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ABSTRACT: Alcoholic myopathy is a common pathology characterized by wasting due to reduced protein synthesis, although the mechanisms involved remain unclear. Women are particularly sensitive and malnutrition exacerbates the myopathy. This study aimed to address (i) whether long-term alcohol feeding alters expression of heat shock proteins (HSPs) in male and female rats; (ii) the effect of immediate alcohol dosing with or without raised levels of endogenous acetaldehyde; and (iii) the effect of starvation. To address this, (i) male and female rats were fed alcohol in the long-term (6-7 weeks as 35% of energy in a liquid diet) and compared to controls fed the same diet with isoenergetic glucose; (ii) male rats given an immediate bolus (75 mmol ethanol per kilogram body weight intraperitoneally) 2.5 hours before sacrifice and compared to controls given a dose of saline (with or without pretreatment with cyanamide-an acetaldehyde dehydrogenase inhibitor which raises endogenous acetaldehyde); (iii) male rats starved for 1 or 2 days then immediately dosed with alcohol. Protein levels of HSP 27, HSP 60, and HSP 70 were measured in muscles of male rats fed alcohol and pair-fed control rats by SDS-PAGE and Western blotting in study I. Levels of HSP 27, HSP 60, HSP 70, and HSP 90 mRNA were analyzed in hind limb skeletal muscle by reverse transcription-polymerase chain reaction with an endogenous internal standard, glyceraldehyde-3-phosphate-dehydrogenase. (i) Long-term alcohol dosage reduced HSP 27 in male rats but not in females, whereas HSP 90 mRNA increased in long-term alcohol-fed female rats but not in male rats. These changes were reflected by a similar trend in HSP protein content, although statistical significance was not achieved. (ii) There was no effect on any of the HSP mRNAs in rats dosed immediately with alcohol or in combination with cyanamide. (iii) Starvation per se for 2 days was associated with an increase in HSP 27 mRNA. Alcohol administration after 2 days starvation caused a blunting of the increased HSP 27 mRNA in starvation alone. This suggests that long-term alcohol exposure affects HSP gene expression and that this effect is moderated by sex and starvation. This may contribute to, or reflect, the biochemical lesion in alcoholic myopathy.
Metabolism 08/2006; 55(7):843-51. · 2.66 Impact Factor
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ABSTRACT: Alcohol dependency is a complex multi-factorial clinical presentation characterized by etiological ambiguity, poor treatment adherence and unfavorable prognosis. Recent evidence suggest considerable heterogeneity in this patient group across a number of neurological, genetic, psychological and personality parameters which relate directly to the clinical manifestation and course of this chronic condition. The current review examines contemporary cross-disciplinary research reports to present an integrated psychobiological synthesis of the main themes. The psychobiological model proposed offers a template for both clinicians and researchers to evaluate the relative contribution of key indicators to the end-point gestalt of alcohol dependency. Analysis and integration of psychobiological risk factors are illuminated within the context of sub-type identification, tailored treatment interventions and clinical outcome prediction. Implications for current psychiatric practice and the direction of future research are discussed.
Current Psychiatry Reviews 10/2005; 1(3):303-312.
