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To address this question, we utilized in vitro modeling of contraction and mechanotransduction in C2C12 myotubes treated with doxorubicin (DOX; 0.2 \u03bcM for 3 days). Myotubes expressed contractile proteins and organized these into functional myofilaments, as electrical field stimulation (STIM) induced intracellular calcium (Ca<jats:sup>2+<\/jats:sup>) transients and contractions, both of which were prevented by inhibition of membrane depolarization. DOX treatment reduced myotube myosin content, protein synthesis, and Akt (S308) and forkhead box O3a (FoxO3a; S253) phosphorylation and increased muscle RING finger 1 (MuRF1) expression. STIM (1 h\/day) prevented DOX-induced reductions in myotube myosin content and Akt and FoxO3a phosphorylation, as well as increases in MuRF1 expression, but did not prevent DOX-induced reductions in protein synthesis. Inhibition of myosin-actin interaction during STIM prevented contraction and the antiatrophic effects of STIM without affecting Ca<jats:sup>2+<\/jats:sup> cycling, suggesting that the beneficial effect of STIM derives from mechanotransductive pathways. Further supporting this conclusion, mechanical stretch of myotubes recapitulated the effects of STIM to prevent DOX suppression of FoxO3a phosphorylation and upregulation of MuRF1. DOX also increased reactive oxygen species (ROS) production, which led to a decrease in mitochondrial content. Although STIM did not alter DOX-induced ROS production, peroxisome proliferator-activated receptor-\u03b3 coactivator-1\u03b1 and antioxidant enzyme expression were upregulated, and mitochondrial loss was prevented. Our results suggest that the activation of mechanotransductive pathways that downregulate proteolysis and preserve mitochondrial content protects against the atrophic effects of chemotherapeutics. <\/jats:p>","DOI":"10.1152\/ajpcell.00148.2019","type":"journal-article","created":{"date-parts":[[2019,9,18]],"date-time":"2019-09-18T19:04:17Z","timestamp":1568833457000},"page":"C1213-C1228","source":"Crossref","is-referenced-by-count":30,"title":["Electrical stimulation prevents doxorubicin-induced atrophy and mitochondrial loss in cultured myotubes"],"prefix":"10.1152","volume":"317","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9667-8195","authenticated-orcid":false,"given":"Blas A.","family":"Guigni","sequence":"first","affiliation":[{"name":"Department of Medicine, College of Medicine, University of Vermont, Burlington, Vermont"},{"name":"Department of Molecular Physiology and Biophysics, College of Medicine, University of Vermont, Burlington, 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