Chronic consumption of alcohol leads to various histological, biochemical, and physiological changes in skeletal muscle (Lang et al., 2005). These changes can result in chronic alcohol-related myopathy (CAM), a disorder marked by muscle wasting and weakness, particularly in fast-twitch muscles (Preedy et al., 2001). The degree of skeletal muscle atrophy correlates with the amount of alcohol consumed over a lifetime, potentially eroding up to 20% of total muscle mass and significantly reducing strength under extreme conditions (Ekbom et al., 1964; Rossouw et al., 1976; Martin et al., 1985; Estruch et al., 1998; Aagaard et al., 2003). Affecting approximately 40%–60% of chronic alcoholics, CAM is more prevalent than alcohol-induced liver cirrhosis yet remains under-researched (Preedy et al., 2003). The intricate pathophysiological mechanisms that contribute to the development and progression of CAM are still to be fully elucidated.

Preclinical studies in rodents have enhanced our understanding of CAM. Rodent studies, utilizing various methods of ethanol (EtOH) administration (such as liquid diet or drinking water), consistently demonstrate significant muscle atrophy and weakness following prolonged EtOH exposure (Lang et al., 1999; Crowell et al., 2019; Moser et al., 2022; Moser et al., 2023; Ganjayi et al., 2023). These effects are observed independently of caloric intake and other influential factors like diet and lifestyle, suggesting an obvious link between EtOH and CAM. Historically, research has concentrated on EtOH’s role in diminishing muscle mass via impeding protein synthesis via mTORC1 signaling (Preedy et al., 1991; Lang et al., 2001; Steiner and Lang, 2015; Simon et al., 2023). However, these studies narrow the focus on this single mechanism, potentially neglecting other contributing or upstream factors. For this article, we suggest that the onset and progression of CAM might also be attributed to EtOH’s direct or indirect effects on skeletal muscle lipids.

The relationship between EtOH-induced changes in skeletal muscle lipid and muscle atrophy is complex and incompletely defined. It has been reported that downregulation of cardiolipin synthase (crucial for cardiolipin production) reduces myofiber cross-sectional area, muscle mass, and force in the tibialis anterior muscle of young mice (Yoo et al., 2024). Furthermore, others have demonstrated that reductions in lysophospholipids content (particularly lyso-PC) in young mice made the extensor digitorum longus muscle 20% weaker (Ferrara et al., 2021). Additionally, treating muscle cells with palmitate, which leads to ceramide accumulation, increased expression of pro-atrophic genes expression and reduced protein synthesis rates (Woodworth-Hobbs et al., 2014). Similarly, in drosophila, muscle-specific knockdown of phosphatidylserine synthase increased rates of apoptosis and autophagy, reduced muscle mass, and impaired motor function (Kim et al., 2024). Though more correlative, several preclinical studies using denervation, immobilization, and high fat feeding demonstrated that intramyocellular lipids (including triglycerides and diglycerides) increased in skeletal muscle and were associated with changes in muscle mass (Kumar and Sharma, 2009; Vigelsø et al., 2016; Fan and Xiao, 2020; Kimura et al., 2021). In humans, unfavorable changes in muscle PC and phosphatidylethanolamine (PE) content also correlate with reduced insulin sensitivity (Newsom et al., 2016) and age-related declines in muscle size and strength (Hinkley et al., 2020).

Based on the lipid species reported to change due to chronic alcohol consumption, we posit that alcohol-induced alterations in lipid metabolism and transport (e.g., skeletal muscle lipid uptake, storage, and oxidation) result in lipotoxicity, leading to apoptosis. Briefly, changes in lipid metabolism can alter membrane compositions, protein distribution and function, and gene expression. Free fatty acids play vital roles, including energy generation and reserve, components of the cell membrane, and ligands for nuclear receptors (de Vries et al., 1997; Turner et al., 2014; Al Saedi et al., 2022). However, disturbances in fatty acid homeostasis, such as inefficient metabolism or intensified release from storage sites, may result in increased free fatty acid levels, leading to an unfavorable accumulation of intracellular lipids (Figure 1). Cells can adjust to free fatty acid intake to a limited extent, yet prolonged exposure to free fatty acids can become deleterious, impairing mitochondrial function, generating ROS, and producing proinflammatory cytokines. Indeed, overloading cells with palmitate, palmitic acid, or ceramides can cause lipotoxicity and apoptosis in otherwise healthy cells (de Vries et al., 1997; Lin et al., 2012; Shan et al., 2013; Yuan et al., 2013; Zorov et al., 2014; Zhang et al., 2017; Li et al., 2019; Mansuri et al., 2021). In the presence of alcohol, apoptosis has been implicated as a mechanism leading to cellular damage in cardiomyocytes, hepatocytes, endothelial cells, thymocytes, lymphocytes, and neural cells (Ewald and Shao, 1993; Beckemeier and Bora, 1998; Baker et al., 1999; Spyridopoulos et al., 2001; Yin and Ding, 2003; Hwang et al., 2005; Pasala et al., 2015; Jan and Chaudhry, 2019). We are aware of only a few studies that assessed apoptosis in chronic alcohol myopathy (CAM) (Fernández-Solà et al., 2002; FernÁndez-SolÀ et al., 2003; Nakahara et al., 2003). The most well-designed and in-depth was conducted in skeletal muscle biopsies of 30 male high-dose well-nourished chronic alcohol consumers and 12 nonalcoholic controls, with apoptosis being assessed by TUNEL, BAX, and BCL-2 immunohistochemical assays (FernÁndez-SolÀ et al., 2003). Chronic alcoholics had significantly higher apoptotic indices in TUNEL, BAX, and BCL-2 muscle assays, and apoptotic indices were higher in alcoholics with skeletal myopathy compared to those without skeletal myopathy (FernÁndez-SolÀ et al., 2003). It can therefore be speculated that alcohol-induced lipoapoptosis could be occurring in skeletal muscle, causing atrophy and weakness in individuals and animals that consume alcohol chronically. These findings collectively underscore the complex relationship between lipid composition and muscle health and offer valuable insights into underlying mechanisms by which lipids may contribute to alcohol-induced tissue dysfunction.

The current article highlights the significance of lipids as a primary factor influencing CAM. While the existing descriptive data provides valuable insights, it lacks a definitive causal link. To advance our understanding, comprehensive omics studies that focus on the skeletal muscle lipidome are essential. Identifying specific lipids altered by chronic EtOH consumption will pave the way for targeted isolation of lipids that affect muscle size. This approach will enable more focused mechanistic studies to investigate the precise impact of lipids on protein anabolic and catabolic pathways. Such data is crucial for the field, as it extends the literature base beyond what is typically studied in CAM, by aiming to clarify the role of lipids in modulating specific gene and protein alterations.

We suggest that the development and progression of CAM may be due, in part, to the direct or indirect influence of EtOH on skeletal muscle lipids (Figure 1). Chronic EtOH consumption significantly alters lipid composition and metabolism within skeletal muscle, a fact supported by numerous studies published over several decades. These lipid alterations can significantly impact muscle size and function. Recent research has shown that specific changes in lipids can modulate anabolic and catabolic signaling pathways in conditions such as aging, diabetes, and cancer cachexia (Das et al., 2011; Gilbert, 2021; Al Saedi et al., 2022). In summary, this article posits that lipids play a key role in the pathogenesis of CAM, with further research necessary to substantiate this hypothesis.