A hexokinase effect in the inhibition of oxidative phosphorylation in heart muscle mitochondria by Adriamycin

The inhibitory action of the anticancer antibiotic, Adriamycin, on succinate-dependent oxidative phosphorylation in heart mitochondria was markedly potentiated by the presence of hexokinase in the reaction medium. This 'hexokinase effect' was not observed in the oxidation of NAD+-linked substrates, or when liver or kidney mitochondria were used in place of heart mitochondria. These results offer a biochemical explanation for the extreme cardiac toxicity of the drug.

Cardiac remodeling in Drosophila arises from changes in actin gene expression and from a contribution of lymph gland-like cells to the heart musculature

Understanding the basis of normal heart remodeling can provide insight into the plasticity of the cardiac state, and into the potential for treating diseased tissue. In Drosophila, the adult heart arises during metamorphosis from a series of events, that include the remodeling of an existing cardiac tube, the elaboration of new inflow tracts, and the addition of a layer of longitudinal muscle fibers. We have identified genes active in all these three processes, and studied their expression in order to characterize in greater detail normal cardiac remodeling. Using a Transglutaminase-lacZ transgenic line, that is expressed in the inflow tracts of the larval and adult heart, we confirm the existence of five inflow tracts in the adult structure. In addition, expression of the Actin87E actin gene is initiated in the remodeling cardiac tube, but not in the longitudinal fibers, and we have identified an Act87E promoter fragment that recapitulates this switch in expression. We also establish that the longitudinal fibers are multinucleated, characterizing these cells as specialized skeletal muscles. Furthermore, we have defined the origin of the longitudinal fibers, as a subset of lymph gland cells associated with the larval dorsal vessel. These studies underline the myriad contributors to the formation of the adult Drosophila heart, and provide new molecular insights into the development of this complex organ. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

Molecular convergence of hexosamine biosynthetic pathway and ER stress leading to insulin resistance in L6 skeletal muscle cells

Augmentation of hexosamine biosynthetic pathway (HBP) and endoplasmic reticulum (ER) stress were independently related to be the underlying causes of insulin resistance. We hypothesized that there might be a molecular convergence of activated HBP and ER stress pathways leading to insulin resistance. Augmentation of HBP in L6 skeletal muscle cells either by pharmacological (glucosamine) or physiological (high-glucose) means, resulted in increased protein expression of ER chaperones (viz., Grp78, Calreticulin, and Calnexin), UDP-GlcNAc levels and impaired insulin-stimulated glucose uptake. Cells silenced for O-glycosyl transferase (OGT) showed improved insulin-stimulated glucose uptake (P < 0.05) but without any effect on ER chaperone upregulation. While cells treated with either glucosamine or high-glucose exhibited increased JNK activity, silencing of OGT resulted in inhibition of JNK and normalization of glucose uptake. Our study for the first time, demonstrates a molecular convergence of O-glycosylation processes and ER stress signals at the cross-road of insulin resistance in skeletal muscle.

Oxidation of succinate in heart, brain, and kidney mitochondria in hypobaria and hypoxia

Exposure of rats to hypobaric stress for periods of up to 36 h caused a consistent change in the succinate-NT reductase activity of the heart mitochondria whereas there was no significant change in the activities of either succinate dehydrogenase and succinate-NT reductase of the brain and the kidney. Mitochondrial succinate dehydrogenase of the heart, the brain and the kidney was activated 2- to 7-fold with the substrate and malonate. The activations obtained with oxalate, citrate and dinitrophenol were relatively lower in comparison to succinate and malonate. Benzohydroquinone and 2-nitrophenol had no stimulatory effect on the heart, the brain and the kidney mitochondria. THE ACTIVATIONS OBTAINED WITH THE VARIOUS EFFECTORS PARTIALLY (OR COMPLETELY IN THE CASE OF SUCCINATE) REVERSED ON WASHING THE MITOCHONDRIAL SAMPLES WITH THE SUCROSE HOMOGENIZING MEDIUM. The effect of ubiquinol, which also activated the enzyme, was only partially reversed after the second preincubation with succinate in the brain and the kidney whereas in the heart the activity was fully reversed. The increased activity of succinate dehydrogenase obtained with ATP and ADP was further enhanced by Mg2+ exclusively in the brain mitochondria, suggesting the possibility of Mg2+-AIP complex as the active species. Succinate-NT reductase of the heart, the brain and the kidney mitochondria showed a high activation with ubiquinone whereas its reduced form had no stimulatory effect.

