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. 2025 Feb;1871(2):167584.
doi: 10.1016/j.bbadis.2024.167584. Epub 2024 Nov 23.

Chronic alcohol consumption exacerbates ischemia-associated skeletal muscle mitochondrial dysfunction in a murine model of peripheral artery disease

Emma Fletcher  1 , Dimitrios Miserlis  2 , Evlampia Papoutsi  1 , Jennifer L Steiner  3 , Bradley Gordon  3 , Gleb Haynatzki  4 , Pal Pacher  5 , Panagiotis Koutakis  6
Affiliations

Chronic alcohol consumption exacerbates ischemia-associated skeletal muscle mitochondrial dysfunction in a murine model of peripheral artery disease

Emma Fletcher et al. Biochim Biophys Acta Mol Basis Dis. 2025 Feb.

Abstract

Purpose: Peripheral artery disease (PAD) causes ischemic mitochondriopathy-associated muscle damage, amplifying patient disability and mortality. Although alcohol and a high-fat diet enhance PAD predisposition and severity, their impact on PAD myopathy is unclear. Using our murine model of PAD, we investigated the combined effect of chronic alcohol and fat consumption on intramuscular oxidative stress and mitochondrial content, function, and quality control. The potential relationship between intramuscular aldehyde dehydrogenase 2 (ALDH2) content, oxidative stress and mitochondriopathy was also explored.

Methods: Twenty-four male, 24 female, 8-month-old C57BL/6 J mice received high-fat-sucrose (HFS) or low-fat-sucrose (LFS) diets for 16-weeks, followed by either 20 % ethanol (EtOH) supplemented in the drinking water or continued water access for another 12-weeks (n = 12 mice/4 groups). The left femoral artery was ligated to induce hindlimb ischemia (HLI), and mice 4-weeks post-ligation were euthanized.

Results: Chronic HLI was associated with an ischemic muscle mitochondriopathy, which was exacerbated by concurrent HFS and EtOH feeding. Intramuscular ALDH2 was also reduced in mice consuming HFS + EtOH, particularly in the ischemic limb, but increased in their LFS + EtOH-consuming counterparts. Moreover, reduced ALDH2 was strongly correlated with markers of oxidative stress and mitochondrial dysfunction.

Conclusions: ALDH2 could be a promising therapeutic target to optimize intramuscular mitochondrial function in PAD patients, particularly those who habitually consume a diet high in fat and alcohol.

Keywords: Aldehyde dehydrogenase-2; Chronic alcohol and fat consumption; Hindlimb ischemia; Intramuscular mitochondrial dysfunction; Oxidative stress; Peripheral artery disease.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Panagiotis Koutakis reports financial support was provided by National Institute on Aging. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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