miR-23a is decreased during muscle atrophy by a mechanism that includes calcineurin signaling and exosome-mediated export
Skeletal muscle atrophy is prevalent in chronic diseases, and microRNAs (miRs may play a key role in the wasting process. miR-23a was previously shown to inhibit the expression of atrogin-1 and muscle RING-finger protein-1 (MuRF1 in muscle. It also was reported to be regulated by cytoplasmic nuclear factor of activated T cells 3 (NFATc3 in cardiomyocytes. The objective of this study was to determine if miR-23a is regulated during muscle atrophy and to evaluate the relationship between calcineurin (Cn/NFAT signaling and miR-23a expression in skeletal muscle cells during atrophy. miR-23a was decreased in the gastrocnemius of rats with acute streptozotocin-induced diabetes, a condition known to increase atrogin-1 and MuRF1 expression and cause atrophy. Treatment of C2C12 myotubes with dexamethasone (Dex for 48 h also reduced miR-23a as well as RCAN1.4 mRNA, which is transcriptionally regulated by NFAT. NFATc3 nuclear localization and the amount of miR-23a decreased rapidly within 1 h of Dex administration, suggesting a link between Cn signaling and miR-23a. The level of miR-23a was lower in primary myotubes from mice lacking the Î±- or Î²-isoform of the CnA catalytic subunit than wild-type mice. Dex did not further suppress miR-23a in myotubes from Cn-deficient mice. Overexpression of CnAÎ² in C2C12 myotubes prevented Dex-induced suppression of miR-23a. Finally, miR-23a was present in exosomes isolated from the media of C2C12 myotubes, and Dex increased its exosomal abundance. Dex did not alter the number of exosomes released into the media. We conclude that atrophy-inducing conditions downregulate miR-23a in muscle by mechanisms involving attenuated Cn/NFAT signaling and selective packaging into exosomes. Â© 2014 the American Physiological Society.
American Journal of Physiology - Cell Physiology
Hudson, M. B.; Woodworth-Hobbs, M. E.; Zheng, B.; Rahnert, J. A.; Blount, M. A.; Gooch, Jennifer L.; Searles, C. D.; and Russ Price, S., "miR-23a is decreased during muscle atrophy by a mechanism that includes calcineurin signaling and exosome-mediated export" (2014). PCOM Scholarly Papers. 493.