Comparison of rates of protein synthesis in skeletal muscle measured in vivo and in the perfused hemicorpus [proceedings].
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Animals↗
Biomedical subjects
V R Preedy
Publications and source records attributed to V R Preedy.
The acute and chronic effects of ethanol on cardiac muscle protein synthesis in the rat in vivo.
An investigation was made into the acute and chronic effects of ethanol on rates of protein synthesis in the hearts of young rats (80-100 g body weight). Acute ethanol administration (75 mmol/kg body weight, IP) significantly reduced the fractional rate of protein synthesis by 20% after 2.5 hr, compared with saline-treated controls. Chronic ethanol feeding (36% of total calories) for 6 weeks significantly reduced cardiac wet weight by 11%, when compared to rats fed isovolumetric amounts of the same diet in which ethanol was substituted by isocaloric glucose. Neither the concentration nor the content of mixed cardiac proteins relative to body weight were overtly altered by chronic ethanol feeding, although, the total content of mixed cardiac proteins were significantly decreased. RNA concentrations and RNA relative to body weight increased slightly, but total cardiac DNA decreased. Indices for the capacity or potential of the heart to synthesis protein (indicated by the RNA/protein and RNA/DNA ratios) and the "DNA-unit" (protein/DNA ratio) were increased in response to chronic ethanol treatment. The fractional and absolute rates of mixed protein synthesis in the heart were (relatively) unaltered by chronic ethanol treatment, as was RNA efficiency and synthesis relative to DNA. It was concluded that the heart displays contrasting responses to acute and chronic ethanol exposure.
Animals↗
Lysosomal and nonlysosomal protease activities of the brain in response to ethanol feeding.
The contribution of impaired degradative processes to the cellular changes occurring in the brain as a consequence of chronic ethanol exposure was assessed. Male Wistar rats were fed nutritionally adequate liquid diets containing ethanol as 35% of total dietary calories. Controls were pair-fed identical amounts of the same diet in which ethanol was replaced by isocaloric glucose. The results showed that at the end of 3 weeks the activities of neutral protease (nonlysosomal) and cathepsin D (lysosomal) were unaltered. However, there were significant elevations in the activities of the lysosomal enzyme cathepsin B, regardless of whether the activities were expressed relative to wet weight ( p = 0.005), protein (p = 0.006), or DNA (p = 0.045). In addition, we showed that the activities of cathepsin B were not significantly affected by additions of carnosine or acetaldehyde, in vitro. However, neutral protease activities were increased by carnosine additions in vitro. We conclude that selective alterations in brain protease activities may be contributing factors in the genesis of alcoholic brain disorders.
Acetaldehyde↗
Brain nucleic acid composition and fractional rates of protein synthesis in response to chronic ethanol feeding: comparison with skeletal muscle.
Brain atrophy is a common feature of chronic alcohol misuse, although the pathogenic mechanisms are unknown. We propose that defects in protein synthesis are contributing events. To test this hypothesis the experimental effects of chronic (i.e., 2 and 3 weeks) ethanol feeding on brain nucleic acid composition and rates of protein synthesis in vivo were investigated. These were compared with those of skeletal muscle (represented by the plantaris). Male Wistar rats, used at mean body weights of either 82 g (first study for 2 weeks ) or 93 g (second study for 3 weeks) were fed a nutritionally complete liquid diet in which ethanol comprised a third of the total calories. Control rats were pair-fed identical amounts of the same diet, in which ethanol was substituted by isoenergetic glucose. At 2 weeks there were small reductions (i.e., approximately 5-10%) in the weight of the whole brain, cortex, and brain stem. Ethanol-induced reductions in the total protein content of the brain stem was found at 2 weeks, although these changes did not achieve significance. At 3 weeks the weights of whole brain were significantly reduced compared to a greater reduction in skeletal muscle weights. Total protein contents were reduced at 3 weeks in the whole brain and skeletal muscle. At 2 weeks there were decreases in the RNA contents of the cortex, brain stem, and entire brain. There were also reductions in cerebellum RNA composition only when expressed relative to DNA. The DNA composition of the brain was relatively unaffected by chronic ethanol feeding. At 3 weeks, total RNA and DNA were reduced in the whole brain and muscle. Fractional rates of protein synthesis (i.e., the percentage of tissue protein pool renewed each day) in the brain were unaltered after 3 weeks of ethanol feeding, but were reduced in skeletal muscles, largely as a consequence of reduced RNA composition. In conclusion, only moderate changes in the brain were found in ethanol feeding. These data can be compared to skeletal muscle, which shows that ethanol induces profound reductions in protein, RNA, and protein synthesis rates.
Alcoholism↗
Total contractile protein contents and gene expression in skeletal muscle in response to chronic ethanol consumption in the rat.
