Chronic alcohol exposure induces muscle atrophy (myopathy) in zebrafish and alters the expression of microRNAs targeting the Notch pathway in skeletal muscle.
Muscle wasting is estimated to affect 40-60% of alcoholics, and is more common than cirrhosis among chronic alcohol abusers. The molecular and cellular mechanisms underlying alcohol-related musculoskeletal dysfunction are, however, poorly understood. Muscle-specific microRNAs (miRNAs) referred to as myoMirs are now known to play a key role in both myogenesis and muscle atrophy. Yet, no studies have investigated a role for myoMirs in alcohol-related skeletal muscle damage. We developed a zebrafish model of chronic ethanol exposure to better define the mechanisms mediating alcohol-induced muscle atrophy. Adult fish maintained at 0.5% ethanol for eight weeks demonstrated significantly reduced muscle fiber cross-sectional area (∼12%, P < 0.05) compared to fish housed in normal water. Zebrafish miRNA microarray revealed marked changes in several miRNAs with ethanol treatment. Importantly, miR-140, a miRNA that shows 100% sequence homology with miR-140 from both mouse and human, is decreased 10-fold in ethanol treated fish. miR-140 targets several members of the Notch signaling pathway such as DNER, JAG1, and Hey1, and PCR data show that both Hey1 and Notch 1 are significantly up-related (3-fold) in muscle of ethanol treated fish. In addition, miR-146a, which targets the Notch antagonist Numb, is elevated in muscle from ethanol-treated fish. Upregulation of Notch signaling suppresses myogenesis and maintains muscle satellite cell quiescence. These data suggest that miRNAs targeting Notch are likely to play important roles in alcohol-related myopathy. Furthermore, zebrafish may serve as a useful model for better understanding the role of microRNAs in alcohol-related tissue damage.
Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
Andrew
A
Khayrullin
Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
Lauren
L
Smith
Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
Dhwani
D
Mistry
Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
Amy
A
Dukes
Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
Y Albert
YA
Pan
Medical College of Georgia, Augusta University, Augusta, GA 30912, USA. Electronic address: mhamrick@augusta.edu.
Mark W
MW
Hamrick
D000818:Animals; D000431:Ethanol / Q000009:adverse effects*; D018398:Homeodomain Proteins / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism*; D009133:Muscular Atrophy / Q000139:chemically induced*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D060888:Real-Time Polymerase Chain Reaction; D051881:Receptor, Notch1 / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism*; D015854:Up-Regulation; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000378:metabolism
D018398:Homeodomain Proteins; D035683:MicroRNAs; D009419:Nerve Tissue Proteins; D051881:Receptor, Notch1; D051880:Receptors, Notch; D029961:Zebrafish Proteins; C437805:notch1a protein, zebrafish; D000431:Ethanol
Myogenesis; Satellite cells; miR-146a; mir-140; myoMirs