefit in limiting injury or improving recovery in the ischemic rat tibialis anterior. The value of ischemic preconditioning in reducing imposed ischemic-reperfusion-induced functional deficits in skeletal muscle remains to be demonstrated.     

The effect of muscle repair on postoperative facial skeletal growth in children with bilateral cleft lip and palate

Systems for testing genetic toxicology are components of carcinogenic and genetic risk assessment. Present routine genotoxicity-testing is based on at least 20 years of development during which many different test systems have been introduced and used. Today, it is clear that no single test is capable of detecting all genotoxic agents. Therefore, the usual approach is to perform a standard battery of in-vitro and in-vivo tests for genotoxicity. Work-groups of the European Union (EU), the Organization for Economic Co-operation and Development (OECD), and, very recently, the work-group of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) have defined such standard battery tests. These and some currently used supplementary or confirmatory tests are briefly discussed here. Additional test systems for the assessment of genotoxic and carcinogenic hazard and risk are seriously needed. These tests must be more relevant to man than are current assays and less demanding in respect of cost, time and number of animals. Another aspect for reassessment derives from the actual situation in the pharmaceutical industry. Companies have to prepare for the world economy of the 21st century. Therefore, pharmaceutical research is speeding up tremendously by use of tools such as genomics, combinatorial chemistry, high throughput screening and proteomics. Toxicology and genotoxicology need to re-evaluate their changing environment and must find ways to respond to these needs. In conclusion, genetic toxicology needs to answer questions coming from two major directions: hazard and risk identification and high throughput testing.     

Calcium transients and the effect of a photolytically released calcium chelator during electrically induced contractions in rabbit rectococcygeus smooth muscle

Intracellular Ca2+ was determined with the fura-2 technique during electrically induced contractions in the rabbit rectococcygeus smooth muscle at 22 degreesC. The muscles were electrically activated to give short, reproducible contractions. Intracellular [Ca2+] increased during activation; the increase in [Ca2+] preceded force development by approximately 2 s. After cessation of stimulation Ca2+ fell, preceding the fall in force by approximately 4 s. The fluorescence properties of fura-2 were determined with time-resolved spectroscopy using synchrotron light at the MAX-storage ring, Lund, Sweden. The fluorescence decay of free fura-2 was best described by two exponential decays (time constants approximately 0.5 and 1.5 ns) at low Ca2+ (pCa 9). At high Ca2+ (pCa 4.5), fluorescence decay became slower and could be fitted by one exponential decay (1.9 ns). Time-resolved anisotropy of free fura-2 was characteristic of free rotational motion (correlation time 0.3 ns). Motion of fura-2 could be markedly inhibited by high concentrations of creatine kinase. Time-resolved spectroscopy measurements of muscle fibers loaded with fura-2 showed that the fluorescence lifetime of the probe was longer, suggesting an influence of the chemical environment. Anisotropy measurements revealed, however, that the probe was mobile in the cells. The Ca2+-dependence of contraction and relaxation was studied using a photolabile calcium chelator, diazo-2, which could be loaded into the muscle cells in a similar manner as fura-2. Photolysis of diazo-2 leads to an increase in its Ca2+-affinity and a fall in free Ca2+. When muscles that had been loaded with diazo-2 were illuminated with UV light flashes during the rising phase of contraction, the rate of contraction became slower, suggesting a close relation between intracellular Ca2+ and the cross-bridge interaction. In contrast, photolysis during relaxation did not influence the rate of force decay, suggesting that relaxation of these contractions is not determined by the rate of Ca2+ removal or due to an increased Ca2+ sensitivity, but instead is limited by other processes such as deactivation by dephosphorylation or detachment of tension-bearing cross-bridges, possibly regulated by thin filament systems.     

Inhibitory effect of forskolin on myosin phosphorylation-dependent and independent contractions in bovine tracheal smooth muscle

