Lesion level–dependent systemic muscle wasting after spinal cord injury is mediated by glucocorticoid signaling in mice

Author:

Harrigan Markus E.1234ORCID,Filous Angela R.134ORCID,Vadala Christopher P.134ORCID,Webb Amy5,Pietrzak Maciej5ORCID,Sahenk Zarife678,Prüss Harald910ORCID,Reiser Peter J.11ORCID,Popovich Phillip G.3412ORCID,Arnold W. David1314ORCID,Schwab Jan M.1341215ORCID

Affiliation:

1. Department of Neurology, Spinal Cord Injury Division (Paraplegiology), College of Medicine, Ohio State University, Wexner Medical Center, Columbus, OH 43210, USA.

2. Medical Scientist Training Program, College of Medicine, Ohio State University, Wexner Medical Center, Columbus, OH 43210, USA.

3. Neuroscience Research Institute, Ohio State University, Columbus, OH 43210, USA.

4. Belford Center for Spinal Cord Injury, Ohio State University, Wexner Medical Center, Columbus, OH 43210, USA.

5. Department of Biomedical Informatics, College of Medicine, Ohio State University, Wexner Medical Center, Columbus, OH 43210, USA.

6. Center for Gene Therapy, Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA.

7. Department of Pediatrics and Neurology, Nationwide Children’s Hospital and Ohio State University, Columbus, OH 43205, USA.

8. Department of Pathology and Laboratory Medicine, Nationwide Children’s Hospital, Columbus, OH 43205, USA.

9. Department of Neurology and Experimental Neurology, Charité—Universitätsmedizin, 10117 Berlin, Germany.

10. German Center for Neurodegenerative Diseases (DZNE), 10117 Berlin, Germany.

11. Division of Biosciences, College of Dentistry, Ohio State University, Columbus, OH 43210, USA.

12. Department of Neuroscience, Ohio State University, Wexner Medical Center, Columbus, OH 43210, USA.

13. NextGen Precision Health, University of Missouri, Columbia, MO 65211, USA.

14. Department of Physical Medicine and Rehabilitation, University of Missouri, Columbia, MO 65212, USA.

15. Department of Physical Medicine and Rehabilitation, Ohio State University, Wexner Medical Center, Columbus, OH 43210, USA.

Abstract

An incomplete mechanistic understanding of skeletal muscle wasting early after spinal cord injury (SCI) precludes targeted molecular interventions. Here, we demonstrated systemic wasting that also affected innervated nonparalyzed (supralesional) muscles and emerged within 1 week after experimental SCI in mice. Systemic muscle wasting caused muscle weakness, affected fast type 2 myofibers preferentially, and became exacerbated after high (T3) compared with low (T9) thoracic paraplegia, indicating lesion level–dependent (“neurogenic”) mechanisms. The wasting of nonparalyzed muscle and its rapid onset and severity beyond what can be explained by disuse implied unknown systemic drivers. Muscle transcriptome and biochemical analysis revealed a glucocorticoid-mediated catabolic signature early after T3 SCI. SCI-induced systemic muscle wasting was mitigated by (i) endogenous glucocorticoid ablation (adrenalectomy) and (ii) pharmacological glucocorticoid receptor (GR) blockade and was (iii) completely prevented after T3 relative to T9 SCI by genetic muscle-specific GR deletion. These results suggest that neurogenic hypercortisolism contributes to a rapid systemic and functionally relevant muscle wasting syndrome early after paraplegic SCI in mice.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

General Medicine

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