Biomedical subjects

M E Young

Publications and source records attributed to M E Young.

At least 19 recordsLinked to original sources

PubMed2001

Uncoupling protein 3 transcription is regulated by peroxisome proliferator-activated receptor (alpha) in the adult rodent heart.

Relatively little is known concerning the regulation of uncoupling proteins (UCPs) in the heart. We investigated in the adult rodent heart 1) whether changes in workload, substrate supply, or cytokine (TNF-alpha) administration affect UCP-2 and UCP-3 expression, and 2) whether peroxisome proliferator-activated receptor alpha (PPARalpha) regulates the expression of either UCP-2 or UCP-3. Direct comparisons were made between cardiac and skeletal muscle. UCP-2, UCP-3, and PPARalpha expression were reduced when cardiac workload was either increased (pressure overload by aortic constriction) or decreased (mechanical unloading by heterotopic transplantation). Similar results were observed during cytokine administration. Reduced dietary fatty acid availability resulted in decreased expression of both cardiac UCP-2 and UCP-3. However, when fatty acid (the natural ligand for PPARalpha) supply was increased (high-fat feeding, fasting, and STZ-induced diabetes), cardiac UCP-3 but not UCP-2 expression increased. Comparable results were observed in rats treated with the specific PPARalpha agonist WY-14,643. The level of cardiac UCP-3 but not UCP-2 expression was severely reduced (20-fold) in PPARalpha-/- mice compared to wild-type mice. These results suggest that in the adult rodent heart, UCP-3 expression is regulated by PPARalpha. In contrast, cardiac UCP-2 expression is regulated in part by a fatty acid-dependent, PPARalpha-independent mechanism.

Animals↗

PubMed2001

Regulation of cardiac and skeletal muscle malonyl-CoA decarboxylase by fatty acids.

Malonyl-CoA decarboxylase (MCD) catalyzes the degradation of malonyl-CoA, an important modulator of fatty acid oxidation. We hypothesized that increased fatty acid availability would increase the expression and activity of heart and skeletal muscle MCD, thereby promoting fatty acid utilization. The results show that high-fat feeding, fasting, and streptozotocin-induced diabetes all significantly increased the plasma concentration of nonesterified fatty acids, with a concomitant increase in both rat heart and skeletal muscle MCD mRNA. Upon refeeding of fasted animals, MCD expression returned to basal levels. Fatty acids are known to activate peroxisome proliferator-activated receptor-alpha (PPARalpha). Specific PPARalpha stimulation, through Wy-14643 treatment, significantly increased the expression of MCD in heart and skeletal muscle. Troglitazone, a specific PPARgamma agonist, decreased MCD expression. The sensitivity of MCD induction by fatty acids and Wy-14643 was soleus > extensor digitorum longus > heart. High plasma fatty acids consistently increased MCD activity only in solei, whereas MCD activity in the heart actually decreased with high-fat feeding. Pressure overload-induced cardiac hypertrophy, in which PPARalpha expression is decreased (and fatty acid oxidation is decreased), resulted in decreased MCD mRNA and activity, an effect that was dependent on fatty acids. The results suggest that fatty acids induce the expression of MCD in rat heart and skeletal muscle. Additional posttranscriptional mechanisms regulating MCD activity appear to exist.

Animals↗

PubMed2001

Entropy and variability discrimination.

Two experiments examined college students' discrimination of complex visual displays that involved different degrees of variability or "entropy." Displays depicted 16 black and white line drawings of various types (e.g., a brain, a clock, a hand); the participants were required to classify a display in terms of its variability (e.g., a low-variability display contains many identical items, whereas a high-variability display contains few identical items). The participants' accuracy and reaction time scores on a 2-alternative forced-choice discrimination disclosed that people can and do use entropy to classify different levels of visual display variability. Individuals differed in their use of absolute rather than relative entropy.

Adult↗

PubMed2000

Streptozotocin-induced changes in cardiac gene expression in the absence of severe contractile dysfunction.