Localized agglutinin staining in muscle capillaries from normal and very old atrophic human muscle using winged bean ( Psophocarpus tetragonolobus ) lectin

The winged bean (Psophocarpus tetragonolobus) agglutinin (total lectin) and its basic (WBA I) and acidic isoform (WBA II) were used to analyze capillaries in sections from human muscle. The microvessels were clearly labeled after incubation with the lectins in both normal muscle and in old muscles with age-related type II atrophy or muscle fiber grouping. Muscle fibers, nerves, and connective tissue remained unstained. The total lectin detected muscle capillaries from all blood group AB0 individuals. The isoform WBA I reacted only with blood vessels in blood group A and B individuals, while the blood vessels in blood group 0 individuals were demonstrated with WBA II. WBA I staining was inhibited by p-nitrophenyl α-galactopyranoside and N-acetylgalactosamine, whereas 2′-fucosyllactose and preincubation with an antibody against type-1 chain H abolished capillary staining with WBA II. The study demonstrates the usefulness of WBA as a marker of capillaries in human muscle.

Drosophila indirect flight muscle specific Act88F actin mutants as a model system for studying congenital myopathies of the human ACTA1 skeletal muscle actin gene

Most human ACTA1 skeletal actin gene mutations cause dominant, congenital myopathies often with severely reduced muscle function and neonatal mortality. High sequence conservation of actin means many mutated ACTA1 residues are identical to those in the Drosophila Act88F, an indirect flight muscle specific sarcomeric actin. Four known Act88F mutations occur at the same actin residues mutated in ten ACTA1 nemaline mutations, A138D/P, R256H/L, G268C/D/R/S and R372C/S. These Act88F mutants were examined for similar muscle phenotypes. Mutant homozygotes show phenotypes ranging from a lack of myofibrils to almost normal sarcomeres at eclosion. Aberrant Z-disc-like structures and serial Z-disc arrays, ‘zebra bodies’, are observed in homozygotes and heterozygotes of all four Act88F mutants. These electron-dense structures show homologies to human nemaline bodies/rods, but are much smaller than those typically found in the human myopathy. We conclude that the Drosophila indirect flight muscles provide a good model system for studying ACTA1 mutations.

Nonlinear measures of heart rate time series: influence of posture and controlled breathing

In this study, we investigated measures of nonlinear dynamics and chaos theory in regards to heart rate variability in 27 normal control subjects in supine and standing postures, and 14 subjects in spontaneous and controlled breathing conditions. We examined minimum embedding dimension (MED), largest Lyapunov exponent (LLE) and measures of nonlinearity (NL) of heart rate time series. MED quantifies the system's complexity, LLE predictability and NL, a measure of deviation from linear processes. There was a significant decrease in complexity (P<0.00001), a decrease in predictability (P<0.00001) and an increase in nonlinearity (P=0.00001) during the change from supine to standing posture. Decrease in MED, and increases in NL score and LLE in standing posture appear to be partly due to an increase in sympathetic activity of the autonomous nervous system in standing posture. An improvement in predictability during controlled breathing appears to be due to the introduction of a periodic component. (C) 2000 published by Elsevier Science B.V.

Homomorphic Analysis and Modeling of ECG Signals

Homomorphic analysis and pole-zero modeling of electrocardiogram (ECG) signals are presented in this paper. Four typical ECG signals are considered and deconvolved into their minimum and maximum phase components through cepstral filtering, with a view to study the possibility of more efficient feature selection from the component signals for diagnostic purposes. The complex cepstra of the signals are linearly filtered to extract the basic wavelet and the excitation function. The ECG signals are, in general, mixed phase and hence, exponential weighting is done to aid deconvolution of the signals. The basic wavelet for normal ECG approximates the action potential of the muscle fiber of the heart and the excitation function corresponds to the excitation pattern of the heart muscles during a cardiac cycle. The ECG signals and their components are pole-zero modeled and the pole-zero pattern of the models can give a clue to classify the normal and abnormal signals. Besides, storing only the parameters of the model can result in a data reduction of more than 3:1 for normal signals sampled at a moderate 128 samples/s

Use of finite wordlength FIR digital filter structures with improved magnitude and phase characteristics for reduction of muscle noise in EEG signals

One of the main disturbances in EEG signals is EMG artefacts generated by muscle movements. In the paper, the use of a linear phase FIR digital low-pass filter with finite wordlength precision coefficients is proposed, designed using the compensation procedure, to minimise EMG artefacts in contaminated EEG signals. To make the filtering more effective, different structures are used, i.e. cascading, twicing and sharpening (apart from simple low-pass filtering) of the designed FIR filter Modifications are proposed to twicing and sharpening structures to regain the linear phase characteristics that are lost in conventional twicing and sharpening operations. The efficacy of all these transformed filters in minimising EMG artefacts is studied, using SNR improvements as a performance measure for simulated signals. Time plots of the signals are also compared. Studies show that the modified sharpening structure is superior in performance to all other proposed methods. These algorithms have also been applied to real or recorded EMG-contaminated EEG signal. Comparison of time plots, and also the output SNR, show that the proposed modified sharpened structure works better in minimising EMG artefacts compared with other methods considered.

