Stress hormone axis dysregulation contributes to skeletal muscle mitochondrial and metabolic remodeling during chronic-plus-binge ethanol exposure

Alcohol-associated skeletal muscle dysfunction is a common complication of chronic alcohol misuse, but the mechanisms linking ethanol exposure to muscle mitochondrial injury and metabolic remodeling remain unclear. Because chronic alcohol exposure can disturb stress-hormone regulation, we investigated whether hypothalamic–pituitary–adrenal axis dysregulation and corticotropin-releasing factor receptor 1-sensitive signaling contribute to skeletal muscle remodeling during chronic-plus-binge ethanol exposure. Male C57BL/6 mice underwent a chronic-plus-binge ethanol feeding model, with or without the corticotropin-releasing factor receptor 1 antagonist antalarmin. Skeletal muscle phenotypes were assessed by physical performance, histology, immunoblotting, mitochondrial ultrastructure, and metabolic analyses. Ethanol-treated C2C12 myotubes were used to examine myogenic differentiation, cellular bioenergetics, and glucocorticoid receptor-sensitive responses. Plasma metabolomics assessed systemic metabolic alterations. A cross-sectional cohort of 55 long-term drinkers, including an age- and BMI-balanced analytic subset of 44 participants, was analyzed for associations among alcohol intake, morning cortisol, and appendicular skeletal muscle mass index. Chronic-plus-binge ethanol exposure reduced body and hindlimb muscle weights, increased circulating creatine kinase, reduced myofiber cross-sectional area, altered fiber-type composition, increased MuRF1 and Atrogin-1, and decreased myogenic regulatory proteins. Ethanol exposure also disrupted mitochondrial ultrastructure, reduced oxidative phosphorylation protein abundance, and altered metabolic protein profiles in skeletal muscle. Short-term ethanol exposure reduced mitochondrial respiration and increased extracellular acidification in differentiated C2C12 myotubes. In a separate acute ethanol-challenge cohort, ethanol increased hypothalamic CRH- and c-Fos-positive signals, pituitary ACTH- and c-Fos-positive signals, and serum corticosterone concentrations. During chronic-plus-binge exposure, antalarmin partially attenuated muscle loss, impaired physical performance, myofiber atrophy, atrophy-protein induction, OXPHOS protein loss, and selected systemic metabolic alterations. Additionally, in C2C12 myotubes, glucocorticoid receptor blockade with mifepristone attenuated combined ethanol–hydrocortisone-induced MuRF1 and Atrogin-1 expression and partially preserved selected OXPHOS proteins. In the human cohort, heavy alcohol intake was associated with higher morning serum cortisol and lower appendicular skeletal muscle mass index. These findings support a contributory role for stress-hormone dysregulation and CRF1-sensitive signaling in ethanol-associated skeletal muscle atrophy, mitochondrial remodeling, and metabolic dysfunction.