UNLABELLED: Diabetes mellitus alters energy substrate metabolism and gene expression in the heart. It is not known whether the changes in gene expression are an adaptive or maladaptive process. To answer this question, we determined both the time-course and the extent of the alteration of gene expression induced by insulin-deficient diabetes. Transcript analysis with real-time quantitative polymerase chain reaction (PCR) was performed in rat hearts 1 week (acute group) or 6 months (chronic group) after administration of streptozotocin (55 mg/kg). In the acute group, insulin-dependent diabetes induced a 55-70% decrease of both glucose transporter 1 (GLUT1) and GLUT4 transcripts, a slight decrease of liver-specific carnitine palmitoyltransferase I (CPT I), and no change in muscle-specific CPT I. The uncoupling protein UCP-3 increased three-fold, with no change in UCP-2. These metabolic alterations were accompanied by an isoform switching from the normally expressed alpha myosin heavy chain (MHC) to the fetal isoform betaMHC mRNA, by a 50% decrease of cardiac alpha-actin mRNA, a 30% decrease of the sarcoplasmic Ca++-ATPase mRNA, and a 50% decrease of muscle creatine kinase (P<0.01 v controls). All genomic changes were also present in the chronic group. Genomic markers of ventricular dysfunction [tumor necrosis factor alpha (TNF-alpha), inducible nitric oxide synthase, cyclo-oxygenase-2] were not affected by chronic diabetes. In both groups, there were no changes in resting left ventricular function by echocardiography. CONCLUSION: The heart adapts to insulin-deficient diabetes by a rapid and simultaneous response of multiple genes involved in cardiac metabolism and function. This genomic adaptation resembles the adaptation of cardiac hypertrophy, remains stable over time, and does not lead to major contractile dysfunction.

Animals↗

PubMed2000

Seeing things from a different angle: the pigeon's recognition of single geons rotated in depth.

In 2 experiments involving computer-rendered versions of single shapes or "geons," the extent to which depth rotation affects the visual discrimination performance of pigeons in both go/no-go and forced-choice tasks was documented. The pigeons were able to recognize geons at most rotations in depth; however, the pigeons' recognition performance was better at the training view than at most other views. Aspects of these results are both consistent with and problematic for object-centered and viewer-centered theories of object recognition.

Animals↗

PubMed2000

Display variability and spatial organization as contributors to the pigeon's discrimination of complex visual stimuli.

Three experiments assessed the contributions of display variability and spatial organization to the pigeon's discrimination of 16-icon visual displays. After training to discriminate 4 x 4 arrays of same and different computer icons, 4 pigeons were shown testing displays that systematically manipulated the variability of the depicted icons and their spatial organization on the display screen. Display variability and spatial organization each reliably controlled the pigeon's behavior. These seemingly separate effects could be collectively explained by the pigeon's discriminating the amount of variability or entropy in localized regions of the display.

Animals↗

PubMed2000

Anaplerosis of the citric acid cycle: role in energy metabolism of heart and skeletal muscle.

Efficient energy transfer in heart and skeletal muscle requires a series of moiety-conserved cycles. The intermediaries of the metabolic cycles are finely regulated to maintain a dynamic state of equilibrium. In heart muscle, depletion of the citric acid cycle (TCA cycle) through a block of 2-oxoglutarate dehydrogenase results in a rapid decline of contractile function, which is reversed by the addition of substrates promoting flux through the carboxylating enzymes, malic enzyme, pyruvate carboxylase and propionyl-CoA carboxylase. Anaplerosis describes a pathway, which replenishes a metabolic cycle. We show that enzymes for anaplerosis of the TCA cycle are expressed in heart and skeletal muscles. The role of anaplerosis of the TCA cycle in skeletal muscle is not entirely clear, but there is substantial evidence for its operational control during exercise. While the anaplerotic flux of carbon into the TCA cycle exceeds the removal of cycle intermediates, this process is only transient and reverses with prolonged exercise. It remains to be determined, however, whether the initial increase in TCA cycle intermediates is obligatory in order to attain high rates of TCA cycle flux, or primarily reflects a mass action phenomenon owing to increased substrate availability for anaplerotic pathways.

Animals↗

PubMed2000

Positive and negative patterning in human causal learning.

