Myopathic Animals Research Articles

Correlation between changes in morphology, electrical properties, and angiotensin-converting enzyme activity in the failing heart

Evidence is available that morphologic and electrophysiologic abnormalities are present in the failing heart. In the present work, the progressive changes in electrical properties and morphology of the failing heart of Syrian cardiomyopathic hamsters (TO2) were investigated at different stages of the pathological process, and the possible role of the renin–angiotensin system was studied. Cardiomyopathic hamsters 2 and 11 months of age were used. Age-matched normal hamsters (F1B) were utilized as controls. Measurements of membrane potential, conduction velocity and refractoriness were made with conventional intracellular electrodes connected to a high impedance DC amplifier. Serum and cardiac angiotensin-converting enzyme (ACE) activities were measured in controls and cardiomyopathic animals. The results indicated that interstitial fibrosis and calcification were present in the heart of 2-month old Syrian cardiomyopathic hamsters. Measurements of the resting potential performed in the isolated right ventricle of 2-month old Syrian cardiomyopathic hamsters indicated an average value of −66.7±0.96 mV ( n=25); in the controls of the same age was −78.5±1 mV ( n=25, P<0.05); and in 11-month old cardiomyopathic hamsters was −67.8±0.83 mV ( n=10). The duration of the action potential measured at 50 and 90% of repolarization in 2-month old hamsters was well above the controls. The conduction velocity measured in the isolated right ventricle of 2-month old Syrian cardiomyopathic hamsters (44.2±1.6 cm/s, n=12) was not different from the control (43.7±1.1 cm/s, n=7, P>0.05) but was significantly larger than that recorded from the ventricle of 11-month old animals (37.8±2.9 cm/s, n=11, P<0.05). ACE activity was 0.26±0.01 nmol/mg×min in the heart of controls at 2 months of age and did not change with age. Although in the 2-month old cardiomyopathic hamsters the enzyme activity (0.28±0.04 nmol/mg×min) was not different from the controls ( P>0.05), in myopathic animals at 11 months of age, the enzyme activity (0.56±0.027 nmol/mg×min) was greater than controls ( P<0.05). The ACE activity in plasma followed the same pattern. The conclusion from these experiments is, that some parameters like resting potential, action potential duration, and morphological abnormalities appeared quite early in the failing process. The decline in conduction velocity, however, appeared later on, concurrently with the activation of plasma and cardiac renin–angiotensin systems.

Electrophysiologic properties and ventricular fibrillation in normal and myopathic hearts

This study tests the hypothesis that moderate myocardial dysfunction is associated with altered myocardial anisotropic properties and structurally altered ventricular fibrillation (VF). Mongrel dogs were randomized to either a control group or a group that was rapidly paced at 250 beats/min until the left ventricular ejection fraction was < or = 40%. Changes in anisotropic properties and the electrical characteristics of VF associated with the development of moderate myocardial dysfunction were assessed by microminiature epicardial mapping studies. In vivo conduction, refractory periods, and repolarization times were prolonged in both longitudinal and transverse directions in myopathic animals versus controls. VF was different in myopathic versus control animals. There were significantly more conducted deflections during VF in normal hearts compared with myopathic hearts. Propagated deflection-to-deflection intervals during VF were significantly longer in myopathic hearts compared with controls (125.5 +/- 49.06 versus 103.4 +/- 32.9 ms, p = 0.009). There were no abnormalities in cell size, cell shape, or the number of intercellular gap junctions and there was no detectable change in the expression of the gap junction proteins Cx43 and Cx45. Moderate myocardial dysfunction is associated with significant electrophysiological abnormalities in the absence of changes in myocardial cell morphology or intercellular connections, suggesting a functional abnormality in cell-to-cell communication.

