Date Published: , 2017
Publisher: National Institute on Alcohol Abuse and Alcoholism
Author(s): Liz Simon, Sarah E. Jolley, Patricia E. Molina.
Skeletal muscle dysfunction (i.e., myopathy) is common in patients with alcohol use disorder. However, few clinical studies have elucidated the significance, mechanisms, and therapeutic options of alcohol-related myopathy. Preclinical studies indicate that alcohol adversely affects both anabolic and catabolic pathways of muscle-mass maintenance and that an increased proinflammatory and oxidative milieu in the skeletal muscle is the primary contributing factor leading to alcohol-related skeletal muscle dysfunction. Decreased regenerative capacity of muscle progenitor cells is emerging as an additional mechanism that contributes to alcohol-induced loss in muscle mass and impairment in muscle growth. This review details the epidemiology of alcoholic myopathy, potential contributing pathophysiologic mechanisms, and emerging literature on novel therapeutic options.
Alcoholic myopathy is common among people with AUD and may manifest as an acute or chronic condition. Acute alcoholic myopathy is present in 0.5 to 2.0 percent of alcoholics, with an estimated overall prevalence of 20 cases per 100,000 people in the Western Hemisphere (Preedy et al. 2003). Chronic alcoholic myopathy is one of the most common types of myopathy, with an overall prevalence of 2,000 cases per 100,000 people. Based on these prevalence estimates, chronic alcohol-related myopathy is 10 times more common than the most common inherited myopathy (i.e., nemaline myopathy), which has a prevalence of 200 cases per 100,000 individuals, and 67 to 1,000 times more common than Duchenne’s muscular dystrophy with an estimated prevalence of 2 to 30 per 100,000 people (Preedy et al. 2003). However, it is difficult to ascertain the exact prevalence, because the spectrum of clinical disease in alcohol-related myopathy varies (Estruch et al. 1993). In a study of alcoholics without a known diagnosis of myopathy, up to 46 percent exhibited myopathic changes on muscle biopsies and presented with demonstrable reductions in strength compared with healthy control subjects (Urbano-Marquez et al. 1995). The role of this subclinical disease in the development of future clinically evident symptoms remains poorly understood.
Clinically, acute alcoholic myopathy is characterized by weakness, pain, tenderness, and swelling of affected muscles. It often occurs after an alcohol binge characterized by consumption of 4 to 5 alcoholic drinks during a single episode, resulting in blood alcohol levels of 0.08 g/dL or above, and resolves within 1 to 2 weeks of abstinence from alcohol (Perkoff 1971). A common manifestation of acute alcoholic myopathy is a breakdown of muscle tissue and release of muscle-fiber content into the blood (i.e., rhabdomyolysis). It most severely affects muscles close to the body’s midline (i.e., proximal muscles), primarily the pelvic and shoulder girdles, in a focal and asymmetric fashion. Clinical evidence of this type of myopathy may be associated with laboratory evidence of muscle injury, accompanied by elevations in the enzyme creatinine kinase and the protein myoglobin that is found in heart and skeletal muscle. This so-called rhabdomyolytic variant of acute alcoholic myopathy, which in severe cases may precipitate acute renal failure, represents the most common nontraumatic cause of rhabdomyolysis in hospitalized patients (Urbano-Marquez and Fernández-Solà 2004).
Alcohol exposure seems to influence a variety of processes in the cells that may contribute to the altered protein synthesis and degradation levels described above. These include inflammatory reactions, oxidative stress, mitochondrial dysfunction, impaired muscle regeneration, as well as epigenetic and microRNA (miRNA)-related mechanisms (see figure 2).
In vivo and in vitro exposure to alcohol can modify gene expression through epigenetic mechanisms in several tissues, including the liver, brain, and immune system (Shukla and Lim 2013; Zakhari 2013). Emerging evidence also suggests that epigenetic modulation may mediate fetal alcohol spectrum disorders (Zakhari 2013). Epigenetic modulation involves chemical modifications of the DNA, such as methylation; histone modifications, such as methylation, acetylation and deacetylation, phosphorylation, addition of ubiquitin molecules (i.e., ubiquitinylation), addition of adenosine-diphosphate ribose (i.e., ADP-ribosylation), and addition of small ubiquitin-like molecules (i.e., sumoylation); as well as the actions of noncoding microRNAs (miRNAs). Unlike genetic alterations (i.e., mutations) or defects, epigenetic alterations do not alter the DNA sequence itself and can be reversed by therapy. Thus, elucidating alcohol-induced epigenetic changes opens new avenues for therapy of alcohol abuse and the resulting organ damage, such as the use of compounds that prevent histone deacetylation (i.e., histone deacetylase inhibitors), miRNA modulation, and similar approaches.
Human studies have demonstrated significant reductions in muscle mass associated with chronic alcohol consumption. Computerized tomography imaging of a region of the lower back (i.e., the L4 vertebrae) in a small cohort of chronic alcoholic subjects demonstrated a significantly reduced muscle area compared with healthy control subjects (Thapaliya et al. 2014). Similar results were found by Kvist and colleagues (1993) who noted significantly reduced femoral and gluteal muscle areas in chronic alcoholics, even though total lean body mass as determined from total potassium content did not differ significantly.
Currently, the only known effective treatment for alcoholic myopathy is complete abstinence from alcohol (see figure 3). Fortunately, up to 85 percent of patients with biopsy-proven alcoholic myopathy demonstrate objective functional improvement in muscle strength within the first year of alcohol-drinking cessation and complete normalization of strength by the fifth year of abstinence (Estruch et al. 1998; Fernández-Solà et al. 2000). Even for patients unable to completely abstain from alcohol, reduced cumulative alcohol consumption results in improvements in muscle strength over time (Estruch et al. 1998; Fernández-Solà et al. 2000). Acute alcoholic myopathy usually reverses within days or weeks of abstinence, whereas chronic myopathic changes usually resolve within 2 to 12 months (Peters et al. 1985). Moreover, nutritional optimization, including correction of vitamin and electrolyte deficiencies, is associated with greater improvement of muscle health (Urbano-Marquez and Fernández-Solà 2004).
Alcohol-related muscle disease is the most common clinical manifestation of AUD. Despite the high prevalence of disease, alcohol-related myopathy frequently is unrecognized. Most importantly, myopathy significantly contributes to long-term impairments in physical function and diminishes health-related quality of life for people with AUD. Therefore, research on the mechanisms underlying alcoholic myopathy and potential therapeutic approaches to ameliorate the disease, particularly in individuals with comorbid conditions, is extremely relevant. Researchers increasingly are recognizing the molecular pathways contributing to alcohol-induced muscle wasting, including reductions in mTOR-mediated protein synthesis and excessive protein degradation by activation of the UPP and autophagic–lysosomal system. In the settings of acute inflammation, oxidative stress, and/or mitochondrial dysfunction, exacerbation of these pathways is associated with accelerated muscle wasting. Clinical manifestations of muscle wasting include impairments in muscle dynamics (i.e., strength, power, and force) and loss of mechanical unloading, which also promote alcohol-related bone loss. Identification of these key pathways offers novel targets for therapeutics aimed at reducing the burden of alcohol-related muscle disease. Further studies are needed to understand the role of exercise and drug interventions, such as growth hormone regulators, myostatin antagonists, and androgen modulation, on alcohol-related muscle wasting.