Alcohol induces mitochondrial fragmentation and stress responses to maintain normal muscle function in Caenorhabditis elegans

Abstract

<jats:title>Abstracts</jats:title><jats:p>Chronic excessive ethanol consumption produces distinct toxic and adverse effects on different tissues. In skeletal muscle ethanol causes alcoholic myopathy characterized by myofiber atrophy and loss of muscle strength. Alcoholic myopathy is more prevalent than all inherited muscle diseases combined. Current evidence indicates that ethanol directly impairs muscle organization and function. However, the underlying mechanism by which ethanol causes its toxicity to muscle is poorly understood. Here, we show that the nematode <jats:italic>C. elegans</jats:italic> recapitulates key aspects of alcoholic myopathy when exposed to ethanol. As in mammals, ethanol exposure impairs muscle strength and organization and induces the expression of protective genes, including oxidative stress response. In addition, ethanol exposure causes a fragmentation of mitochondrial networks aligned with myofibril lattices. This ethanol-induced mitochondrial fragmentation is dependent on mitochondrial fission factor DRP-1 (dynamin-like protein 1), and its receptor proteins on the mitochondrial outer membrane. Our data indicate that this fragmentation contributes to activation of mitochondrial unfolded protein response (UPR). We also found that robust perpetual mitochondrial UPR activation effectively counters muscle weakness caused by ethanol exposure. Our results strongly suggest that modulation of mitochondrial stress responses provides a mechanism to ameliorate alcohol toxicity and damage to muscle.</jats:p><jats:sec><jats:title>Significance</jats:title><jats:p>Chronic alcohol abuse causes the damage and toxicity to peripheral tissues, including muscle. Alcohol perturbs the structure and function of striated skeletal and cardiac muscles. These toxic effects of alcohol on striated muscles negatively impact morbidity and mortality to alcohol misusers. Here, we demonstrate that the nematode <jats:italic>C. elegans</jats:italic> also exhibits key features of alcoholic myopathy when exposed to ethanol. Ethanol exposure impairs muscle organization and strength, and induces the expression of genes that cope with alcohol toxicity. Particularly, we find that ethanol toxicity is centered on mitochondria, the power plants of the cell. As an adaptive protective response to mitochondrial dysfunction, ethanol-exposed cells induce global transcriptional reprogramming to restore normal mitochondrial function. Upregulation of this transcriptional reprogramming in <jats:italic>C. elegans</jats:italic> effectively blocks ethanol-induced muscle weakness, a key feature of alcoholic myopathy. Thus, the modulation of mitochondrial stress responses is a potentially promising therapeutic strategy to ameliorate alcohol toxicity to muscle.</jats:p></jats:sec>

Polydatin attenuates chronic alcohol consumption-induced cardiomyopathy through a SIRT6-dependent mechanism

“…These data reveal that alcohol has a greater impact on cellular mitochondrial fission, which coincides with several previous research studies conducted on liver tissue and in Caenorhabditis elegans. 64,65 On the other hand, the removal of injured mitochondria through autophagic sequestration and lysosomal degradation by mitophagy is essential to the maintenance of cardiomyocyte homeostasis in physiological and pathological conditions. 56 Although limited evidence is currently available with regard to the involvement of mitophagy during the pathogenesis of ACM, several studies have shown that chronic ethanol administration induced a disruption of autophagosomal processing and lysosomal function and led to the accumulation of autophagosomes in the liver tissue.…”

Mitochondrial dynamics and biogenesis indicators may serve as potential biomarkers for diagnosis of myasthenia gravis

“…Previous studies have shown that mitochondria serve a role in the development of rare neuromuscular diseases, such as Duchenne and Becker muscular dystrophy (20,21). Mitochondrial dysfunction affects muscle function, leading to atrophy (22). Muscle weakness is the primary symptom of MG.…”

UNC-2 CaV2 Channel Localization at Presynaptic Active Zones Depends on UNC-10/RIM and SYD-2/Liprin-α inCaenorhabditis elegans

“…Thrashing assay. Detailed protocol was described previously (Oh et al, 2020). Age-matched adult animals (24 h post-L4) were placed in 1 ml M9 buffer on an unseeded nematode growth media plate.…”