Alcoholic Muscle Disease Research Articles

Drinking Off(s) the Clock: Chronic Alcohol Suppresses Skeletal Muscle Molecular Clock

Circadian rhythms generated both centrally in the suprachiasmatic nucleus (SCN) and peripherally at the tissue level assist in the maintenance of physiological homeostasis, while circadian disruption is a characteristic of several diseases. The intrinsic skeletal muscle core clock has emerged as a key feature of metabolic control and influences several aspects of muscle physiology including contractile strength and mitochondrial content. Alcoholic muscle disease or myopathy is characterized by skeletal muscle weakness and myofiber atrophy resulting from the prolonged consumption of alcohol. Despite alcoholic myopathy being more prevalent than alcoholic liver disease, the entirety of mechanisms leading to its onset remains unknown. Alcohol disrupts normal cyclic expression of several core clock genes within the brain and liver, and we previously reported that acute alcohol intoxication disrupts the skeletal muscle core clock. Thus, the goal of this work was to determine whether the chronic consumption of alcohol dysregulates the skeletal muscle core molecular clock and clock-controlled genes (CCGs) in concert with alcoholic myopathy. Methods: C57BL/6Hsd female mice (12wks old) were pair fed a control liquid diet (CON) or an isocaloric ethanol (EtOH) containing liquid diet of increasing concentration (up to 32% kcal EtOH) for 7 weeks. Gastrocnemius muscles were collected from CON (n=4) and EtOH (n=3-4) mice every 4-hours for 24-hours. RNA was isolated, cDNA synthesized, and RT-PCR was performed. Results: Body weight and fat mass between groups was similar at sacrifice while liver mass was increased by alcohol. Lean mass assessed by MRI tended to be decreased by alcohol (p=0.06). Chronic alcohol consumption disrupted genes of the core clock including suppressing the rhythmic peak in expression of brain muscle ARNT like-1 (Bmal1), period (Per) 1 and 2, and cryptochrome 2 (Cry2). Genes involved in the regulation of Bmal1 also exhibited lower rhythmic peaks including Rev-erb (NR1D1) and myoblast determination protein 1 (MyoD), with significant reductions apparent at several of the 4-hour time points. The CCG D-box binding PAR BZIP transcription factor (DBP) was also suppressed at the end of the light phase and beginning of the dark active phase (ZT8 and ZT12). Skeletal muscle atrophy related genes forkhead box O1 (Foxo1), regulated in development and DNA damage response 1 (Redd1) and muscle RING-finger protein 1 (Murf1) were also altered by alcohol at the start of the dark (active) cycle. These data contrasted our previously described acute model in which subtle rhythmic shifts and large changes in the expression of several genes were observed specifically when blood alcohol levels (~4-12hr) were elevated. Therefore, there is a differential response of the skeletal muscle to acute and chronic alcohol consumption with prolonged intake leading to a lower amplitude of change over the 24-hour cycle of several core clock related genes. Future work will focus on determining the contribution of these disruptions to metabolic and functional perturbations characteristic of chronic alcoholic myopathy and the impact of these disruptions on the development of alcoholic myopathy.

The importance of alcohol-induced muscle disease.

Alcohol-induced muscle disease (AIMD) is a composite term to describe any muscle pathology (molecular, biochemical, structural or physiological) resulting from either acute or chronic alcohol ingestion or a combination thereof. The chronic form of AIMD is arguably the most prevalent skeletal muscle disorder in the Western Hemisphere affecting more than 2000 subjects per 100,000 population and is thus much more common than hereditary disorders such as Becker or Duchenne muscular dystrophy. Paradoxically, most texts on skeletal myopathies or scientific meetings covering muscle disease have generally ignored chronic alcoholic myopathy. The chronic form of AIMDs affects 40-60% of alcoholics and is more common than other alcohol-induced diseases, for example, cirrhosis (15-20% of chronic alcoholics), peripheral neuropathy (15-20%), intestinal disease (30-50%) or cardiomyopathy (15-35%). In this article, we summarise the pathological features of alcoholic muscle disease, particularly biochemical changes related to protein metabolism and some of the putative underlying mechanisms. However, the intervening steps between the exposure of muscle to ethanol and the initiation of the cascade of responses leading to muscle weakness and loss of muscle bulk remain essentially unknown. We argue that alcoholic myopathy represents: (a) a model system in which both the causal agent and the target organ is known; (b) a myopathy involving free-radical mediated pathology to the whole body which may also target skeletal muscle and (c) a reversible myopathy, unlike many hereditary muscle diseases. A clearer understanding of the mechanisms responsible for alcoholic myopathy is important since some of the underlying pathways may be common to other myopathies.