In bovine tracheal smooth muscle, carbachol (CCh, 1 microM) and high K+ (72.7 mM) induced sustained increases in cytosolic Ca2+ level ([Ca2+]i), myosin light chain (MLC) phosphorylation and force of contraction. Forskolin (FK, 1-10 microM) inhibited the CCh-induced increase in [Ca2+]i, MLC phosphorylation and force in parallel. In contrast, FK inhibited the high K(+)-induced contraction and MLC phosphorylation without changing [Ca2+]i. In the absence of extracellular Ca2+ (with 0.5 mM EGTA), CCh (10 microM) and caffeine (20 mM) induced transient increase in [Ca2+]i and contractile force by releasing Ca2+ from cellular store. FK strongly inhibited the CCh-induced Ca2+ transient, but failed to inhibit the caffeine-induced Ca2+ transient. In the absence of external Ca2+, 12-deoxyphorbol 13-isobutylate (DPB, 1 microM) induced sustained contraction without increase in [Ca2+]i and MLC phosphorylation. FK inhibited this contraction without changing [Ca2+]i. In permeabilized muscle, Ca2+ induced contraction in a concentration-dependent manner. FK (10 microM) and cAMP (1-100 microM) shifted the Ca(2+)-force curve to the higher Ca2+ levels. CCh with GTP, GTP gamma S or DPB enhanced contraction in the presence of constant level of Ca2+. Forskolin and cAMP also inhibited the enhanced contractions in the permeabilized muscle. In the permeabilized, thiophosphorylated muscle, ATP induced contraction in the absence of Ca2+. cAMP (300 microM) had no effect on this contraction. These results suggest that forskolin inhibits agonist-induced contraction in tracheal smooth muscle by multiple mechanisms of action; 1) inhibition of MLC phosphorylation by reducing Ca2+ influx and Ca2+ release, 2) inhibition of MLC phosphorylation by changing the MLC kinase/phosphatase balance, and 3) inhibition of regulatory mechanism which is not dependent on MLC phosphorylation.     

Specificity and symmetry in the interaction of calmodulin domains with the skeletal muscle myosin light chain kinase target sequence

The specificity of interaction of the isolated N- and C-terminal domains of calmodulin with peptide WFFp (Ac-KRRWKKNFIAVSAANRFK-amide) and variants of the target sequence of skeletal muscle myosin light chain kinase was investigated using CD and fluorescence. Titrations show that two molecules of either domain bind to 18-residue target peptides. For WFFp, the C-domain binds with 4-fold higher affinity to the native compared with the non-native site; the N-domain shows similar affinity for either site. The selectivity of the C-domain suggests that it promotes occupancy of the correct binding site for intact calmodulin on the target sequence. Far UV CD spectra show the extra helicity induced in forming the 2:1 C-domain-peptide or the 1:1:1 C-domain-N-domain-peptide complex is similar to that induced by calmodulin itself; binding of the C-domain to the Trp-4 site is essential for developing the full helicity. Calmodulin-MLCK-peptide complexes show an approximate two-fold rotational relationship between the two highly homologous domains, and the 2:1 C (or N)-domain-peptide complexes evidently have a similar rotational symmetry. This implies that a given domain can bind sequences with opposite peptide polarities, significantly increasing the possible range of conformations of calmodulin in its complexes, and extending the versatility and diversity of calmodulin-target interactions.     

The effect of allopurinol on interstitial purine metabolism and tissue damage in skeletal muscle I-R injury

The causes and manners of death in medico-legal cases from a five-year period were examined. Alcoholics died more often of combined alcohol/drug intoxication and of carbon monoxide poisoning. They had a lower frequency of heart diseases, and there was no support for the existence of an alcoholic heart muscle disease. Lobar pneumonia was only found in alcoholics. There were, as expected, higher frequencies of the known alcohol-related diseases such as hepatic coma, bleeding oesophageal varices and alcohol intoxication. An observed higher frequency of death before the age of 35 could be attributed to alcohol-related diseases. The manners of death showed surprisingly small differences, as the main finding was a higher frequency of alcoholics with undeterminable manner of death.     

The effect of ATP analogs on posthydrolytic and force development steps in skinned skeletal muscle fibers

ATP, 2-deoxy ATP (dATP), CTP, and UTP support isometric force and unloaded shortening velocity (Vu) to various extents (Regnier et al., Biophys. J. 74:3044-3058). Vu correlated with the rate of cross-bridge dissociation after the power stroke and the steady-state hydrolysis rate in solution, whereas force was modulated by NTP binding and cleavage. Here we studied the influence of posthydrolytic cross-bridge steps on force and fiber shortening by measuring isometric force and stiffness, the rate of tension decline (kPi) after Pi photogeneration from caged Pi, and the rate of tension redevelopment (ktr) after a sudden release and restretch of fibers. The slope of the force versus [Pi] relationship was the same for ATP, dATP, and CTP, but for UTP it was threefold less. ktr and kPi increased with increasing [Pi] with a similar slope for ATP, dATP, and CTP, but had an increasing magnitude of the relationship ATP < dATP < CTP. UTP reduced ktr but increased kPi. The results suggest that the rate constant for the force-generating isomerization increases with the order ATP < dATP < CTP < UTP. Simulations using a six-state model suggest that increasing the force-generating rate accounts for the faster kPi in dATP, CTP, and UTP. In contrast, ktr appears to be strongly affected by the rates of NTP binding and cleavage and the rate of the force-generating isomerization.     

