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Intermittent glucocorticoid steroid dosing enhances muscle repair without eliciting muscle atrophy
Mattia Quattrocelli, … , Alexis R. Demonbreun, Elizabeth M. McNally
Mattia Quattrocelli, … , Alexis R. Demonbreun, Elizabeth M. McNally
Published May 8, 2017
Citation Information: J Clin Invest. 2017;127(6):2418-2432. https://doi.org/10.1172/JCI91445.
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Research Article Metabolism Muscle biology

Intermittent glucocorticoid steroid dosing enhances muscle repair without eliciting muscle atrophy

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Abstract

Glucocorticoid steroids such as prednisone are prescribed for chronic muscle conditions such as Duchenne muscular dystrophy, where their use is associated with prolonged ambulation. The positive effects of chronic steroid treatment in muscular dystrophy are paradoxical because these steroids are also known to trigger muscle atrophy. Chronic steroid use usually involves once-daily dosing, although weekly dosing in children has been suggested for its reduced side effects on behavior. In this work, we tested steroid dosing in mice and found that a single pulse of glucocorticoid steroids improved sarcolemmal repair through increased expression of annexins A1 and A6, which mediate myofiber repair. This increased expression was dependent on glucocorticoid response elements upstream of annexins and was reinforced by the expression of forkhead box O1 (FOXO1). We compared weekly versus daily steroid treatment in mouse models of acute muscle injury and in muscular dystrophy and determined that both regimens provided comparable benefits in terms of annexin gene expression and muscle repair. However, daily dosing activated atrophic pathways, including F-box protein 32 (Fbxo32), which encodes atrogin-1. Conversely, weekly steroid treatment in mdx mice improved muscle function and histopathology and concomitantly induced the ergogenic transcription factor Krüppel-like factor 15 (Klf15) while decreasing Fbxo32. These findings suggest that intermittent, rather than daily, glucocorticoid steroid regimen promotes sarcolemmal repair and muscle recovery from injury while limiting atrophic remodeling.

Authors

Mattia Quattrocelli, David Y. Barefield, James L. Warner, Andy H. Vo, Michele Hadhazy, Judy U. Earley, Alexis R. Demonbreun, Elizabeth M. McNally

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Figure 1

Pulse dosing of GC steroids improves sarcolemmal repair.

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Pulse dosing of GC steroids improves sarcolemmal repair.
Prednisone and ...
Prednisone and deflazacort, both GC steroids, were given 1 day prior to injury. (A) Laser injury was applied to isolated muscle fibers in the presence of FM4-64, which marks sarcolemmal injury. A single dose of GC steroid reduced FM4-64 accumulation. Shown is Z-stack rendering of FM4-64 dye accumulation of laser-injured sarcolemmal sites at 300 seconds after injury. Quantitation shows that GC pulse associated with decreased dye accumulation over time as well as a decreased area of injury. (B) Imaging of annexin A6 (ANXA6) cap formation at the site of sarcolemmal injury. Pulse dosing of prednisone and deflazacort associated with smaller repair caps, consistent with reduced injury and enhanced repair. Shown is Z-stack rendering of GFP-tagged ANXA6 cap of laser-injured sarcolemmal sites at 300 seconds after injury. Quantitation of GC dosing demonstrated faster, smaller cap formation over time and faster recovery of GFP-tagged ANXA6 at injury site. FM4-64 and ANXA6-GFP pictures were acquired simultaneously. F/F0, average fluorescence ratio versus average fluorescence at time 0 of imaging series. n = 50 myofibers (5 mice)/group. *P < 0.05 vs. vehicle, 1-way ANOVA test with Bonferroni’s multiple comparison; #P < 0.05 vs. vehicle, 2-way ANOVA test with Bonferroni’s multiple comparison.
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