In Vivo Rates of Skeletal Muscle Protein Synthesis in Rats Are Decreased by Acute Ethanol Treatment but Are Not Ameliorated by Supplemental α-Tocopherol

Some studies have shown that reductions in tissue protein synthesis, under a variety of cytotoxic conditions, are ameliorated by alpha-tocopherol (ATC) supplementation. We have also shown evidence of increased oxidative stress and reduced protein synthesis rates in alcohol-exposed muscle. Serum levels of ATC fall and rates of muscle protein synthesis are reduced in patients with alcoholic myopathy. We therefore tested the hypothesis that treatment with ATC could ameliorate the ethanol-induced changes in muscle protein synthesis, a contributory event in the pathogenesis of alcoholic muscle disease. Studies were carried out on gastrocnemius (Type II fiber-predominant and usually considered representative of the musculature as a whole), soleus (Type I fiber-predominant) and plantaris (Type II fiber-predominant) muscles. For comparative purposes, we also investigated the liver. Young male Wistar rats (90 g body weight) were injected intraperitoneally (i.p.) daily with ATC (30 mg/kg body weight) in Intralipid fat emulsion (0.1 mL/100 g body, i.p.) for 5 d. Controls were similarly injected with the Intralipid vehicle alone. After ATC supplementation, rats were given ethanol (75 mmol/kg body weight, i.p., 2.5 h) or saline (0.15 mol/L NaCl, i. p.). Fractional rates of tissue protein synthesis (i.e., the percentage of the tissue protein pool renewed each day, k(s), %/d) and RNA activities [i.e., the amount of protein synthesis each day per unit RNA, k(RNA), mg protein/d/mg RNA)] were then measured. Supplementation increased ATC concentrations in plasma, gastrocnemius and liver. There was no effect of ATC supplementation alone on k(s) in any of the tissues. ATC supplementation in the absence of alcohol increased k(RNA) in the plantaris muscle. In nonsupplemented groups, acute ethanol treatment reduced skeletal muscle (soleus, plantaris and gastrocnemius) k(s). Hepatic k(s) was not altered by ethanol, although ATC concentrations in this tissue increased due to ethanol. However, none of the changes in muscle k(s) or k(RNA) due to ethanol were significantly affected by ATC supplementation. In conclusion, ATC supplementation does not appear beneficial in ameliorating acute alcohol toxicity in skeletal muscle as defined by reductions in protein synthesis.

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.

ALCOHOLIC MUSCLE DISEASE

Histopathological abnormalities of muscle are common in chronic alcoholics and can be classified into the rare acute myopathy, with myonecrosis, and the much more common chronic myopathy, with a selective atrophy of type II muscle fibres (particularly IIb fibres). The patients may often be asymptomatic and, except for florid cases of acute rhabdomyolysis, clinical features do not help to distinguish the two. Serum creatine kinase activity is an insensitive guide to the presence of the muscle abnormalities. These abnormalities cannot be adequately explained by co-existing alcoholic liver disease, malnutrition or peripheral neuropathy, and probably represent the result of direct toxicity to the muscle fibres. Acute myopathy may occur as a result of damage to cell membranes although intracellular phosphate deficiency has also been proposed as a crucial factor. Atrophy of type II fibres occurs in other metabolic myopathies and its development in chronic alcoholism could represent the result of metabolic or endocrinological derangement induced by ethanol. Alternatively, direct toxicity to muscle cell pathways of carbohydrate catabolism or fatty acid oxidation may occur. Previous suggestions of enhanced muscle breakdown in chronic alcoholics is contested by recent work and reduced protein synthesis may be of more pathogenic importance. Abstention from alcohol reverses the muscle abnormalities.

Alcoholic muscle disease.

Alcoholic muscle disease.

The Effect of Ethyl Alcohol on Striated Muscle: Some Clinical and Pathological Observations

Electrophysiological and pathological studies have been performed on three patients with recurrent focal swelling of the calf muscles simulating deep venous thrombosis, and in a patient with both cardiomyopathy and skeletal muscle disease. In all patients there were elevated CPK levels, histological evidence of an acute myopathy, heavy alcohol intake prior to the development of symptoms, and improvement in hospital with the cessation of alcohol consumption. These patients illustrate a form of alcoholic muscle disease which may be more common than generally realised.

MUSCLE AND LIVER SERUM ENZYME ACTIVITIES IN HEALTHY VOLUNTEERS GIVEN ALCOHOL ON A DIET POOR IN CARBOHYDRATES

AbstractIn order to elucidate the importance of a short‐age of carbohydrates in the food for the occurrence of alcoholic muscle disease, muscle and liver enzymes (LDH isoenzymes, GOT, GPT and CPK) have been assayed in the serum of six healthy volunteers after alcohol ingestion on a diet poor in carbohydrates (group I). Twelve healthy subjects fed the carbohydrate‐poor diet without alcohol addition (group II) and six other subjects given alcohol when on the average Swedish diet (group III) served as controls. In the group given alcohol in addition to the carbohydrate‐poor diet an increase of LDH‐1 and LDH‐2 was observed. No other noticeable enzyme increases were registered. It is concluded that a lack of carbohydrate may be a factor involved in the pathogenesis of alcoholic myopathy.