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

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 4

GC steroids decrease extent of acute muscle injury in WT muscle.

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GC steroids decrease extent of acute muscle injury in WT muscle. Acute m...
Acute muscle injury was induced with cardiotoxin (ctx) injection in the tibialis anterior muscles of normal mice. (A) Diagram depicting the treatments performed in parallel in WT mice. Colored arrows, GC steroid injection; gray arrows, vehicle injections. (B) GC steroid regimens comparably reduced the extent of injury 7 days after cardiotoxin injection. (Left) Representative H&E images of tibialis anterior muscles with prednisone treatments. The dotted lines outline the injury area, which includes necrosis, fibrosis, immune cell infiltrates, and centrally nucleated fibers. (Right) Injury extent quantitation (10 replicates). (C) GC regimens comparably decreased macrophage infiltration within the area of injury 7 days after cardiotoxin injection. Data are depicted as quantitation of F4-80+ cells/mm2 in gastrocnemius muscles by immunostaining. (D) GC steroid regimens comparably reduced serum CK at 24 hours after injury, with no significant changes after 7 days. (E) Fibrosis was comparably reduced in the presence of all GC regimens both 7 and 14 days after muscle injury. Data are depicted as quantitation of hydroxyproline content in gastrocnemius muscles. Gray, WT vehicle; light blue, WT prednisone predose; blue, WT prednisone weekly; dark blue, WT prednisone daily; light purple, WT deflazacort predose; purple, WT deflazacort weekly; dark purple, WT deflazacort daily. n = 6 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.