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At least 667 records · Page 37Linked to original sources
PubMed1993

Loss of cardiac myofibrils: mechanism of contractile deficits induced by taurine deficiency.

It is well established that taurine deficiency is associated with myocardial contractile dysfunction; however, the mechanism is unknown. As a follow-up to finding reduced force generation in taurine-depleted rat cardiac trabeculae, using either calcium or strontium activation, this study examined alterations in ventricular fine structure and contractile proteins in animals made taurine deficient by in vivo treatment with a taurine transport antagonist, guanidinoethane sulfonate. Observations of ventricular ultrastructure showed disordered contractile filaments and clear losses of myofibrillar bundles in association with taurine deficiency. Biochemical analyses of ventricular contractile proteins using polyacrylamide gel electrophoresis confirmed losses of the major sarcomeric proteins, myosin and actin. These findings provide a possible mechanism for the contractile deficits and cardiomyopathy described in taurine-deficient animals.

Actins↗
PubMed1994

Beta-adrenergic receptors, adenylate cyclase activation, and myofibril enzyme activity in hypothyroid rats.

A previous study in intact animals assessed cardiovascular alterations in surgically thyroidectomized rats. Hemodynamic challenge via isoproterenol infusion identified abnormal left ventricular relaxation. Challenge by aortic occlusion revealed a latent deficiency in left ventricular contractility which was not apparent during beta-agonist challenge. The present study utilized left ventricular cardiac tissue obtained from the identical control and thyroidectomized animals from which intact heart hemodynamic information had been obtained. Biochemical systems were selected for evaluation based on demonstrated hemodynamic alterations, i.e., beta-adrenergic receptor number/function and contractile protein enzyme properties. The number of beta-receptors on hypothyroid cardiac membranes was significantly decreased, but receptor agonist affinity was not influenced. Basal adenylate cyclase activity in cardiac membranes from control and thyroidectomized rats was nearly identical; however, isoproterenol activation was diminished in hypothyroid cardiac membrane, particularly at the higher levels of beta-agonist stimulation. Adenylate cyclase enzyme activation by forskolin was not influenced by thyroidectomy; however, activation by sodium fluoride was reduced approximately 30% when compared with preparations from control rats. Cardiac myofibrillar enzyme activity for adenosinetriphosphatase (ATPase) was significantly lower in thyroidectomized rats. Despite reduced ATPase activity, myofibrillar calcium sensitivity was unaltered. Myofibrillar creatine kinase enzyme activity was not influenced by thyroidectomy; therefore, compartmentalized ATP regeneration potential via creatine kinase was enhanced relative to substrate utilization via ATPase. Thus hemodynamically significant cardiac influences of hypothyroidism are mediated, at least in part, via 1) reduced beta-receptor number, 2) diminished catecholamine-induced activation of adenylate cyclase, and 3) reduced myofibrillar ATPase activity.

Adenylyl Cyclases↗
PubMed1994

Temperature and pH effects on Ca2+ sensitivity of cardiac myofibrils: a comparison of trout with mammals.

Active salmonids maintain myocardial contractility at temperatures that are cardioplegic for mammals. We postulated that myofibrillar Ca2+ sensitivity in the trout heart might 1) exhibit lower temperature dependence and/or 2) be greater over the range of physiological temperatures. Temperature-induced changes in intracellular pH may also play a role as alkalosis typically increases calcium affinity of myofibrillar adenosinetriphosphatase (ATPase). Ca2+ sensitivities of ventricular myofibrillar ATPase were determined in rats and in rainbow trout (Oncorhynchus mykiss) over a physiological range of pH and temperatures. Maximal myofibrillar ATPase activities of each species were similar and equally affected by temperature. Trout myofibrillar ATPase lost Ca2+ dependence at 37 degrees C. At constant pH, reduced temperature decreased calcium affinity more in trout (0.35 pCa/10 degrees C) than in rat (0.08-0.16 pCa/10 degrees C). Under alpha-stat conditions, the effects of temperature were reduced in both trout (0.2 pCa/10 degrees C) and rat (no significant effect). Over trout physiological temperatures, Ca2+ sensitivity was greater than rat at 37 degrees C. Qualitatively similar results were observed in studies measuring tension in skinned trout ventricular fibers. One mechanism by which the trout heart is able to maintain contractility at low temperatures is through the inherent higher Ca2+ sensitivity of the contractile element compared with mammalian species.

Adenosine Triphosphatases↗
PubMed1978

Action of caffeine on calcium transport by isolated fractions of myofibrils, mitochondria, and sarcoplasmic reticulum from rabbit heart.

