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 9

Transcriptome profiling of prednisone-treated mdx muscles.

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Transcriptome profiling of prednisone-treated mdx muscles. (A) RNA-seq w...
(A) RNA-seq was conducted on GC-treated mdx quadriceps muscle (n = 5 per condition). Principal component analysis discriminated gene-expression profiles according to mdx vehicle and weekly and daily GC dosing. (B) Unbiased hierarchical clustering based on differentially expressed genes also separated samples in regimen-specific groups. (C) Analysis of differentially expressed genes in paired comparisons for enriched GO terms. Highlighted are GO term groups of interest. Both daily and weekly GC steroids enriched for GO terms of membrane repair, growth regulation, immune response, and steroid metabolism. Weekly versus daily GC steroids only enriched for steroid metabolism. (D–F) Heat maps of annotated gene lists. Green denotes higher values, while red indicates lower values of gene mRNA quantitation, as compared with row mean value. n = 5 mice/group. (B–F) Adjusted P value < 0.05 for all genes and GO terms was reported using edgeR differential expression (treated vs. vehicle paired comparisons) and Panther GO enrichment tests (details in Supplemental Methods).