Investigations of patterning discriminations by nonhuman animals have generally found that positive patterning is easier to learn than negative patterning. Studies of patterning discriminations in human causal learning tasks have failed to document any differences between positive and negative patterning. In the present study, human participants predicted an outcome on trials involving either a compound cue or its elements. Positive and negative patterning problems were successfully solved in a within-subjects design; negative patterning problems proved to be more difficult when an additional, 50% contingent cue was included (Experiment 2), but not when it was excluded (Experiment 1). Possible reasons for these results are discussed. The discussion concludes with an analysis of exemplar models (e.g., Pearce, 1994) of human causal learning and considers the conditions under which these models do and do not anticipate our results.

Adult↗

PubMed2000

Exercise diminishes the activity of acetyl-CoA carboxylase in human muscle.

Studies in rats suggest that increases in fatty acid oxidation in skeletal muscle during exercise are related to the phosphorylation and inhibition of acetyl-CoA carboxylase (ACC), and secondary to this, a decrease in the concentration of malonyl-CoA. Studies in human muscle have not revealed a consistent decrease in the concentration of malonyl-CoA during exercise; however, measurements of ACC activity have not been reported. Thus, whether the same mechanism operates in human muscle in response to physical activity remains uncertain. To investigate this question, ACC was immunoprecipitated from muscle of human volunteers and its activity assayed in the same individual at rest and after one-legged knee-extensor exercise at 60, 85, and 100% of knee extensor VO2max. ACC activity was diminished by 50-75% during exercise with the magnitude of the decrease generally paralleling exercise intensity. Treatment of the immunoprecipitated enzyme with protein phosphatase 2A restored activity to resting values, suggesting the decrease in activity was due to phosphorylation. The measurement of malonyl-CoA in the muscles revealed that its concentration is 1/10 of that in rats, and that it is diminished (12-17%) during the higher-intensity exercises. The respiratory exchange ratio increased with increasing exercise intensity from 0.84 +/- 0.02 at 60% to 0.99 0.04 at 100% VO2max. Calculated rates of whole-body fatty acid oxidation were 121 mg/min at rest and 258 +/- 35, 264 +/- 63, and 174 +/- 76 mg/min at 60, 85, and 100% VO2max, respectively. The results show that ACC activity, and to a lesser extent malonyl-CoA concentration, in human skeletal muscle decrease during exercise. Although these changes may contribute to the increases in fat oxidation from rest to exercise, they do not appear to explain the shift from mixed fuel to predominantly carbohydrate utilization when exercise intensity is increased.

Acetyl-CoA Carboxylase↗

PubMed2000

Serial causation: occasion setting in a causal induction task.

The temporal relations among candidate causes were studied in a causal induction task using a design that is known to produce occasion setting in animal learning preparations. For some subset of the observations, one event, the occasion setter, was accompanied by another event, the conditional cause; for another subset of the observations, the conditional cause occurred alone. The efficacy of the conditional cause depended on whether it was or was not accompanied by the occasion setter. Participants used the occasion setter to modulate their effect expectancy to the conditional cause when the events were presented serially, but not simultaneously. Current causal induction models are unable to account for the full range of effects that we observed; the relative roles of time, attention, and cue distinctiveness are discussed.

Association Learning↗

PubMed1999

Decreased myocardial nNOS, increased iNOS and abnormal ECGs in mouse models of Duchenne muscular dystrophy.

Duchenne muscular dystrophy is a devastating neuromuscular disease caused by lack of the protein, dystrophin, in skeletal muscle and heart, although the biochemical mechanism by which dystrophin loss causes muscle dysfunction is unknown. Here we show that the dystrophin-deficient mdx mouse and a mouse lacking both dystrophin and the dystrophin-related protein, utrophin (dko), have abnormal electrocardiograms (ECGs). In skeletal muscle, dystrophin is normally associated with neuronal nitric oxide synthase (nNOS) at the sarcolemma. Consequently, we have measured NOS isoform activities in hearts from control, mdx and dko mice. In control mouse hearts, eNOS and nNOS activities increased by 120% and 47%, respectively, between 2 and 6 months of age. In mdx mice, myocardial nNOS activity was decreased by 60%, 84% and 80% at 2, 6 and 12 months of age, respectively. Similarly, hearts from dko mice showed a 65% decrease in nNOS activity compared to controls at 2 months of age. Endothelial NOS (eNOS) activity was not affected by dystrophin loss, but inducible NOS (iNOS) activity was seven-fold higher than control in the mdx mouse heart by 12 months of age. We conclude that lack of dystrophin in the mdx mouse results in abnormal ECGs that are associated with decreased myocardial nNOS and increased iNOS activities.

