Abstract
Alcohol-related myopathy (Alc-M) is highly prevalent among heavy drinkers, although its pathogenesis is not well understood. We hypothesize that Alc-M is mediated by combined effects of insulin/IGF resistance and oxidative stress, similar to the effects of ethanol on liver and brain. We tested this hypothesis using an established model in which adult rats were pair-fed for 8 weeks with isocaloric diets containing 0% (N = 8) or 35.5% (N = 13) ethanol by caloric content. Gastrocnemius muscles were examined by histology, morphometrics, qRT-PCR analysis, and ELISAs. Chronic ethanol feeding reduced myofiber size and mRNA expression of IGF-1 polypeptide, insulin, IGF-1, and IGF-2 receptors, IRS-1, and IRS-2. Multiplex ELISAs demonstrated ethanol-associated inhibition of insulin, IRS-1, Akt, and p70S6K signaling, and increased activation of GSK-3β. In addition, ethanol-exposed muscles had increased 4-hydroxy-2-nonenal immunoreactivity, reflecting lipid peroxidation, and reduced levels of mitochondrial Complex IV, Complex V, and acetylcholinesterase. These results demonstrate that experimental Alc-M is associated with inhibition of insulin/IGF/IRS and downstream signaling that mediates metabolism and cell survival, similar to findings in alcoholic liver and brain degeneration. Moreover, the increased oxidative stress, which could be mediated by mitochondrial dysfunction, may have led to inhibition of acetylcholinesterase, which itself is sufficient to cause myofiber atrophy and degeneration.
Highlights
Alcohol abuse is a leading cause of morbidity and mortality world-wide [1]
The results suggest that chronic alcohol-induced myopathy is mediated by broad impairments of insulin/insulin-like growth factor (IGF) signaling through Akt, as well as increased oxidative stress
This study demonstrates that the Long Evans rat model of chronic ethanol feeding is suitable for investigating mechanisms of alcohol-related myopathy
Summary
Alcohol abuse is a leading cause of morbidity and mortality world-wide [1]. In the United States alone, alcohol abuse adds billions to annual healthcare costs due to disabilities resulting from neuropsychiatric disorders, stroke, dementia, cardiovascular disease, peripheral neuropathy, and liver disease [2]. The true magnitude of this problem is further exposed by the co-factor role heavy alcohol abuse plays in the pathogenesis of colorectal, lung, breast, head and neck cancers, neurodevelopmental disorders, accidents, family fall-outs, and socioeconomic failures [3]. Myopathy is an under-appreciated consequence of chronic alcohol abuse. Acute alcoholic myopathy, which occurs in up to 5% of chronic heavy drinkers, is characterized by rhabdomyolysis [4].
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