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ABSTRACT: Skeletal muscle atrophy is a common feature in alcoholism that affects up to two-thirds of alcohol misusers, and women appear to be particularly susceptible. There is also some evidence to suggest that malnutrition exacerbates the effects of alcohol on muscle. However, the mechanisms responsible for the myopathy remain elusive, and some studies suggest that acetaldehyde, rather than alcohol, is the principal pathogenic perturbant. Previous reports on rats dosed acutely with ethanol (<24 h) have suggested that increased proto-oncogene expression (i.e., c-myc) may be a causative process, possibly via activating preapoptotic or transcriptional pathways. We hypothesized that 1) increases in c-myc mRNA levels also occur in muscle exposed chronically to alcohol, 2) muscle of female rats is more sensitive than that from male rats, 3) raising acetaldehyde will also increase c-myc, 4) prior starvation will cause further increases in c-myc mRNA expression in response to ethanol, and 5) other genes involved in apoptosis (i.e., p53 and Bcl-2) would also be affected by alcohol. To test this, we measured c-myc mRNA levels in skeletal muscle of rats dosed either chronically (6-7 wk; ethanol as 35% of total dietary energy) or acutely (2.5 h; ethanol as 75 mmol/kg body wt ip) with ethanol. All experiments were carried out in male Wistar rats (approximately 0.1-0.15 kg body wt) except the study that examined gender susceptibility in male and female rats. At the end of the studies, rats were killed, and c-myc, p53, and Bcl-2 mRNA was analyzed in skeletal muscle by RT-PCR with an endogenous internal standard, GAPDH. The results showed that 1) in male rats fed ethanol chronically, there were no increases in c-myc mRNA; 2) increases, however, occurred in c-myc mRNA in muscle from female rats fed ethanol chronically; 3) raising endogenous acetaldehyde with cyanamide increased c-myc mRNA in acute studies; 4) starvation per se increased c-myc mRNA levels and at 1 day potentiated the acute effects of ethanol, indicative of a sensitization response; 5) the only effect seen with p53 mRNA levels was a decrease in muscle of rats starved for 1 day compared with fed rats, and there was no statistically significant effect on Bcl-2 mRNA in any of the experimental conditions. The increases in c-myc may well represent a preapoptotic effect, or even a nonspecific cellular stress response to alcohol and/or acetaldehyde. These data are important in our understanding of a common muscle pathology induced by alcohol.
AJP Endocrinology and Metabolism 12/2003; 285(6):E1273-81. · 4.75 Impact Factor
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ABSTRACT: Excessive ingestion of the macronutrient, alcohol, causes devastating complications in the brain leading to atrophy and impaired cognitive function with corresponding increases in morbidity and mortality and, consequently, reduced quality of life measures. The pathogenic mechanisms are unknown, but various studies have shown that the immediate early genes and heat shock (ie, stress or chaperone) proteins are increased in alcohol-exposed tissue. However, many of these studies have been performed in vitro or have failed to consider either the nutritional elements in the experimental design by appropriate use of pair-feeding or whether there are regional and/or gender differences. We hypothesized that (1) increased expression of heat shock proteins and/or oncogenes occur as a consequence of alcohol-feeding in vivo, and sensitivities are related to different (2) gender and (3) brain regions. To test this, we fed male and female rats nutritionally complete diets containing ethanol as 35% of total calories (treated) or isocaloric amounts of the same diet in which ethanol was replaced by isocaloric glucose (controls). At the end of 6 weeks, rats were killed and c-Fos and heat shock protein-70 (HSP70) mRNA analyzed in midbrain, cortex, brainstem, and cerebellum by reverse transcription-polymerase chain reaction (RT-PCR) with an endogenous internal standard, beta-actin. The results showed that there were distinct regional differences (P at least <.05) in both c-Fos (cerebellum > cortex > midbrain and brainstem) and HSP70 (brainstem and cerebellum > cortex and midbrain). However, the only significant effect of alcohol feeding occurred in the HSP70 mRNA in midbrain of male rats, which was reduced by approximately 50% (P <.01). In contrast, no corresponding effect of alcohol feeding was observed in c-Fos mRNA levels in either midbrain or other regions of female rats. These data show that chronic ethanol feeding has no demonstrable effect on c-Fos mRNA expression in the brain when using nutritionally complete liquid diet regimens with concomitant pair-feeding. HSP70 mRNA, in contrast, is reduced by alcohol feeding and appears to be regional and gender dependent.
Metabolism 01/2003; 51(12):1562-8. · 2.66 Impact Factor
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ABSTRACT: A pilot study was conducted to investigate the hypothesis that dietary tryptophan manipulation would influence self-report affective status in alcoholic males. No significant effect of dietary manipulation was observed on the tryptophan/large neutral amino acids ratio or psychological indices of affect. The notion that dietary manipulation may be utilized in improving mood state in alcoholic males was not supported.
