Identification of driver genes and biological signaling for alcoholic myopathy

Long-term alcohol consumption contributes to muscle weakness and atrophy. However, the mechanism and biological functions are still not clear. In this study, we aim to identify the significantly changed genes and potential signaling pathways in the gastrocnemius and plantaris muscle from C57BL/6Hsd mice by analyzing RNA sequence. The GSE183665 dataset was created by using the Illumina NovaSeq 6000 (Mus musculus). The KEGG and GO analyses showed that "cell migration", "cell adhesion", and "apoptosis" are major biological processes in the skeletal muscles. Moreover, we identified a number of genes including POSTN, GNAI2, MMP2, ELN, CCND1, CXCL12, COL6A1, COL6A2, SFRP2, and FSTL1 by using the PPI network and Reactome map. Thus, our study may shed light on the development of drugs on alcohol myopathy.

Alcohol-induced damage to skeletal muscles in women with chronic alcohol intoxication

In Russia, there is a high level of alcohol consumption among women in doses that represent a high risk of developing alcoholic diseases, manifested, in particular, by damage to skeletal muscles.The purpose of the study. Analysis of clinical, biochemical, neurophysiological, as well as morphometric and immunohistochemical features of alcoholic skeletal muscle damage in women with chronic alcohol intoxication.Material and methods. A clinical and laboratory examination of 30 women aged 20 to 60 years with chronic alcohol intoxication was performed, which included the determination of creatine phosphokinase (CPK) and insulin-like growth factor I (IGF-I) in blood plasma, stimulation and needle electromyography (EMG), as well as morphological and immunohistochemical examination of biopsies of the quadriceps femoris.Results. Myopathic syndrome in the form of proximal para-or tetraparesis was observed in 73.3% of the examined women in combination with a decrease in IGF-1 at normal values of CPK in blood plasma. The EMG results indicated the absence of changes in the parameters of the potentials of motor units, characteristic of primary muscular lesions, and of conduction disturbances along the femoral nerve. Morphometric and immunohistochemical studies of skeletal muscle biopsies showed a decrease in the cross-sectional area of muscle fibers of types I and II without signs of muscle tissue necrosis.Conclusion. Chronic alcoholic myopathy is a common manifestation of alcoholic disease in women with long-term alcohol intoxication. The severity of the atrophic process in the skeletal muscle is comparable to the degree of proximal paresis. Violations of systemic protein synthesis and acceleration of apoptosis are considered as pathogenetic mechanisms of the atrophic process in the muscles in chronic alcoholic myopathy in women.

Pathophysiological mechanisms of alcoholic myopathy - Lessons from rodent models

Skeletal muscle dysfunction is highly prevalent and is one of the earliest pathological tissue changes among people with at-risk alcohol use. Clinical studies to elucidate pathophysiological mechanisms of alcohol-mediated muscle disease are hampered due to ethical considerations, and confounded by nutritional, lifestyle, and comorbid conditions. Rodent models have been developed to study the impact of at-risk alcohol consumption and alcohol-mediated end organ injury, including skeletal muscle dysfunction. This review discusses results from well-established rodent models of alcohol administration and highlights key pathophysiological mechanisms underlying alcoholic myopathy identified in rodent models. Salient pathways include impaired regenerative capacity, altered anabolic/catabolic balance, impaired mitochondrial bioenergetic function, and skeletal muscle morphological and contractile changes.

The Bibliometric Analysis of the Alcohol-induced Muscle Disease Based on CiteSpace

Myopathy of the skeletal muscles is caused by excessive misuse of ethanol and affects half to two-thirds of pathological alcohol abusers. It is possible to identify alcohol-induced skeletal muscle disruptions as either 'acute or chronic'. Medium to moderate alcohol has positive or defensive effects (such as cardiovascular) on some organ systems, but long-term drinking and acute toxicity can adversely impact multiple organ systems and potentially increase mortality. Therefore we need a detailed understanding of the study status of alcoholic myopathy. References for researching alcoholic myopathy can be given by the review of this article.Search the Web of Science (WOS) central archive for alcoholic myopathy research papers from 2000 to 2020, and use CiteSpace and WOS databases for their own literature statistics techniques to evaluate the number of written articles, research organizations, citations to literature and identification of keywords.A total of 947 publications were collected after screening and the number of articles published grew year by year. The average number of released publications is 47.355. Most documents have been released by a total of 7 countries. Among them, 397 papers were published by the US, ranked first among all nations. Its intermediate centrality is also the largest, suggesting that other countries have more recognition of its scientific findings. The papers published by Emory Univ and Kobe Univ are well regarded in the field, among the top 7 academic institutions with publication volumes. There are 28 core authors and a total of 263 written articles. Highly cited papers are classified into 40 categories, of which 11 are prominently clustered categories. Co-occurrence study of keywords reveals that keywords such as skeletal muscle, oxidative stress, ethanol, alcohol, etc. are very common. The literature on alcoholic myopathy is primarily focused in Western countries, and autophagy, ROS and antioxidants are the latest study hotspots.

