This study was carried out in an attempt to differentiate between the contribution of liver impairment and direct actions of alcohol in myopathy of alcoholic liver disease. Using an animal model of cirrhosis we have previously shown that protein synthetic potential in muscle was not significantly altered. We therefore investigated the possibility that muscle degradation is increased. Cirrhosis was induced by carbon tetrachloride gavage in male rats receiving phenobarbitone in their drinking water. Controls were given phenobarbitone alone. After 135 days the free, latent and total activities of the lysosomal enzymes cathepsin B and cathepsin D in gastrocnemius muscle were unaffected by the induction of experimental cirrhosis when expressed relative to tissue wet weight, protein or DNA. The non-lysosomal enzyme neutral protease was also measured in gastrocnemius muscle from control and cirrhotic rats. There was no difference between the two groups in the free, latent or total activities. Addition of ethanol and acetaldehyde to the assay mixtures in some cases significantly altered the relative activities of the proteases in latent and free compartments of the cirrhotic tissues. In control tissues a different pattern of response emerged. It is concluded that in cirrhosis, at least in the carbon tetrachloride-induced rat model, there is no change of the activity of cathepsin B and D and the neutral protease activity in gastrocnemius. Small but significant effects of ethanol and its metabolite acetaldehyde on latent and free muscle protease activity were demonstrated.

Acetaldehyde↗

PubMed1995

The acute effects of ethanol and acetaldehyde on the synthesis of mixed and contractile proteins of the jejunum.

An investigation was made into the acute effects of ethanol and acetaldehyde with or without enzyme inhibitors of alcohol dehydrogenase (4-methylpyrazole) and aldehyde dehydrogenase (cyanamide) on fractional rates of protein synthesis of mixed and contractile proteins of the jejunum. Ethanol decreased the fractional rates of mixed and contractile protein synthesis (i.e. ks, defined as the percentage of tissue protein renewed each day) by approximately 25%. Pretreatment with 4-methylpyrazole followed by treatment with ethanol further reduced mixed and contractile ks by approximately 30%, when compared with saline plus saline and 4-methylpyrazole plus saline groups. The greatest reductions in ks of mixed and contractile proteins occurred with cyanamide pretreatment followed by ethanol treatment; mixed and contractile protein ks in the cyanamide plus ethanol group decreased by approximately 60% when compared with saline plus saline and cyanamide plus saline groups, whereas ks decreased by approximately 45% when compared with the saline plus ethanol injected group. Acetaldehyde treatment alone caused no significant inhibition of protein synthesis. However, 4-methylpyrazole pretreatment plus acetaldehyde treatment significantly reduced mixed and contractile ks by approximately 20% when compared with the saline group, and by approximately 15% when compared with the 4-methylpyrazole plus saline and saline plus acetaldehyde groups. These data show that ethanol alone and perhaps high levels of acetaldehyde may be responsible for the inhibition of intestinal protein synthesis and related pathological derangements, e.g. motility disturbances due to loss of contractile proteins.

Acetaldehyde↗

PubMed1994

Alcoholic muscle disease: features and mechanisms.

Approximately 50 per cent of all chronic alcohol misusers have alcoholic muscle disease. Chronic alcoholic skeletal muscle myopathy is characterized by a selective atrophy of type II fibres, so that up to 20 per cent of the entire skeletal musculature is lost. The pathogenetic mechanism for the myopathy is currently unknown but a model has been described in which various anatomically-distinct skeletal muscles are employed to reflect type I and II fibres, i.e. the soleus and plantaris, respectively. In chronic studies, rats were fed nutritionally complete liquid diets containing either ethanol or glucose (controls) for up to 6 weeks. In acute studies, rats were given single boluses of ethanol and rates of protein synthesis were examined at 2.5 h. The results show that the myopathy is due to defective skeletal muscle protein synthesis. The information gained from these studies enhances our understanding of skeletal muscle diseases characterized by preferential effects on anaerobic fibres and should be applicable to disease processes in other toxic or metabolic myopathies.

Adult↗

PubMed1994

Ethanol toxicity and cardiac protein synthesis in vivo.

Long- and short-term alcohol consumption induce a variety of cardiovascular changes, including alterations in hemodynamic variables and tissue biochemistry. In many instances some of the perturbations may be considered as compensatory adjustments, and indeed, there is some controversy that moderate long-term consumption may cause alterations in plasma lipid profiles, conferring cardiovascular protection by reducing the incidence of coronary artery disease. In the long term, however, ethanol misuse may induce a specific disease entity, namely alcoholic heart muscle disease, and short-term ethanol exposure may also perturb tissue contractility and hemodynamic indices. The mechanisms of these changes are unknown, but central to many of the metabolic and functional disturbances are alterations in tissue protein synthesis, perhaps precipitated or exacerbated by free radial formation or by the formation of protein-acetaldehyde adducts. Methods for measuring protein synthesis in vivo are reviewed, and their application to elucidating the mechanisms involved in cardiac abnormalities is described, including the effects of ethanol. Our results demonstrate that the effects of alcohol toxicity also occur at the subcellular level, and the synthesis of mitochondrial proteins are reduced in vivo, perhaps even contribution to defects in energy generation, the normal function of which is required to maintain contractility.

Animals↗

PubMed1994