We studied the effects of caffeine on calcium transport by subcellular organelles isolated from rabbit myocardium. Caffeine increased myofibrillar basic and calcium-activated ATPase activity at 20 mM but not at lower concentrations. Mitochondrial and sarcoplasmic reticulum (SR) calcium accumulation was measured both by dual wavelength spectrophotometry with the calcium-sensitive dye, murexide, and by Millipore filtration with 45Ca. In mitochondria, caffeine impaired phosphate-assisted calcium transport but did not alter the closely related parameters of oxygen uptake, P/O ratio (nmol adenosine diphosphate consumed/n ats oxygen consumed, state 3 respiration) or limited calcium loading. In SR, caffeine impaired calcium accumulation. New methods were used to characterize calcium accumulation in the absence of oxalate according to first order reaction kinetics. Caffeine increased the rate constant while decreasing the calcium accumulated. It also increased the associated calcium-activated ATPase activity at low (30 mM) but not high (240 micrometer) external calcium concentration. In the presence of oxalate, caffeine decreased the rate of calcium accumulation, more with low than high calcium concentration. Net efflux of 45Ca from preloaded SR also was increased by caffeine. The findings indicate that caffeine impairs active calcium accumulation by making SR vesicle membranes more permeable to calcium.

Animals↗
PubMed1981

Phosphorylation and adenosine triphosphatase activity of myofibrils from thyrotoxic rabbit hearts.

Cardiac hypertrophy induced by thyrotoxic stress leads to an increase in the rate of force development, velocity of shortening, tension-dependent heat generation, and myosin ATPase activity. We did studies to see whether alterations in covalent phosphorylation of myofibrillar proteins correlate with these changes. The protein preparations were isolated from control and thyrotoxic hearts of male albino rabbits freeze-clamped in situ. We measured myofibrillar ATPase, and the covalent phosphate content of ventricular myosin 19,000 (mol wt) light chain (P-light chain) and troponin I (TnI). The myofibrillar ATPase activity was increased 2-fold in the thyrotoxic preparations with no change in the level of myofibrillar phosphorylation. The covalent phosphate content of TnI was 1.21 +/- 0.09 mol P/mol TnI in control hearts and 1.14 +/- 0.04 mol P/mol TnI in thyrotoxic hearts. The covalent phosphate content of the light chain fraction was 0.41 +/- 0.06 mol P/mol P-light chain in control hearts and 0.37 +/- 0.04 mol P/mol P-light chain in thyrotoxic hearts. The dependence of the normalized myofibrillar ATPase on free calcium concentration was the same in control and thyrotoxic preparations. Thus the mechanical, thermal, and biochemical changes found in hearts from thyrotoxic animals probably occur with no change in phosphorylation of TnI or myosin light chains.

Adenosine Triphosphatases↗
PubMed1995

Effects of Levosimendan, a cardiotonic agent targeted to troponin C, on cardiac function and on phosphorylation and Ca2+ sensitivity of cardiac myofibrils and sarcoplasmic reticulum in guinea pig heart.

A new cardiotonic agent, (R)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)-phenyl] hydrazono]propanedinitrile (Levosimendan), has been developed and screened for its ability to bind to cardiac troponin C. In perfused hearts, low concentrations of 0.03 or 0.1 mumol/L Levosimendan increased +dP/dt, but did not affect the speed of relaxation and produced only a slight increase in spontaneous heart rate in the hearts perfused with 0.1 mumol/L of the drug. In these same hearts, perfusion with 0.03 mumol/L Levosimendan did not alter the 32P incorporation into troponin I or C protein, whereas a slight but significant increase was noted for phospholamban, with no detectable change in tissue cAMP levels. Administration of 0.1 or 0.3 mumol/L Levosimendan significantly increased myocardial cAMP levels as well as the phosphorylation of phospholamban, troponin I, and C protein. Levosimendan (0.03 to 10 mumol/L) reversibly increased force generated by detergent-extracted fiber bundles over a range of submaximally activating free Ca2+ concentrations with no significant effect on maximum force or on Ca2+ binding to myofilament troponin C. There was no direct effect of Levosimendan on Ca2+ uptake by vesicles of sarcoplasmic reticulum (SR). In contrast, under conditions optimal for cAMP-dependent phosphorylation, Levosimendan slightly but significantly lowered the concentration of Ca2+, yielding half-maximal uptake rates by the SR vesicles. Our results indicate that at low concentrations Levosimendan acts preferably as a Ca2+ sensitizer, whereas at higher concentrations its action as a phosphodiesterase inhibitor contributes to the positive inotropic effect.

Analysis of Variance↗
PubMed1997

Involvement of phosphorylation in doxorubicin-mediated myofibril degeneration. An immunofluorescence microscopy analysis.