Alcohol induces mitochondrial fragmentation and stress responses to maintain normal muscle function in Caenorhabditis elegans

AbstractsChronic excessive ethanol consumption produces distinct toxic and adverse effects on different tissues. In skeletal muscle ethanol causes alcoholic myopathy characterized by myofiber atrophy and loss of muscle strength. Alcoholic myopathy is more prevalent than all inherited muscle diseases combined. Current evidence indicates that ethanol directly impairs muscle organization and function. However, the underlying mechanism by which ethanol causes its toxicity to muscle is poorly understood. Here, we show that the nematode C. elegans recapitulates key aspects of alcoholic myopathy when exposed to ethanol. As in mammals, ethanol exposure impairs muscle strength and organization and induces the expression of protective genes, including oxidative stress response. In addition, ethanol exposure causes a fragmentation of mitochondrial networks aligned with myofibril lattices. This ethanol-induced mitochondrial fragmentation is dependent on mitochondrial fission factor DRP-1 (dynamin-like protein 1), and its receptor proteins on the mitochondrial outer membrane. Our data indicate that this fragmentation contributes to activation of mitochondrial unfolded protein response (UPR). We also found that robust perpetual mitochondrial UPR activation effectively counters muscle weakness caused by ethanol exposure. Our results strongly suggest that modulation of mitochondrial stress responses provides a mechanism to ameliorate alcohol toxicity and damage to muscle.SignificanceChronic alcohol abuse causes the damage and toxicity to peripheral tissues, including muscle. Alcohol perturbs the structure and function of striated skeletal and cardiac muscles. These toxic effects of alcohol on striated muscles negatively impact morbidity and mortality to alcohol misusers. Here, we demonstrate that the nematode C. elegans also exhibits key features of alcoholic myopathy when exposed to ethanol. Ethanol exposure impairs muscle organization and strength, and induces the expression of genes that cope with alcohol toxicity. Particularly, we find that ethanol toxicity is centered on mitochondria, the power plants of the cell. As an adaptive protective response to mitochondrial dysfunction, ethanol-exposed cells induce global transcriptional reprogramming to restore normal mitochondrial function. Upregulation of this transcriptional reprogramming in C. elegans effectively blocks ethanol-induced muscle weakness, a key feature of alcoholic myopathy. Thus, the modulation of mitochondrial stress responses is a potentially promising therapeutic strategy to ameliorate alcohol toxicity to muscle.

Cellular and molecular signatures of alcohol-induced myopathy in women

Alcoholic myopathy is characterized by the reduction in cross-sectional area (CSA) of muscle fibers and impaired anabolic signaling. The goal of the current study was to investigate the causes and compare the changes in CSA and fiber type composition with the modifications of anabolic and catabolic signaling pathways at the early stages of chronic alcohol consumption in women. Skeletal muscle samples from 5 female patients with alcohol abuse (AL; 43 ± 5 yr old; alcohol abuse duration 5,6 ± 0,6 yr) were compared with the muscle from the control group of 8 healthy women (C; 35 ± 4 yr old). The average daily dose of alcohol consumption was 110 ± 10 ml of pure ethanol. In women patients, a significant decrease in CSA of type I and II muscle fibers, titin and nebulin content, plasma IGF-1 level and total IRS-1, p-Akt and p-4E-BP1 in vastus lateralis was found in comparison with the control group. The p-AMPK level was found to be increased versus the control group. In women patients with chronic alcoholic myopathy 1) both fast and slow muscle fibers are subjected to atrophy; 2) impairments in IGF-I-dependent signaling and pathways controlling translation initiation (AMPK/mTOR/4E-BP1), but not translation elongation, are observed; 3) the level of calpain-1 and ubiquitinated proteins increases, unlike E3 ligases content.

Mechanisms Underlying Muscle Protein Imbalance Induced by Alcohol

Both acute intoxication and longer-term cumulative ingestion of alcohol negatively impact the metabolic phenotype of both skeletal and cardiac muscle, independent of overt protein calorie malnutrition, resulting in loss of skeletal muscle strength and cardiac contractility. In large part, these alcohol-induced changes are mediated by a decrease in protein synthesis that in turn is governed by impaired activity of a protein kinase, the mechanistic target of rapamycin (mTOR). Herein, we summarize recent advances in understanding mTOR signal transduction, similarities and differences between the effects of alcohol on this central metabolic controller in skeletal muscle and in the heart, and the effects of acute versus chronic alcohol intake. While alcohol-induced alterations in global proteolysis via activation of the ubiquitin-proteasome pathway are equivocal, emerging data suggest alcohol increases autophagy in muscle. Further studies are necessary to define the relative contributions of these bidirectional changes in protein synthesis and autophagy in the etiology of alcoholic myopathy in skeletal muscle and the heart.