An investigation was carried out to determine changes in the contents of skeletal muscle myofibrillary proteins (i.e., the contractile fraction composed principally of actin and myosin) and gene expression in skeletal muscle in response to ethanol feeding. Male Wistar rats were fed a nutritionally complete liquid diet, which contained 35% of total calories as ethanol. Controls were pair-fed isocaloric amounts of the same diet, in which ethanol was replaced by isocaloric glucose. Total mixed and contractile protein contents of the gastrocnemius in ethanol-fed rats were rapidly reduced by ethanol feeding: a response was discernible as early as 1 week after the commencement of the ethanol feeding regimen (approx. -10%, p < 0.025 and p = 0.05 for mixed and myofibrillary proteins, respectively). At 2, 4, and 6 weeks, mixed and myofibrillary protein contents were further reduced in alcohol-fed rats, by between 12% and 22%, compared to pair-fed controls. Similar changes occurred in the soluble (i.e., sarcoplasmic) protein fractions of skeletal muscle. At 2 weeks the composition of total messenger RNA and individual messenger RNA species was measured. Total messenger RNA content per muscle was reduced by 35% (p < 0.05). Messenger RNA levels for alpha-actin, beta-myosin heavy chain, and carbonic anhydrase III were not significantly altered. In conclusion, skeletal muscle protein contents are rapidly reduced by ethanol feeding, compared to pair-fed controls, though mRNA species encoding specific isoforms of myosin and actin are not affected. It is possible that chronic ethanol feeding may significantly alter the stability of mRNAs encoding other contractile proteins, or alternatively, defects in translation may predominate.
Actins↗
Protein metabolism in alcoholism: effects on specific tissues and the whole body.
Ethanol is one of the few nutrients that is profoundly toxic. Alcohol causes both whole-body and tissue-specific changes in protein metabolism. Chronic ethanol missuse increases nitrogen excretion with concomitant loss of lean tissue mass. Even acute doses of alcohol elicit increased nitrogen excretion. The loss of skeletal muscle protein (i.e., chronic alcoholic myopathy) is one of several adverse reactions to alcohol and occurs in up to two-thirds of all ethanol misusers. There are a variety of other diseases and tissue abnormalities that are entirely due to ethanol-induced changes in the amounts of individual proteins or groups of tissue proteins; for example, increased hepatic collagen in cirrhosis, reduction in myosin in cardiomyopathy, and loss of skeletal collagen in osteoporosis. Ethanol induces changes in protein metabolism in probably all organ or tissue systems. Clinical studies in alcoholic patients without overt liver disease show reduced rates of skeletal muscle protein synthesis though whole-body protein turnover does not appear to be significantly affected. Protein turnover studies in alcohol misusers are, however, subject to artifactual misinterpretations due to non-abstinence, dual substance misuse (e.g., cocaine or tobacco), specific nutritional deficiencies, or the presence of overt organ dysfunction. As a consequence, the most reliable data examining the effects of alcohol on protein metabolism is derived from animal studies, where nutritional elements of the dosing regimen can be strictly controlled. These studies indicate that, both chronically and acutely, alcohol causes reductions in skeletal muscle protein synthesis, as well as of skin, bone, and the small intestine. Chronically, animal studies also show increased urinary nitrogen excretion and loss of skeletal muscle protein. With respect to skeletal muscle, the reductions in protein synthesis do not appear to be due to the generation of reactive oxygen species, are not prevented with nitric oxide synthase inhibitors, and may be indirectly mediated by the reactive metabolite acetaldehyde. Changes in skeletal muscle protein metabolism have profound implications for whole body physiology, while protein turnover changes in organs such as the heart (exemplified by complex alterations in protein profiles) have important implications for cardiovascular function and morbidity.
Alcoholism↗
Acute dosage with dexrazoxane, but not doxorubicin, is associated with increased rates of hepatic protein synthesis in vivo.
An investigation was carried out into the effects of dexrazoxane and doxorubicin on hepatic protein synthesis in vivo. The protocol included 8 groups of rats and involved a pretreatment stage of 30 min followed by a treatment stage of either 2.5 or 24 h. Male Wistar rats (=0.15-0.20 kg) were pretreated with either dexrazoxane (100 mg/kg; 5 ml/kg) or saline (0.15 mol/l NaCl; 5 ml/kg). At 30 min after the pretreatment, rats were again injected with either doxorubicin (5 mg/kg; 10 ml/kg) or saline (0.15 mol/l NaCl; 10 ml/kg) in the treatment phase. Rats were sacrificed at either 2.5 or 24 h after the last doxorubicin or saline injection. Rate of protein synthesis were measured 10 min prior to sacrificing rats, with a flooding dose of L-[4-3H]phenylalanine. Liver was analyzed for the protein synthetic capacity (Cs, mg RNA/g protein), the fractional rate of protein synthesis (k(s), %/d), and the RNA activity (kRNA mg protein/d/mg RNA). Complementary analysis included plasma albumin, total protein and activities of alkaline phosphatase, and aspartate aminotransferase. In the 2.5-h study, doxorubicin alone had no effect on any of the above variables. Dexrazoxane alone increased Cs, k(s) and kRNA at 2.5 h. Combined dexrazoxane + doxorubicin increased hepatic Cs and k(s) with concomitant reductions in total plasma protein. In the 24-h study, doxorubicin alone had no effect on any of the variables. Dexrazoxane alone had no effect on either Cs, k(s), or kRNA but raised plasma activities of alkaline phosphatase and aspartate aminotransferase. Combined dexrazoxane + doxorubicin increased Cs and k(s) and decreased total plasma protein and increased plasma aspartate aminotransferase activities at 24 h. In conclusion, there is no evidence that acutely doxorubicin per se has measurable effects on hepatic protein synthesis in vivo in an acute period. However, acutely dexrazoxane increases hepatic protein synthesis, which may represent its putative cytotoxic effects, as indicated by raised serum activities of liver enzymes. A combination of both dexrazoxane + doxorubicin appears to have a greater effect in increasing liver protein synthesis than dexrazoxane alone.
