Alcoholic Myopathy: Pathophysiologic Mechanisms and Clinical Implications

Abstract

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.

Figure 1

Principal effects of chronic alcohol abuse on anabolic and catabolic mechanisms that maintain skeletal muscle mass. Protein synthesis and breakdown are regulated by multiple factors, including anabolic hormones, nutrients, and myokines. Alcohol, depicted here by its chemical formulation, influences multiple aspects of both the anabolic and catabolic arms of the pathway. Numerous regulatory components of these pathways are altered by chronic alcohol exposure (see boxes). NOTE: 4EBP1 = eukaryotic initiation factor 4E binding protein; FOXO1 = Forkhead box protein O1; IGF-1 = insulin-like growth factor; IL-1 = interleukin 1; IL-6 = interleukin 6; IRS-1 = insulin receptor substrate 1; JNK = c-Jun N-terminal kinase; mTOR = mammalian target of rapamycin; MuRF1 = muscle RING-finger protein-1; P-I-3K = phosphatidylinositide 3-kinase; PTP1B = protein tyrosine phosphatase 1B; S6K1 = S6 kinase 1; TNF-α = tumor necrosis factor alpha; UPS = ubiquitin proteasome system.

Figure 2

Mechanisms contributing to alcohol-induced loss of muscle mass and impairment in muscle growth. Decreased skeletal-muscle regenerative capacity is reflected as decreased myogenic gene expression, which prevents satellite-cell differentiation and myotube fusion and myofiber maturation. Chronic heavy alcohol consumption leads to skeletal-muscle inflammation, which favors expression of profibrotic factors such as transforming growth factor β(TGF-β), stimulating an increase in the expression and activation (phosphorylation) of transcription factors such as Smad (P-Smad). This in turn results in altered gene expression of matrix metalloproteinases (MMPs) and increased collagen deposition in the extracellular matrix (ECM) of skeletal muscle, which can prevent adequate satellite-cell activation, proliferation, and differentiation. Direct and indirect evidence indicates that alcoholic myopathy is associated with decreased mitochondrial function, enhanced reactive oxygen species (ROS) generation, and decreased total oxidative capacity, particularly in type 2 fibers. An increased proinflammatory and oxidative milieu in skeletal muscle likely is the underlying mechanism leading to the decreased regenerative capacity, development of a profibrotic milieu, and diminished metabolic efficiency.

Figure 3

Aggravating conditions of, and therapeutic options for, alcoholic myopathy. Alcoholic myopathy may be further exacerbated by critical illness, prolonged hospitalization, chronic infection (e.g., HIV), malnutrition, and inactivity. Therapeutic options to achieve muscle mass accretion and restoration of skeletal muscle function include complete abstinence or at least decreased alcohol consumption, as well as aerobic exercise and/or resistance training. Other approaches currently being tested in myopathies of different etiologies also could prove effective for alcoholic myopathy. These include manipulation of the growth-hormone axis through administration of either insulin-like growth factor-1 (IGF-1), the principal mediator of growth-hormone action, or ghrelin, an upstream regulator of the growth hormone/mammalian target of rapamycin (mTOR) axis. Inhibition of myostatin, a negative regulator of muscle growth, may reduce Smad signaling, thereby preventing loss of muscle mass. Finally, exercise may lead to upregulation of Forkhead box protein O1 (FOXO1). Further studies are needed to determine the efficacy of these therapies for amelioration of alcoholic myopathy.