Aging↗

PubMed1999

Creatine uptake in isolated soleus muscle: kinetics and dependence on sodium, but not on insulin.

The increased use of creatine by athletes as a dietary supplement to improve their physical performance assumes that increased serum creatine levels will increase intracellular skeletal muscle creatine. Despite this common assumption, skeletal muscle creatine uptake awaits full characterization. Consequently, we have investigated 14C-labelled creatine uptake in isolated, incubated rat soleus (type I) muscle preparations at 37 degrees C. We found that the apparent Km for creatine uptake was 73 microM and the Vmax was 77 nmol h-1 gww-1. Creatine uptake was 82% inhibited by 2 mM beta-guanidinopropionic acid, the structural analogue of creatine. In addition, a decrease in buffer Na+ concentration, from 145 to 25 mM, reduced the rate of 14C-labelled creatine uptake by 77%, indicating that uptake is largely Na+-dependent in soleus muscle. Insulin had no effect on the rate of creatine uptake in vitro. The total creatine content was 34% lower, but the rate of creatine uptake in the presence of 100 microM extracellular creatine was 45% higher, in soleus than in extensor digitorum longus (type II) muscle. However, at 1 mM extracellular creatine, the maximal rate of uptake was not significantly different for the two muscle types, implying that soleus muscle has a lower Km for creatine uptake. We suggest that intracellular creatine levels may play a role in the regulation of skeletal muscle creatine uptake.

Animals↗

PubMed1999

GTP promotes the formation of early-import intermediates but is not required during the translocation step of protein import into chloroplasts.

Protein import into chloroplasts is an energy-requiring process mediated by a proteinaceous import apparatus. Although previous work has shown that low levels of ATP or GTP can support precursor binding, the role of GTP during the import process remains unclear. Specifically, it is unknown whether GTP plays a separate role from ATP during the early stages of protein import and whether GTP has any role in the later stages of transport. We investigated the role of GTP during the various stages of protein import into chloroplasts by using purified GTP analogs and an in vitro import assay. GTP, GDP, the nonhydrolyzable analog GMP-PNP, and the slowly hydrolyzable analogs guanosine 5'-O-(2-thiodiphosphate) and guanosine 5'-O-(3-thiotriphosphate) were used in this study. Chromatographically purified 5'-guanylyl-imido-diphosphate and guanosine 5'-O-(3-thiotriphosphate) were found to inhibit the formation of early-import intermediates, even in the presence of ATP. We also observed that GTP does not play a role during the translocation of precursors from the intermediate state. We conclude that GTP hydrolysis influences events leading to the formation of early-import intermediates, but not subsequent steps such as precursor translocation.

Adenosine Triphosphate↗

PubMed1999

The pigeon's variability discrimination with lists of successively presented visual stimuli.

Pigeons previously trained to peck 1 button (same) after the successive presentation of 16 identical pictures and to peck a 2nd button (different) after the successive presentation of 16 nonidentical pictures were tested on lists involving different degrees of variability, different list lengths, and different temporal organizations of list items. The pigeons' performances on this successive same-different task revealed a strong sensitivity to list entropy; but, their discrimination was also affected by their memory for list items and by the accumulated evidence for a same versus a different response. Statistical models confirmed and quantified the importance of these additional factors.

Animals↗

PubMed1998

Inactivation of aconitase and oxoglutarate dehydrogenase in skeletal muscle in vitro by superoxide anions and/or nitric oxide.

Strips of rat soleus muscle were incubated in media containing a superoxide generating system and/or the nitric oxide donor sodium nitroprusside (SNP) before the maximal catalytic activities of aconitase, citrate synthase, and oxoglutarate dehydrogenase were measured. The maximal activities of aconitase and oxoglutarate dehydrogenase were both decreased by 25-30% by superoxide anions; however, only the maximal activity of aconitase was decreased, by approximately 50%, by incubation of muscles with SNP. Furthermore, when both superoxide and NO were present in the medium, aconitase activity was decreased by 70%. The maximal activity of citrate synthase was not affected by any of the treatments. This is the first time that superoxide anions or NO has been shown to inactivate aconitase and oxoglutarate dehydrogenase in skeletal muscle. It is suggested that these effects may be responsible for some alterations in skeletal muscle metabolism, and these possibilities are discussed.