Loss of myofilaments has been observed in both adaptive cardiac responses (i.e., hypertrophy) as well as in chemotheraputic use of antineoplastic drugs with cardiotoxic side effects (i.e., doxorubicin). An understanding of the degenerative process is a prerequisite for determining approaches to limit the cardiomyopathic changes associated with chronic heart disease or long-term chemotheraputic treatments. However, little is known about the specific events and molecular changes that initiate the degenerative process. To study this process, neonatal rat cardiomyocytes were treated with doxorubicin, which induced rapid and widespread thin-filament degeneration as observed by fluorescence confocal microscopy. Which demonstrated deterioration of sarcomeric thin-filament structure. Changes in the spontaneous beating of cardiomyocytes corresponding with myofibrillar degeneration were apparent using differential interference contrast video microscopy. After finding induction of kinase activity by doxorubicin in cultured cardiomyocytes, the protective effects of specific inhibitors of kinase activity were assessed for their ability to inhibit doxorubicin-induced myofibrillar break-down. Doxorubicin-induced changes appeared similar to the degeneration observed after treatment with a protein kinase activator (phorbol 12-myristate 13-acetate) or a serine-threonine protein phosphatase inhibitor (okadaic acid). Collectively, these results indicate that activation of protein kinase is an important event in the initiation of myofibrillar degeneration by doxorubicin. Further analyses of myofibrillar proteins with respect to biochemical modifications will be necessary to determine if phosphorylation events transmit signal(s) to initiate degeneration.

Animals↗
PubMed1989

Repetitive titin epitopes with a 42 nm spacing coincide in relative position with known A band striations also identified by major myosin-associated proteins. An immunoelectron-microscopical study on myofibrils.

A direct titin-thick filament interaction in certain regions of the A band is suggested by results using four new monoclonal antibodies specific for titin in immunoelectron microscopy. Antibodies T30, T31 and T32 identify quasi-repeats in the titin molecule characterized by a 42-43 nm repeat spacing. These stripes seem to coincide with striations established by others on negatively stained cryosections of the A band. Antibodies T30 and T32 recognize epitopes matching five or two of the seven striations per half sacromere known to harbor both the myosin-associated C-protein and an 86K (K = 10(3) Mr) protein. Antibody T31 labels two stripes in the P zone, which correspond to the two positions where decoration is seen with 86K protein, but not with C-protein. The single titin epitope defined by antibody T33 is located 55 nm prior to the center of the M band. This position seems to coincide with the M7 striation defined by others on negatively stained A bands. The T33 epitope position proves that the titin molecule, which is known to be anchored at the Z line, also penetrates into the complex architecture of the M band. The titin epitopes described here enable us to begin to correlate known ultrastructural aspects of the interior part of the A band with the disposition of the titin molecule in the sarcomere. They raise the question of whether there is a regular interaction pattern between titin and the thick filaments.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2003

Metabolic consequences of functional complexes of mitochondria, myofibrils and sarcoplasmic reticulum in muscle cells.

Regulation of mitochondrial respiration both by endogenous and exogenous ADP in the cells in situ was studied in isolated and permeabilized cardiomyocytes, permeabilized cardiac fibers and 'ghost' fibers (all with a diameter of 10-20 micro m) at different (0-3 micro moll(-1)) free Ca(2+) concentrations in the medium. In all these preparations, the apparent K(m) of mitochondrial respiration for exogenous ADP at free Ca(2+) concentrations of 0-0.1 micro moll(-1) was very high, in the range of 250-350 micro moll(-1), in contrast to isolated mitochondria in vitro (apparent K(m) for ADP is approximately 20 micro moll(-1)). An increase in the free Ca(2+) concentration (up to 3 micro moll(-1), which is within physiological range), resulted in a very significant decrease of the apparent K(m) value to 20-30 micro moll(-1), a decrease of V(max) of respiration in permeabilized intact fibers and a strong contraction of sarcomeres. In ghost cardiac fibers, from which myosin was extracted but mitochondria were intact, neither the high apparent K(m) for ADP (300-350 micro moll(-1)) nor V(max) of respiration changed in the range of free Ca(2+) concentration studied, and no sarcomere contraction was observed. The exogenous-ADP-trapping system (pyruvate kinase + phosphoenolpyruvate) inhibited endogenous-ADP-supported respiration in permeabilized cells by no more than 40%, and this inhibition was reversed by creatine due to activation of mitochondrial creatine kinase. These results are taken to show strong structural associations (functional complexes) among mitochondria, sarcomeres and sarcoplasmic reticulum. Inside these complexes, mitochondrial functional state is controlled by channeling of ADP, mostly via energy- and phosphoryl-transfer networks, and apparently depends on the state of sarcomere structures.

Adenosine Diphosphate↗