Morphological investigations of the myocardium ofcardiomyopathic hamsters during the postnatal development and experimental hypoxia. A quantitative ultrastructural study

The hereditary cardiomyopathy of the Syrian hamster (strain BIO 8262) as a model of human cardiomyopathy was investigated during postnatal development using ultrastructural morphometric analysis. The aim of the study was to establish basic ultrastructural morphometric data of cardiomyocytes of this model during all stages of the disease in comparison to corresponding stages of normal development, and to compare the ultrastructural resistance of normal and myopathic myocardium against acute hypoxic stress. The postnatal development of this cardiomyopathy is characterized by focal myolytic lesions already in the first postnatal days, extended myofibrillic and mitochondrial damage developing after the 1st month, and features of hypertrophy, disarray of myofibrils, thickening, and clumping of z-lines after the 4th month. Morphometric parameters of myopathic cardiomyocytes differing from those of the control are diminished volume density of myofibrils by about 10% of the control values in middle age, slightly increased volume density of sarcoplasmic reticulum and t-tubules in the 1st months, significant increase of them after the 3rd month, and significant alterations of many mitochondrial parameters indicating degenerations (numeric density, volume density, average volume, volume density of cristae, and of destroyed areas, and ratio of surface to volume density of mitochondrial cristae). Acute isobaric hypoxia was applied to myopathic and healthy hamsters of corresponding age (at day 100). Evaluation of ultrastructural morphometric parameters of cardiomyocytes revealed that especially mitochondria were more affected by hypoxia in the myopathic animals. The average mitochondrial volume was significantly more increased in the myopathic condition, the ratio of surface to volume density of cristae significantly diminished. Our ultrastructural - morphometric study has shown, that morphometric parameters in general can be assigned to the stages of cardiomyopathy, and that the ultrastructural differences are best expressed about the 4th month.

Alterations in Ito1, IKr and Ik1 density in the BIO TO-2 strain of syrian myopathic hamsters.

The BIO TO-2 strain of cardiomyopathic hamster provides a model of dilated low output heart failure. The goal of the study was to determine whether changes in potassium currents occur in this model of heart failure. The densities of Ito1, IKr and IK1 in 8-month-old myopathic hamsters were not significantly different from their age-matched controls. The half-maximum activation voltage (V1/2) of IKr and Ito1, as well as the voltage-dependence of Ito1 inactivation were also similar in both groups at 8 months. Ito1 inactivation exhibited a double exponential time-course; the slow component (tau2), but not the rapid component (tau1), was larger in the myopathic animals. The densities of Ito1, IKr and IK1 were not significantly different in the 8- and 10-month-old control animals. However, the densities of Ito1, IKr and IK1 were all significantly lower in the 10-month-old myopathic hamsters relative to the 10-month-old controls. The V1/2 for IKr and Ito1 activation was the same in myopathic and control animals. tau2, but not tau1, of Ito1 inactivation was again larger in the myopathic animals. The voltage-dependence of Ito1 inactivation was shifted slightly, but significantly, positive in the myopathic animals. Lastly, a sustained outwardly rectifying current that activated upon depolarization was found to be larger in the myopathic animals at both 8 and 10 months of age. In conclusion, many of the alterations in potassium current densities in the 10-month-old cardiomyopathic hamsters are qualitatively similar to the changes observed in the failing human heart.

Characteristics of compensatory hypertrophied muscle in the rat: I. Electron microscopic and immunohistochemical studies