Aconitate Hydratase↗

PubMed1998

Fuel oxidation in skeletal muscle is increased by nitric oxide/cGMP--evidence for involvement of cGMP-dependent protein kinase.

The cyclic guanosine-3',5'-monophosphate (cGMP) analogue, 8-bromo-cGMP (1 mM), increased glucose oxidation in isolated soleus muscle. The nitric oxide (NO) donor, sodium nitroprusside (SNP) (15 mM), increased glucose, pyruvate, palmitate and leucine oxidation. Removal of extracellular Ca2+ did not affect SNP-stimulated glucose oxidation (or other glucose utilization parameters), thus eliminating the influx of Ca2+ as a mechanism for the increases. The guanylate cyclase inhibitor, LY-83583 (10 microM), inhibited SNP-stimulated palmitate oxidation and activation of cGMP-dependent protein kinase (PKG). Activation of PKG might supersede any inhibitory effects of NO on respiration to stimulate metabolic fuel oxidation in skeletal muscle.

Aminoquinolines↗

PubMed1998

Evidence for altered sensitivity of the nitric oxide/cGMP signalling cascade in insulin-resistant skeletal muscle.

Nitric oxide activates guanylate cyclase to form cGMP, comprising a signalling system that is believed to be a distinct mechanism for increasing glucose transport and metabolism in skeletal muscle. The effects of a selective cGMP phosphodiesterase inhibitor, zaprinast, on basal glucose utilization was investigated in incubated rat soleus muscle preparations isolated from both insulin-sensitive (lean Zucker; Fa/?) and insulin-resistant (obese Zucker; fa/fa) rats. Zaprinast at 27 microM significantly increased cGMP levels in incubated soleus muscle isolated from lean, but not obese, Zucker rats. Muscles were incubated with 14C-labelled glucose and various concentrations of zaprinast (3, 27 and 243 microM). Zaprinast (at 27 and 243 microM) significantly increased rates of net and 14C-labelled lactate release and of glycogen synthesis in lean Zucker rat soleus muscle; glucose oxidation was also increased by 27 microM zaprinast. In addition, regardless of concentration, the phosphodiesterase inhibitor failed to increase any aspect of 14C-labelled glucose utilization in soleus muscles isolated from obese Zucker rats. The maximal activity of nitric oxide synthase (NOS) was significantly decreased in insulin-resistant obese Zucker muscles. Thus the lack of effect of zaprinast in insulin-resistant skeletal muscle is consistent with decreased NOS activity. To test whether there is a defect in insulin-resistant skeletal muscle for endogenous activation of guanylate cyclase, soleus muscles were isolated from both insulin-sensitive and insulin-resistant Zucker rats and incubated with various concentrations of the NO donor sodium nitroprusside (SNP; 0.1, 1, 5 and 15 mM). SNP significantly increased rates of net and 14C-labelled lactate release, as well as glucose oxidation in muscles isolated from both insulin-sensitive and insulin-resistant rats. A decreased response to SNP was observed in the dose-dependent generation of cGMP within isolated soleus muscles from insulin-resistant rats. A possible link between impaired NO/cGMP signalling and abnormal glucose utilization by skeletal muscle is discussed.

Animals↗

PubMed1998

Prediction of employment outcome one to three years following traumatic brain injury (TBI).

The current study investigated the relationship between age, education (EDUC), pre-injury productivity (PIP), Glasgow Coma Scale score, and a functional rating score at admittance and discharge from rehabilitation (Disability Rating Scale [DRS]) to employment status at one to three years following traumatic brain injury. EDUC, admit DRS, discharge DRS, and PIP all correlated significantly with follow-up employment status, 0.29, -0.32, -0.36, and 0.25 respectively. All possible combinations were then evaluated by Mallow's Cp statistic. The best fitting model was then used in a discriminant function analysis. The discriminant function correctly classified 84% of the employed subjects, 66% of the unemployed, and 75% across both groups. The current results compare favourably with those obtained in previous studies.

Adult↗