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

• Published in: Biochimica et biophysica acta. Molecular basis of disease 2025-02, Vol.1871 (2), p.167584, Article 167584
• Main Authors: Fletcher, Emma, Miserlis, Dimitrios, Papoutsi, Evlampia, Steiner, Jennifer L., Gordon, Bradley, Haynatzki, Gleb, Pacher, Pal, Koutakis, Panagiotis
• Format: Article
• Language: English
• Subjects: Alcohol Drinking - adverse effects; Aldehyde Dehydrogenase, Mitochondrial - genetics; Aldehyde Dehydrogenase, Mitochondrial - metabolism; Aldehyde dehydrogenase-2; Animals; Chronic alcohol and fat consumption; Diet, High-Fat - adverse effects; Disease Models, Animal; Ethanol - administration & dosage; Ethanol - adverse effects; Ethanol - toxicity; Female; Hindlimb - blood supply; Hindlimb - pathology; Hindlimb ischemia; Intramuscular mitochondrial dysfunction; Ischemia - metabolism; Ischemia - pathology; Male; Mice; Mice, Inbred C57BL; Mitochondria, Muscle - metabolism; Mitochondria, Muscle - pathology; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Oxidative stress; Oxidative Stress - drug effects; Peripheral Arterial Disease - etiology; Peripheral Arterial Disease - metabolism; Peripheral Arterial Disease - pathology; Peripheral artery disease
• ISSN: 0925-4439; 1879-260X; 1879-260X
• DOI: 10.1016/j.bbadis.2024.167584

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. 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. 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. 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. [Display omitted] •Chronic alcohol and fat consumption exacerbates ischemic muscle mitochondriopathy.•Mitochondrial dysfunction and oxidative stress coincide with reduced muscle ALDH2.•ALDH2 therapy may aid mitochondrial function in ischemic muscle diseases, like PAD.