Alkaline Phosphatase↗
Response of muscle protein synthesis to parenteral administration of amino acid mixtures in growing rats.
Previous studies have shown that 1-hour infusions of neither glucose nor an amino acid mixture alone stimulates muscle protein synthesis in postabsorptive rats (Biosci Rep 1986;6:177-183). We have therefore investigated whether longer periods of infusion are required to initiate responses. The effects of intravenous infusions of various substrates for 6 hours on rates of skeletal muscle protein synthesis in fasted rats were studied. Fractional rates of protein synthesis (ks, the percent of muscle protein renewed each day) and the ribonucleic acid activity (kRNA, the amount of protein synthesis per unit of ribonucleic acid [milligrams of protein per day per milligram of ribonucleic acid]) were measured with a flooding dose of L-[4-3H]phenylalanine. Infusion of mixed amino acids (15 mg of nitrogen per hour per rat) increased ks and kRNA by approximately 50% in comparison with saline-infused rats, but rates of muscle protein synthesis remained below those observed in fed animals. Doubling the infusion rate of amino acids to 30 mg of nitrogen per hour per rat had no additional effect on ks and kRNA, and addition of glucose (0.3 g/h per rat) or glucose plus lipid also had no significant additive effect. However, infusion of glucose alone (0.3 g/h per rat) increased ks and kRNA by 25% when compared with saline-infused controls. Infusion of the branched-chain amino acids in the same amounts as present in the amino acid mixture increased ks and kRNA by 20% compared with saline-infused controls, but the rate remained significantly lower than that obtained by infusion of mixed amino acids.
Amino Acids↗
Prevalence of malnutrition in alcoholic and nonalcoholic medical inpatients: a comparative anthropometric study.
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Alcoholism↗
Ventricular muscle and lung protein synthesis in vivo in response to fasting, refeeding, and nutrient supply by oral and parenteral routes.
BACKGROUND: Fasting and other catabolic states are characterized by reductions in the rate of protein synthesis. Most studies have investigated tissues such as skeletal muscle or liver, but impairments in the biochemistry of cardiovascular tissues also contribute to enhanced morbidity. The objectives of the present study were (1) to determine the response of protein synthesis in the heart and lung of young rats to overnight fasting; and (2) to determine whether protein synthesis could be ameliorated or modulated by refeeding or provision of enteral or parenteral nutrition. METHODS: Fractional rates of protein synthesis (ie, the percentage of tissue protein renewed each day, ks) were measured in vivo in the ventricular muscle and lungs of young male Wistar rats (body weight, 100 to 130 g) with a "flooding" dose of L-[4(3)H]phenylalanine. Rats were fed ad libitum or fasted overnight. Fasted rats were subjected to various treatments. RESULTS: When nutrient supply in fasted rats recommenced by refeeding for 1 hour, there were small but significant increases in the rates of ventricular protein synthesis, although the infusion of amino acids and glucose for 1 hour had no significant effect. Increases in ventricular ks were also obtained when amino acids were infused for 6 hours. Infusion of glucose alone for 6 hours did not cause a significant increase in ventricular ks. The effect of infusing a mixture of glucose plus amino acids for 6 hours was similar to the effects of amino acids alone. In all instances, ventricular ks in rats infused with amino acid for 6 hours did not attain rates observed in fed rats. ks was reduced in the lung after overnight fasting but was unresponsive to refeeding or to acute or chronic provision of amino acids and glucose by either IV or oral routes. Measurements also suggested that changes in neither insulin nor glucagon per se were responsible for the amino acid-induced increases in heart protein synthesis. However, acute treatment of rats with anti-insulin serum reduced rates of ventricular ks below values observed in fed rats. Anti-insulin serum also increased lung ks. CONCLUSIONS: It was concluded that rates of heart protein synthesis could be increased by the chronic provision (ie, 6 hours) of nutrients by oral or IV routes. In contrast, the lung was insensitive to these treatments. The observations have important implications for clinical situations, which are characterized by diminished cardiopulmonary protein synthesis.
Administration, Oral↗