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

Year: 2023
Type: article
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.
DOI: 10.1126/scitranslmed.adh2156
Authors: Markus E. Harrigan, Angela R. Filous, Christopher P. Vadala, Amy Webb, Maciej Pietrzak, Zarife Sahenk, Harald Prüss, Peter J. Reiser, Phillip G. Popovich, W. David Arnold, Jan M. Schwab
Institutions: The Ohio State University Wexner Medical Center, The Ohio State University, Nationwide Children's Hospital, German Center for Neurodegenerative Diseases, Charité – Universitätsmedizin Berlin, University of Missouri
Language: English
Open Access status: green
Funders: Craig H. Neilsen Foundation, Ohio State University, Wings for Life, European Commission, Birla Institute of Scientific Research, National Institutes of Health, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke
Awards: Reducing Infection Susceptibility by Immune Function Restoration in Spinal Cord Injury, Ohio State University Neuroscience Center Core, Interrogating adrenal dysfunction to prevent muscle wasting after acute spinal cord injury, Protecting Endogenous Recovery from the "Infectious Insult" in Spinal Cord Injury, Medical Scientist Training Program - The Ohio State University, Cancer Center Support Grant, Overcoming Neurogenic “Meta-Inflammation” to Promote Recovery After Spinal Cord Injury
OpenAlex ID: W4389989582
FWCI: 1.154
Cites: 81
Cited by: 12
Related to: 10