Background Complex branched muscle fibers are frequently observed in the muscles of mdx mutant mice and/or in damaged muscles. To investigate whether the complex branched fibers were present in the compensatory hypertrophied muscles of rats, we examined the morphological changes in these muscles. Methods We examined the hypertrophied plantaris (PLA) muscle of the Wistar male rats, prepared by surgical ablation of synergistic muscles. The muscle was examined using three-dimensional analysis with scanning electron microscopy, immunohistochemical detection of proliferating cells using 5-bromo-2′-deoxyuridine (BrdU) and histological and histochemical characterization. Studies were performed at 48 hours, 2, 4, 6, 10, and 15 weeks after surgical preparation. Results The muscle hypertrophy ratio (muscle weight relative to the contralateral intact control side), gradually increased from 2 to 10 weeks, and the peak value (48.6%) occurred at the 10th week. The total number of fibers did not change significantly at any time interval. However, the number of branched muscle fibers increased significantly (P < 0.05) after 6 weeks, and accounted for about 2.5% of the total fibers at the 15th week. Most branched fibers showed complex features resembling the “anastomosing syncytial reticulum” described in myopathic animals. The fibers were observed mainly in the middle and distal portions of the PLA muscle. The proportion and distribution of proliferating cells in the entire PLA muscle corresponded with the distribution of the complex branched fibers. These results were also observed in muscle tissues prepared for histological and histochemical examination. Conclusions The presence of a large proportion of complex branched fibers in a limited segment of the compensatory hypertrophied muscle suggests that this hypertrophy model represents a pathological and/or pathophysiological hypertrophy model rather than a normal physiological process. © 1996 Wiley-Liss, Inc.

Epitopic analysis and quantification of bovine myoglobin with monoclonal antibodies.

Seven rat monoclonal antibodies (MAb) for bovine myoglobin were produced. Five antibodies reacted with surface-absorbed myoglobin whereas the two remainders reacted only in a sandwich type ELISA. The ability of different antibodies to bind simultaneously to myoglobin was examined by competition and additivity experiments and three noncompeting epitope regions were found. A two-site enzyme immunoassay was developed and allowed quantification of 30 ng/ml bovine myoglobin. These antibodies should be valuable tools in comparative studies for immunological reactivity of mammalian myoglobins and for myoglobin measurement in serum and urine of myopathic animals.

Ryanodine and dihydropyridine binding patterns and ryanodine receptor mRNA levels in myopathic hamster heart.

We have determined the densities of sarcolemmal voltage-dependent Ca2+ channels (VDCC) and Ca(2+)-induced Ca2+ release channels (CICR) of sarcoplasmic reticulum (SR) in the cardiomyopathic hamster heart using [3H]PN-200 and [3H]ryanodine, respectively. Partially purified cardiac membrane preparations from myopathic animals exhibit a twofold higher capacity to bind both [3H]PN-200 and [3H]ryanodine. Crude particulate membrane fractions from normal and cardiomyopathic animals reveal no significant difference in receptor densities for [3H]PN-200, whereas densities for [3H]ryanodine binding sites and mRNA levels are significantly (P < 0.05) diminished in cardiomyopathic animals. Inhibition of [3H]ryanodine binding by either Ca2+ or Mg2+ (in mM) as well as temperature dependence for receptor activation for [3H]ryanodine (Q10) is not significantly different, whereas membranes isolated from cardiomyopathic hearts are 1.4-fold and threefold more sensitive to activation by doxorubicin and Ca2+ (in microM), respectively. Vesicles isolated from myopathic hearts are more sensitive to inhibition of Ca2+ uptake by doxorubicin. The higher densities of binding sites for [3H]PN-200 and [3H]ryanodine observed in partially purified membrane fractions from cardiomyopathic hearts are more likely the result of altered patterns with which T-tubule and CICR channels fractionate in preparations from cardiomyopathic hamster heart rather than transcriptional upregulation and may be a consequence of the deficiency in a dystrophin-associated glycoprotein recently identified. Downregulation and functional changes in CICR channels may alter SR Ca2+ transport and contribute to the progression of cardiomyopathy in the hamster.

