Abstract
Glucocorticoid steroids are commonly prescribed for many inflammatory conditions, but chronic daily use produces adverse effects, including muscle wasting and weakness. In contrast, shorter glucocorticoid pulses may improve athletic performance, although the mechanisms remain unclear. Muscle is sexually dimorphic and comparatively little is known about how male and female muscles respond to glucocorticoids. We investigated the impact of once-weekly glucocorticoid exposure on skeletal muscle performance comparing male and female mice. One month of once-weekly glucocorticoid dosing improved muscle specific force in both males and females. Transcriptomic profiling of isolated myofibers identified a striking sexually dimorphic response to weekly glucocorticoids. Male myofibers had increased expression of genes in the IGF1/PI3K pathway and calcium handling, while female myofibers had profound upregulation of lipid metabolism genes. Muscles from weekly prednisone–treated males had improved calcium handling, while comparably treated female muscles had reduced intramuscular triglycerides. Consistent with altered lipid metabolism, weekly prednisone–treated female mice had greater endurance relative to controls. Using chromatin immunoprecipitation, we defined a sexually dimorphic chromatin landscape after weekly prednisone. These results demonstrate that weekly glucocorticoid exposure elicits distinct pathways in males versus females, resulting in enhanced performance.
| Original language | English (US) |
|---|---|
| Article number | e149828 |
| Journal | Journal of Clinical Investigation |
| Volume | 132 |
| Issue number | 6 |
| DOIs | |
| State | Published - Mar 15 2022 |
Funding
Next-generation sequencing was performed at the NUSeq Core at the Center for Genetic Medicine, Northwestern University. Lipidom-ic analyses were performed at the Mass Spectrometry Core within the Research Resources Center at the University of Illinois at Chicago. Serum sex steroid assessment was performed by the Ligand Assay and Analysis Core at the University of Virginia Center for Research in Reproduction. The authors thank Alexis Demonbreun, Megan Roy-Puckelwartz, Andy Vo, and Elizabeth Bartom for technical assistance and helpful advice; Alec Koss and Alexander Willis for technical assistance; Daniel Levine, Hee-Kyung Hong, Yumiko Kobayashi, and Joseph Bass for assistance with HPLC; and Grant Barish for assistance with ChIP. Graphical abstract was created with Biorender.com. This work was supported by NIH grants AR052646 and HL061322 (to EMM); NIH grant DK121875, CCHMC Trustee Award, and CCHMC Heart Institute Translational Grant (to MQ); NIH grant HL141698 (to DYB); and NIH grants AR073655 and DK007169 (to IMS). Next-generation sequencing was performed at the NUSeq Core at the Center for Genetic Medicine, Northwestern University. Lipidomic analyses were performed at the Mass Spectrometry Core within the Research Resources Center at the University of Illinois at Chicago. Serum sex steroid assessment was performed by the Ligand Assay and Analysis Core at the University of Virginia Center for Research in Reproduction. The authors thank Alexis Demonbreun, Megan Roy-Puckelwartz, Andy Vo, and Elizabeth Bartom for technical assistance and helpful advice; Alec Koss and Alexander Willis for technical assistance; Daniel Levine, Hee-Kyung Hong, Yumiko Kobayashi, and Joseph Bass for assistance with HPLC; and Grant Barish for assistance with ChIP. Graphical abstract was created with Biorender.com. This work was supported by NIH grants AR052646 and HL061322 (to EMM); NIH grant DK121875, CCHMC Trustee Award, and CCHMC Heart Institute Translational Grant (to MQ); NIH grant HL141698 (to DYB); and NIH grants AR073655 and DK007169 (to IMS).
ASJC Scopus subject areas
- General Medicine