Intermittent glucocorticoid steroid dosing enhances muscle repair without eliciting muscle atrophy
Mattia Quattrocelli, David Y. Barefield, James L. Warner, Andy H. Vo, Michele Hadhazy, Judy U. Earley, Alexis R. Demonbreun, Elizabeth M. McNally
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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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 7

Daily GC dosing elicits atrophic mdx skeletal muscles, while weekly GC dosing does not.

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Daily GC dosing elicits atrophic mdx skeletal muscles, while weekly GC d...
(A) Daily, but not weekly, GC steroid dosing caused loss of body mass. (B) Weekly GC steroid dosing enhanced grip strength and run-to-exhaustion performance, while daily GC steroid-dosing treatments correlated with reduced grip strength and run performance. (C) Myofiber CSA was increased after weekly, but decreased after daily GC administration in gastrocnemius muscle sections. (D) Max tetanic force of tibialis anterior muscles was increased after weekly treatments and decreased after daily GC administration. (E) Fatigue analysis showed that tetanic force was increased over consecutive contraction bouts after weekly dosing, while daily dosing induced opposite trends. (F) Weekly GC regimen correlated with improved respiratory function, as assessed by WBP. Minute volume was increased and inspiration time was decreased in weekly GC dosing. Daily dosing reversed these beneficial trends. (G) Weekly GC treatments promoted increased CSA and diaphragm thickness, while daily CG dosing reduced CSA and diaphragm thickness. n = 5 mice/group. *P < 0.05 vs. mdx vehicle, 1-way ANOVA test with Bonferroni’s multiple comparison; #P < 0.05 vs. mdx vehicle, 2-way ANOVA test with Bonferroni’s multiple comparison.