Dihydropyridine receptor binding sites in the cardiomyopathic hamster heart are unchanged from control

An increase in the number of voltage dependent calcium channels has been implicated in the overload of calcium found in cardiac tissue of the cardiomyopathic hamster. We examined the binding of [ 3H]-(+)PN200110 to dihydropyridine receptors in cardiac muscle membranes from TO cardiomyopathic hamsters. When compared to random bred controls, there were no differences in either the B max or the K D for [ 3H]-(+)PN200110 binding using homogenates from 35 to 41-day-old TO cardiomyopathic hearts. In 8 to 9-month-old myopathic animals there were only small decreases in B max with no change in K D . We suggest that the calcium overload observed in cardiomyopathic hamster heart may not be due to an increased density of calcium channels as estimated by high affinity dihydropyridine receptor binding sites.

Regulatory proteins in hamster cardiomyopathy.

We have shown in genetic myopathic hamsters that cardiac myofibrillar ATPase regulation by calcium is altered and that there are shifts in myosin isozyme distribution (V1----V3) suggesting abnormalities in multiple components of the contractile apparatus. To focus more on the regulatory proteins (troponin and tropomyosin), individual proteins of the skeletal and cardiac actomyosin system were reconstituted under controlled conditions. In this way, myosin plus actin and troponin-tropomyosin from the normal and myopathic animals could be studied enzymatically. The proteins were isolated from the skeletal or cardiac muscle of random-bred control and cardiomyopathic hamsters (BIO 53:58) at 7 months of age. Sodium dodecyl sulfate gel electrophoretic patterns indicated differences in the troponin I and troponin C regions of myopathic skeletal muscle, but cardiac samples from control and myopathic hamsters showed similarities in their mobilities. This suggests the possibility of different cardiac isozymes in the regulatory protein complex, as reported in our previous studies of cardiac myosin in cardiomyopathy. Calcium sensitivity was markedly decreased in the actomyosin reconstituted with troponin-tropomyosin from skeletal as well as cardiac muscle from myopathic animals. In summary, our data show that the regulatory proteins in skeletal and cardiac muscle of the myopathic hamsters have decreased inhibitory action on Mg2(+)-actomyosin ATPase activity. This loss of calcium regulation along with shifts in cardiac myosin heavy chain may be partially responsible for the impaired cardiac function in the hearts of myopathic hamsters.

Diurnal variation of lung reactivity in normal and myopathic hamsters.

In this study we measured the diurnal variation in lung reactivity in normal and myopathic hamsters. Lung reactivity to an intravenous bolus of 0.7 mg/kg acetylcholine (ACh) was measured as the change in peak airway pressure of anesthetized ventilated animals. In the normal hamsters, lung reactivity was 57% higher during the day (8 A.M., 12 P.M., and 4 P.M.) than during the night (p = 0.01). This increased reactivity was not associated with any changes in baseline pressures. The lung reactivity was correlated to body activity as measured on an electronic activity monitor over seven consecutive days. The hamster, being a nocturnal forager, gradually increased activity at about 6 P.M. and maintained intermittent activity until about 6 A.M. Sleep occurred between 6 A.M. and 6 P.M., and this was when the lung reactivity was greatest. In the myopathic hamsters, although the magnitude of the response to ACh was about 40% lower than that in normal animals, the lung reactivity during the daytime was still about 46% greater than that during the night (p = 0.007). The body activity records from the myopathic animals showed that these animals do not have a normal sleep pattern during the daytime; sleep is not continuous, showing intermittent periods of physical activity. Our results in the normal animals are consistent with observations in man, which show greater problems with airway obstruction and asthmatic attacks during the night.(ABSTRACT TRUNCATED AT 250 WORDS)

Functional state of myofibrils, mitochondria and bound creatine kinase in skinned ventricular fibers of cardiomyopathic hamsters

