A newly published research study demonstrates that stress hormone axis dysregulation and corticotropin-releasing factor receptor 1-sensitive signaling actively contribute to skeletal muscle mitochondrial and metabolic remodeling during chronic-plus-binge ethanol exposure. Skeletal muscle dysfunction is widely recognized as a frequent clinical complication among individuals experiencing chronic alcohol misuse, yet the precise physiological mechanisms linking ethanol ingestion to muscle mitochondrial injury and metabolic disturbance have remained poorly understood. By exploring neuroendocrine and intracellular pathways, the researchers sought to determine whether hypothalamic–pituitary–adrenal axis dysregulation and corticotropin-releasing factor receptor 1-sensitive signaling drive these damaging skeletal muscle alterations under chronic-plus-binge conditions.
To examine the functional and structural effects of ethanol on muscle tissue in vivo, the investigators implemented a chronic-plus-binge ethanol feeding model using male C57BL/6 mice. As part of the experimental design, the animals were evaluated both with and without the administration of antalarmin, a pharmacological antagonist targeting corticotropin-releasing factor receptor 1. The team conducted comprehensive evaluations of skeletal muscle phenotypes across multiple physiological parameters, including physical performance assessments, histological examination, immunoblotting, mitochondrial ultrastructure analysis, and detailed metabolic profiling. In addition, plasma metabolomics was employed to identify and monitor systemic metabolic alterations triggered across the animal model.
The experimental results demonstrated that chronic-plus-binge ethanol exposure induced severe muscle-wasting phenotypes in the male mice. Exposed animals exhibited marked reductions in overall body weight and hindlimb muscle weights, coupled with an increase in circulating creatine kinase, a key clinical indicator of muscle damage. Detailed tissue and molecular examinations showed reduced myofiber cross-sectional area along with clear alterations in muscle fiber-type composition. At the molecular level, ethanol exposure stimulated the expression of the muscle atrophy markers MuRF1 and Atrogin-1, decreased the abundance of myogenic regulatory proteins, disrupted mitochondrial ultrastructure, decreased oxidative phosphorylation protein levels, and shifted metabolic protein profiles in skeletal muscle.
To elucidate the specific upstream stress-hormone signaling pathways involved, the research team analyzed a separate acute ethanol-challenge animal cohort. Following an acute ethanol challenge, the researchers observed pronounced neuroendocrine activation marked by an increase in hypothalamic corticotropin-releasing hormone-positive and c-Fos-positive signals. This central response coincided with significant increases in pituitary adrenocorticotropic hormone-positive and c-Fos-positive signals, as well as elevated concentrations of corticosterone circulating in the bloodstream. These observations confirmed that acute ethanol exposure robustly stimulates the hypothalamic–pituitary–adrenal stress axis and elevates systemic glucocorticoid hormones.
Pharmacological intervention in the chronic-plus-binge mouse model demonstrated that blocking stress-hormone receptor activity can alleviate ethanol-induced muscle deterioration. Treatment with the corticotropin-releasing factor receptor 1 antagonist antalarmin partially attenuated the loss of muscle mass, improved physical performance deficits, and mitigated myofiber atrophy. In addition to structural preservation, antalarmin administration reduced the induction of the atrophy-associated proteins MuRF1 and Atrogin-1, partially prevented the decline in oxidative phosphorylation proteins, and attenuated selected systemic metabolic alterations that were identified through plasma metabolomics profiling.
To assess cellular bioenergetics, myogenic differentiation, and glucocorticoid-dependent mechanisms at the cellular level, the authors conducted complementary in vitro experiments using differentiated C2C12 myotubes. Short-term ethanol exposure directly impaired cellular bioenergetics in the myotubes, resulting in reduced mitochondrial respiration and an increase in extracellular acidification. Furthermore, when myotubes were treated with a combination of ethanol and hydrocortisone, blocking glucocorticoid receptor signaling with the antagonist mifepristone successfully attenuated the upregulation of MuRF1 and Atrogin-1. This targeted glucocorticoid receptor blockade also partially preserved the abundance of selected oxidative phosphorylation proteins within the cultured muscle cells.
To evaluate whether these experimental findings correspond to clinical observations in humans, the authors investigated a cross-sectional cohort of 55 long-term drinkers, which included an analytic subset of 44 participants balanced for age and body mass index. Within this human cohort, heavy alcohol consumption was significantly associated with elevated morning serum cortisol levels and a lower appendicular skeletal muscle mass index. Taken together across animal, cellular, and human investigations, the findings provide coherent evidence that hypothalamic–pituitary–adrenal axis dysregulation and corticotropin-releasing factor receptor 1-sensitive signaling contribute significantly to ethanol-associated skeletal muscle atrophy, mitochondrial ultrastructural remodeling, and metabolic dysfunction.
Subject of Research: Stress hormone axis dysregulation and skeletal muscle remodeling during ethanol exposure
Article Title: Stress hormone axis dysregulation contributes to skeletal muscle mitochondrial and metabolic remodeling during chronic-plus-binge ethanol exposure
Article References: Abdillah, A. M., Moon, J. S., Kwak, J. Y., Lee, S.-H., Lee, H. Y., Jang, H. J., Nga, H. T., Linh, N. T., Kim, C., & Yi, H.-S. (2026). Stress hormone axis dysregulation contributes to skeletal muscle mitochondrial and metabolic remodeling during chronic-plus-binge ethanol exposure. Cell Communication and Signaling. https://doi.org/10.1186/s12964-026-03239-7
Image Credits: AI Generated
DOI: 10.1186/s12964-026-03239-7
Keywords: ethanol exposure, skeletal muscle atrophy, mitochondrial remodeling, hypothalamic-pituitary-adrenal axis, corticotropin-releasing factor receptor 1, antalarmin, MuRF1, Atrogin-1, oxidative phosphorylation, C2C12 myotubes, mifepristone, corticosterone, creatine kinase, plasma metabolomics, morning cortisol, appendicular skeletal muscle mass index
Tags: antalarminappendicular skeletal muscle mass indexAtrogin-1C2C12 myotubescorticosteronecorticotropin-releasing factor receptor 1creatine kinaseethanol exposurehypothalamic-pituitary-adrenal axismifepristonemitochondrial remodelingmorning cortisolMuRF1oxidative phosphorylationplasma metabolomicsskeletal muscle atrophy
