High-Fat Diet Augments the Effect of Alcohol on Skeletal Muscle Mitochondrial Dysfunction in Mice

Abstract

Previous studies have shown that chronic heavy alcohol consumption and consumption of a high-fat (HF) diet can independently contribute to skeletal muscle oxidative stress and mitochondrial dysfunction, yet the concurrent effect of these risk factors remains unclear. We aimed to assess the effect of alcohol and different dietary compositions on mitochondrial activity and oxidative stress markers. Male and female mice were randomized to an alcohol (EtOH)-free HF diet, a HF + EtOH diet, or a low-Fat (LF) + EtOH diet for 6 weeks. At the end of the study, electron transport chain complex activity and expression as well as antioxidant activity and expression, were measured in skeletal muscles. Complex I and III activity were diminished in muscles of mice fed a HF + EtOH diet relative to the EtOH-free HF diet. Lipid peroxidation was elevated, and antioxidant activity was diminished, in muscles of mice fed a HF + EtOH diet as well. Consumption of a HF diet may exacerbate the negative effects of alcohol on skeletal muscle mitochondrial health and oxidative stress.

Alcohol and Skeletal Muscle in Health and Disease

“… 98 In addition, chronic alcohol feeding in the context of high-fat diet for 6 weeks decreased SKM Complex I and III activity, antioxidant activity, as well as increased lipid peroxidation in both male and female mice. 119 A study using parkin-knockout mice fed an alcohol diet for 12 weeks showed that parkin was critical for alcohol-mediated disruption of mitochondrial complex activity, autophagy/mitophagy balance, and apoptosis. 120 Finally, ethanol treatment of primary myoblasts isolated from male and female macaques during 5 days of differentiation decreased extracellular acidification rate, an indicator of glycolysis, and increased maximal oxygen consumption rate.…”

Mitochondrial Dysfunction: At the Nexus between Alcohol-Associated Immunometabolic Dysregulation and Tissue Injury

“…In people with alcohol misuse, cytochrome c oxidase enzyme activity and mitochondrial volume was decreased, and myotubes treated with in vitro ethanol decreased cellular respiration and ETC activity [88,89]. Male and female mice fed a high-fat diet and alcohol exhibited decreased SkM complex I and III activity, with an associated decrease in antioxidant activity [90]. Additionally, chronic alcohol feeding in rats impaired mitochondrial fusion through decreased MFN1 expression, and the sustained loss of mitochondrial fusion impaired bioenergetics and excitation-contraction coupling [91].…”

Potential regulatory role of PGC-1α within the skeletal muscle during metabolic adaptations in response to high-fat diet feeding in animal models

“…Obviously, depending on the duration of feeding, different research groups have explored different perspectives in terms of how HFD contributes to the development of metabolic anomalies and obesity, including insulin resistance, intramuscular lipid droplet accumulation, and mitochondrial function [ 4 , 5 , 20 ]. For example, it has been observed that enhanced muscle mitochondrial oxidative capacity could occur independent of PGC-1α regulation in response to HFD feeding, while prominent interventions like physical activity could promote metabolic health by effectively regulating PPAR proteins in rodents [ 21 , 27 , 35 , 47 ]. We have previously reviewed evidence on the implications of lipid overload and its potential contribution to the development of skeletal muscle insulin resistance and pathological changes in mitochondrial oxidative capacity [ 60 ], without focusing on the molecular mechanisms that could be involved in this process.…”