Functional states of cardiac contractile apparatus and mitochondria were studied in hereditary cardiomyopathic hamsters (CHF 146) and control golden hamsters using cardiac fibers skinned by two different techniques. The Triton X-100 skinned fibers obtained from diseased animals of 175 to 200 days old, or from control animals, demonstrated the same resting and maximal Ca-activated tensions, the same stiffness, the same rate of tension recovery after quick stretch; the fibers from cardiomyopathic animals differed only by a slightly increased calcium sensitivity. Functional activity of myofibrillar creatine kinase in cardiomyopathy was decreased as indicated by a smaller shift in the pMgATP/rigor tension curve to lower [MgATP] in the presence of phosphocreatine and by a slower rate of the tension recovery after quick stretch in the presence of phosphocreatine and ADP (without ATP). The saponin-skinned fibers allow evaluation of the respiration properties of the total tissue mitochondria. Data obtained in the preparations isolated from diseased animals of two ages (75 to 100 and 175 to 200 days) showed that the ratio of maximal ADP-stimulated respiration rate to the respiration rate in the absence of ADP (an analog of respiration control index) was unchanged in myopathy as compared with age-matched controls. However stimulation of respiration after an addition of creatine at submaximal ADP concentration was observed to be respectively 1.45 times and 3.5 times less in the preparations from younger and older myopathic animals as compared with their respective controls, thus indicating the impairment of functional coupling between mitochondrial creatine kinase reaction and oxidative phosphorylation. These results suggest that hereditary cardiomyopathy is associated with alterations in myocardial creatine kinase system, while myofilaments and mitochondria preserve their basic functional properties.

Sarcolemmal Na +Ca 2+ exchange during the development of genetically determined cardiomyopathy

The UM-X7.1 myopathic and control hamsters at 40, 120 and 280 days of age were employed for the examination of heart sarcolemmal Ca 2+-transport activities. Na +-dependent Ca 2+ uptake activities were significantly depressed in myopathic animals at 120 and 280 days of age in comparison to the control values. No difference in Na +-induced Ca 2+ release activities was found between control and experimental sarcolemmal vesicles. ATP-dependent Ca 2+ binding and Ca 2+-stimulated, Mg 2+ ATPase activities were depressed in the experimental animals at 120 and 280 days of age. Similar alterations in the sarcolemmal Na +-dependent Ca 2+ exchange and Ca 2+-pump activities were seen upon treating the control hamsters with 40 mg/kg isoproterenol for 24 hr. It is suggested that a depression in the sarcolemmal Ca 2+ transport activities may contribute to the development of intracellular Ca 2+ overload in the genetically determined cardiomyopathy in hamsters and such a defect may be due to excessive amount circulating catecholamines in these animals.

Multiple cardiac contractile protein abnormalities in myopathic syrian hamsters (BIO 53:58)

Hearts of genetically myopathic male hamsters (BIO 53 : 58) were studied at 1 month, 2 months, 3 months, 4 to 5 months and 7 months of age. The time course of alterations in the cardiac myofibrillar ATPase activity, the relationship of myofibrillar ATPase activity to free [Ca2+], myosin ATPase activity and the distribution of heavy chain myosin isoenzymes were evaluated. Mg2+-Ca2+ ATPase activity of cardiac myofibrils in myopathics was increased in 4 month and 7 month-old hamsters. Elevated Mg2+ ATPase activity was found as early as in 2-month-old hamster. However, there was no loss in the regulation of the myopathic myofibrillar assembly as measured by the PCa response (10(-7) M to 10(-4) M Ca2+). Scans of SDS electrophoresis slab gels of cardiac myofibrillar proteins from control (C) and myopathic animals (M) did not show any differences at any age group (1, 4 and 7 months). There was a significant decrease in myosin Ca2+ ATPase activity and actin activated Mg2+-ATPase activity at 4 to 5 months and 7 months of age in the myopathic hearts. At all ages in normal and myopathic animals cardiac myosin consisted of three isoenzymes, V1, V2 and V3. At all ages in controls and at 1 to 3 months in myopathics, V1 predominated and the isoenzyme distribution was V1 greater than V2 greater than V3. However, in myopathics at 4 to 5 months, the distribution was V1 = V3 greater than V2 and at 7 months was V3 greater than V2 greater than V1. Our experiments suggest alterations in different components of the contractile protein system that occur at different stages of myopathy.