The effect of carbidopa on the pharmacokinetics and metabolism of intravenously administered levodopa in blood plasma and skeletal muscle

The effect of carbidopa on the pharmacokinetics and metabolism of levodopa (L-dopa) in blood plasma and skeletal muscle extracellular fluid (ECF) has been studied by repeated measurements in one beagle dog. The administration of a single dose of L-dopa (25 mg/kg i.v.) without carbidopa pretreatment (controls) resulted in an increase in the concentrations of L-dopa and 3-O-methyldopa (3-OMD) in blood plasma and skeletal muscle ECF dialysates. This effect was clearly potentiated for L-dopa in blood plasma (186% increase in AUC) and 3-OMD in skeletal muscle dialysates (108% increase in AUC) after pretreatment with carbidopa (100 mg/day). In addition, carbidopa prolonged the half-life of the elimination of L-dopa in blood plasma by 48% and in skeletal muscle ECF by 66% but did not influence its blood plasma distribution half-life (t 1/2 alpha = 0.17 h). The elimination half-life of L-dopa in the controls was higher in muscle (t 1/2 beta = 1.76 h) than in blood plasma (t 1/2 beta = 0.50 h). Carbidopa pretreatment resulted in a relatively small increase (29%) in the L-dopa content of skeletal muscle ECF as indicated by the AUC. The accumulation of 3-OMD in muscle dialysates, in contrast to that in plasma, was significantly enhanced after the administration of L-dopa following treatment with carbidopa. In the control experiments, dopamine (DA) was detectable only in the dialysates from muscle ECF.(ABSTRACT TRUNCATED AT 250 WORDS)     

The influence of changes in hand temperature on the indirectly evoked electromyogram of the first dorsal interosseous muscle

The evoked EMG response commonly decreases in amplitude during the first few minutes of anaesthesia. The purpose of this study was to determine if a relationship exists between changes in hand temperature, which are known to occur with induction of anaesthesia, and drift in the EMG signal. The indirectly evoked response of the 1st dorsal interosseous muscle was measured using a Datex Relaxograph in 15 patients undergoing elective surgery. The test arm was wrapped in towels in order to minimize heat loss. Core body temperature, hand temperature, and T1 were recorded at two minute intervals for the next 30 min. Patients then received a bolus of mivacurium 0.08 mg.kg-1 and additional doses were given as needed. Complete recovery was defined as a TOF ratio > 0.90. Regression analysis plotting delta temperature against delta T1 was performed for each individual. The slope of the regression line for the relationship between delta degree C and delta T1 was then used to calculate a correction factor (CF) which might be used to "fine tune" the last measured T1. The initial hand temperature averaged 30.8 +/- 1.4 degrees C and this increased by 4.1 +/- 1.2 degrees C over the next 30 min. During this period T1 decreased by 24.8 +/- 5.9% or -6.05%/degrees C. The final mean T1 value at the end of anaesthesia (uncorrected) was 70.6 +/- 7% of control. The average corrected T1 value was 94.7 +/- 8.5% (range, 83-111%). It is concluded that there was a correlation between delta degree C and delta T1 during the first 30 min of anaesthesia (r2 = 0.77, P < 0.0001). However, in 5 of 15 individuals it was not possible to "temperature correct" the final T1 value to within +/- 10% of control. Hence, while changes in muscle temperature probably play a major role in the T1 drift seen with the Datex monitor, other factors remain to be identified.     

The series elastic component and the force-velocity relation in the anterior byssal retractor muscle of Mytilus edulis during active and catch contractions

1. The length changes of the anterior byssal retractor muscle (ABRM) of Mytilus edulis, following step changes in load, were studied at various phases of active and catch contractions produced by acetylcholine. 2. The load-extension curves of the series elastic component (SEC) were found to be scaled down in proportion to the isometric tension immediately before step changes in load, but remain unchanged irrespective of whether the ABRM was in active or in catch contraction. 3. In hypertonic solutions the compliance of the SEC was reduced in the same manner as that of the SEC in frog skeletal muscle. 4. These results seem to favour the linkage hypothesis for the catch mechanism, though the SEC in the ABRM is suggested to be composed not only of the cross-linkages, but also of the compliance of the myofilaments.     

The effect of flavoxate on uninhibited detrusor contractions and urinary incontinence in the elderly

The effect of flavoxate, a smooth muscle relaxant, was investigated in 6 elderly patients with uninhibited detrusor contractions associated with urinary incontinence. Cystometry was done initially to confirm the diagnosis, immediately after an intravenous injection of 100 mg. flavoxate and after 200 mg. flavoxate orally 4 times daily for 7 days. No consistent drug effect could be detected cystometrically and incontinence was unchanged clinically.