Subclinical autonomic neuropathy in alcoholics: Decreased heart rate variability

Cardiac autonomic neuropathy is known to occur in alcoholics but the extent of its subclinical form is not usually recognized, Heart Rate Variability (HRV) analysis can detect subclinical autonomic neuropathy. In this study the HRV parameters were compared in 20 neurologically asymptomatic alcoholics, 20 age-matched normals and 16 depressives. All were males, ECG was recorded in a quiet room for four minutes in supine position. Time and Frequency domain parameters of HRV were computed by a researcher blind to clinical details. Alcoholics had significantly smaller Coefficient of Variation of R-R intervals (CVR-R) on time domain analysis and smaller HF band (0.15-0.5 Hz) power on spectral analysis. The decreased Heart Rate Variability indicates cardiac autonomic dysfunction.

Diminished chaos of heart rate time series in patients with major depression

Background: Depression and anxiety have been linked to serious cardiovascular events in patients with preexisting cardiac illness. A decrease in cardiac vagal function as suggested by a decrease in heart rate (HR) variability has been linked to sudden death. Methods: We compared LLE and nonlinearity scores of the unfiltered (UF) and filtered time series (very low, low, and high frequency; VLF, LF and HF) of HR between patients with depression (n = 14) and healthy control subjects (n = 18). Results: We found significantly lower LLE of the unfiltered series in either posture, and HF series in patients with major depression in supine posture (p < .002). LLE (LF/UF), which may indicate relative sympathetic activity was also significantly higher in supine and standing postures in patients (p < .05); LF/HF (LLE) was also higher in patients (p < .05) in either posture. Conclusions: These findings suggest that major depression is associated with decreased cardiac vagal function and a relative increase in sympathetic function, which may be related to the higher risk of cardiovascular mortality, in this group and illustrates the usefulness of nonlinear measures of chaos such as LLE in addition to the commonly used spectral measures.

Major depression with ischemic heart disease: Effects of paroxetine and nortriptyline on measures of nonlinearity and chaos of heart rate

Depression is associated with increased cardiovascular mortality in patients with preexisting cardiac illness. A decrease in cardiac vagal function as suggested by a decrease in heart rate variability (HRV) or heart period variability has been linked to sudden death in patients with cardiac disease as well as in normal controls. Recent studies have shown decreased vagal function in cardiac patients with depression as well as in depressed patients without cardiac illness. In this study, we compared 20 h awake and sleep heart period nonlinear measures using quantification of nonlinearity and chaos in two groups of patients with major depression and ischemic heart disease (mean age 59-60 years) before and after 6 weeks of treatment with paroxetine or nortriptyline. Patients received paroxetine, 20-30 mg/day or nortriptyline targeted to 190-570 nmol/l for 6 weeks. For HRV analysis, 24 patients were included in the paroxetine treatment study and 20 patients in the nortriptyline study who had at least 20,000 s of awake data. The ages of these groups were 60.4 +/- 10.5 years for paroxetine and 60.8 +/- 13.4 years for nortriptyline. There was a significant decrease in the largest Lyapunov exponent (LLE) after treatment with nortriptyline but not paroxetine. There were also significant decreases in nonlinearity scores on S-netPR and S-netGS after nortriptyline, which may be due to a decrease in cardiac vagal modulation of HRV. S-netGS and awake LLE were the most significant variables that contributed to the discrimination of postparoxetine and postnortriptyline groups even with the inclusion of time and frequency domain measures. These findings suggest that nortriptyline decreases the measures of chaos probably through its stronger vagolytic effects on cardiac autonomic function compared with paroxetine, which is in agreement with previous clinical and preclinical reports. Nortriptyline was also associated with a significant decrease in nonlinearity scores, which may be due to anticholinergic and/or sympatholytic effects. As depression is associated with a strong risk factor for cardiovascular mortality, one should be careful about using any drug that adversely affects cardiac vagal function. Copyright (C) 2002 S. Karger AG, Basel.

Effect of nortriptyline and paroxetine on measures of chaos of heart rate time series in patients with panic disorder

Tricyclic antidepressants have notable cardiac side effects, and this issue has become important due to the recent reports of increased cardiovascular mortality in patients with depression and anxiety. Several previous studies indicate that serotonin reuptake inhibitors (SRIs) do not appear to have such adverse effects. Apart from the effects of these drugs on routine 12-lead ECG, the effects on beat-to-beat heart rate (HR) and QT interval time series provide more information on the side effects related to cardiac autonomic function. In this study, we evaluated the effects of two antidepressants, nortriptyline (n = 13), a tricyclic, and paroxetine (n = 16), an SRI inhibitor, on HR variability in patients with panic disorder, using a measure of chaos, the largest Lyapunov exponent (LLE) using pre- and posttreatment HR time series. Our results show that nortriptyline is associated with a decrease in LLE of high frequency (HF: 0.15-0.5 Hz) filtered series, which is most likely due to its anticholinergic effect, while paroxetine had no such effect. Paroxetine significantly decreased sympathovagal ratios as measured by a decrease in LLE of LF/HF. These results suggest that paroxetine appears to be safer in regards to cardiovascular effects compared to nortriptyline in this group of patients. (C) 2003 Elsevier Inc. All rights reserved.