The role of alkaline protease in the development of cardiac lesions in myopathic hamsters: Effect of verapamil treatment

The role of alkaline protease in the development of myocardial lesions in myopathic hamsters was studied. There was abnormal elevation of alkaline protease in the myopathic heart at 1 month of age, preceding the development of cardiac lesions. In vivo treatments of verapamil were carried out in 1-month-old myopathic animals for 30 days. Results indicated that the drug treatment was effective in preventing the occurrence of the severe myocardial lesions found in the untreated animals at 2 months of age. Reduced lesion development was associated concomitantly with lowered levels of alkaline protease activity. Withdrawal of drug treatment caused the return of severe lesions and high levels of alkaline protease. The study of the alkaline protease activity in the skeletal muscle of the myopathic hamster also showed a parallel relationship between the enzyme levels and severity of lesions. The results are discussed in light of possible involvement of a serine protease and a Ca 2+-activated protease in producing the cardiac lesions.

Elements in muscle measured in vivo and in vitro with X-ray spectrometry.

Calcium, iron, copper, and zinc concentrations in muscle were measured in vivo by x-ray spectrometry (XRS). The undersurface of the tongue was examined in cardiomyopathic and in normal hamsters. Values were compared to in-vitro analyses of various muscles from the same groups of animals using XRS and chemical analysis. Blood tests as well as histologic and histometric examinations were also performed. The correlated results show that XRS is a relatively sensitive and practical method for measuring chemical elements in muscle, and that it could be developed into a useful clinical test in certain neuromuscular and myocardial diseases. An interesting incidental finding was that, though all the examined muscles of myopathic animals had pathologic changes, only the tongue and myocardium, which are composed exclusively of red fibers, showed excessive calcium accumulation. This suggests either that the basic genetic aberration is not directly related to the oxidative metabolism, or that white muscles have a more efficient system for dealing with calcium overload.

Depressed myosin ATPase activity in hearts of myopathic hamsters: Dissociation from neutral protease activity

Myosin was isolated from the hearts of 210-day-old genetically myopathic Syrian hamsters (Bio 53:58) and its properties compared to the myosin from random bred controls of the same age. The Ca 2+ ATPase was depressed in the myosin from the hearts of myopathic animals. The K +-EDTA ATPase and the total-SH content did not differ significantly in the two groups. Myosin from myopathic animals showed a loss of LC 2. Analyses of myofibrils and actomyosin revealed that the LC 2 was present in these preparations from the myopathic animals and the loss of LC 2 was taking place during the purification of myosin. Despite the presence of LC 2 in the myofibrils and actomyosin, the corresponding ATPase activities were depressed in the myopathic hearts. The loss of LC 2 in myopathic cardiac myosin was found to be due to high levels of neutral protease activity co-purifying with myosin. The protease fraction from myopathic hearts degraded the cardiac LC 2 of control hamster and dog cardiac myosin, however, the Ca 2+ ATPase remained unchanged.

Mitochondrial calcium overloading in cardiomyopathic hamsters

Mitochondria isolated from 21- to 412-day-old cardiomyopathic hamster heart show on the average a two-fold elevation of calcium in situ. Organelles from both normal and BIO 14.6 animals show a defect of oxidative phosphorylation when loaded with calcium. Mitochondria from myopathic animals accumulate less calcium than controls and show a partial inability to retain magnesium. When subjected to sucrose gradients, the mitochondria of 40% of myopathic animals yield a small extra fraction with higher calcium content and greater density. A similar fraction is seen in skeletal muscle of all cardiomyopathic hamsters. It is postulated that, in cells undergoing necrosis, a vicious cycle of mitochondrial calcium over-loading and energy depletion is underlying the terminal event of cell death.

Muscle metabolism and cardiac function of the myopathic hamster following training.

