Heavy alcohol use exacerbates skeletal myopathy in peripheral artery disease

Peripheral artery disease (PAD) is an age-associated vascular condition that contributes to progressive skeletal muscle dysfunction, marked by oxidative stress, mitochondrial abnormalities, and muscle atrophy. Chronic alcohol misuse independently induces similar myopathic changes. Whether alcohol use disorder (AUD) worsens PAD-related skeletal muscle pathology in humans remains unknown. We analyzed gastrocnemius biopsies from PAD patients with heavy alcohol misuse (PAD-AUD), PAD patients without heavy alcohol misuse (PAD-LA), and non-PAD controls with low-to-no alcohol consumption (CON). Markers of oxidative stress, mitochondrial respiration and myofiber morphometrics were compared across groups. Lower extremity function-including walking distance and ankle plantar flexor strength-was also evaluated. Markers of muscle oxidative stress (4-hydroxynonenal (4-HNE), protein carbonyls, and acetaldehyde), mitochondriopathy and myofiber morphometric damage, were significantly elevated in PAD-LA patients relative to CON. Functional outcomes, including walking ability and muscle strength, were correspondingly reduced in PAD. Notably, these pathological and functional impairments were further exacerbated in PAD-AUD. Interestingly, levels of the alcohol-detoxifying enzyme aldehyde dehydrogenase 2 (ALDH2) were unchanged in PAD-AUD muscle but were significantly upregulated in PAD-LA. Although traditionally recognized for metabolizing alcohol-derived aldehydes, ALDH2 also facilitates the clearance of endogenous reactive aldehydes generated by mitochondrial oxidative stress, including 4-HNE and protein carbonyls. In PAD-LA patients, elevated ALDH2 levels coincided with reduced oxidative stress and mitochondriopathy, whereas PAD-AUD patients exhibited no ALDH2 upregulation and intramuscular pathology was enhanced. These findings implicate ALDH2 dysfunction as a contributing factor to muscle degeneration in PAD-AUD and support its potential as a therapeutic target for attenuating oxidative stress in PAD.