The effect of 18 wk of treadmill running on skeletal muscle metabolism and myocardial function of normal and myopathic hamsters was examined. BIO 14.6 hamsters could tolerate an exercise intensity of about 18 m/min for 40 min, 5 days/wk. Further increases in speed or number of bouts per day resulted in a falloff in performance. Normal hamsters could tolerate higher speeds and longer exercise bouts. Exercise did not change the severity of lesions of either the heart or skeletal muscle of the myopathic hamsters. A training effect was evidenced by increased succinate dehydrogenase activity in the soleus muscle. Cardiac function was evaluated as contractility measured from left ventricular pressure curves and expressed as (dP/dt)/kP. The results suggested that cardiac contractility was not as severely depressed in the trained BIO 14.6 strain of hamsters as in nontrained controls. However, (dP/dt)/kP was lower in the trained myopathic animals than in normal hamsters. ATP, CP, and glycogen levels were lower in myopathic hamsters with the lowest values occurring in the trained group. These data demonstrate that the BIO 14.6 strain of hamster can tolerate exercise training and that such training may have a positive effect on cardiac function.

Right and left ventricular compliance in the hereditary cardiomyopathy of the Syrian hamster.

Ventricular pressure-volume curves were examined in 10 pre-oedematous cardiomyopathic Syrian hamsters, aged 120 d, and 10 oedematous cardiomyopathic hamsters, aged 210 d, and compared with 10 and 8 age-matched controls, respectively. Previous studies had shown filling pressures and cardiac output to be normal in the pre-oedematous stage. In contrast, the oedematous stage was characterised by elevated filling pressures and increased cardiac output, raising the question whether this stage represents true myocardial failure or circulatory congestion associated with decreased ventricular compliance. Compliance, defined as dV/dP, was derived simulataneously for both ventricles from post-mortem pressure-volume curves from 0 to 2.66 kPa (0 to 20 mmHg). Left ventricular tissue elastic modulus, E, defined as dsigma/depsilon or the incremental stress (sigma) for an increment of strain (epsilon), was derived from the compliance curves and certain linear dimensions of the heart. At isobaric intervals, compliance did not differ between control and myopathic ventricles. At pressures corresponding to previously measured, naturally prevailing end-diastolic pressures, the myopathic ventricles were significantly dilated in both stages; end-diastolic compliance was normal in pre-oedematous hamsters, but was significantly decreased in the oedematous animals. Left ventricular elastic modulus was elevated at all values of sigma in both groups of myopathic animals.

Studies on Adenylate Cyclase – Cyclic AMP System of the Myopathic Hamster (UM-X7.1) Skeletal and Cardiac Muscles

Cyclic AMP content, adenylate cyclase (EC 4.6.1.1) activity and phosphodiesterase I (EC 3.1.4.1) activity of the hind leg skeletal muscle and cardiac muscle in 60- and 150-day-old normal and myopathic (UM-X7.1) hamsters were examined. In 60-day-old myopathic animals, cardiac cyclic AMP levels were higher and phosphodiesterase I activity was lower, without any changes in the basal adenylate cyclase activity, whereas in 150-day-old myopathic hamsters, cardiac cyclic AMP and basal adenylate cyclase activity were lower, without any changes in the homogenate phosphodiesterase I activity. On the other hand, basal adenylate cyclase and phosphodiesterase I activities in the skeletal muscle homogenate from 60- and 150-day-old myopathic animals were not different from the normal values but the skeletal muscle cyclic AMP levels were significantly less in 60-day-old myopathic hamsters only. The plasma cyclic AMP levels in 60-day-old myopathic hamsters, unlike 150-day-old myopathic animals, were higher than the normal. Although these results reveal differences in myopathic cardiac and skeletal muscles, it is concluded that changes in adenylate cyclase-cyclic AMP system in myopathy are dependent upon the degree of disease.