Lesion level-dependent systemic muscle wasting after spinal cord injury is mediated by glucocorticoid signaling in mice
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 S...
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Published in | Science translational medicine Vol. 15; no. 727; p. eadh2156 |
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Main Authors | , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
20.12.2023
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Subjects | |
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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. |
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AbstractList | 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. |
Author | Vadala, Christopher P Filous, Angela R Sahenk, Zarife Reiser, Peter J Harrigan, Markus E Prüss, Harald Schwab, Jan M Webb, Amy Arnold, W David Pietrzak, Maciej Popovich, Phillip G |
Author_xml | – sequence: 1 givenname: Markus E orcidid: 0000-0002-3809-1951 surname: Harrigan fullname: Harrigan, Markus E organization: Belford Center for Spinal Cord Injury, Ohio State University, Wexner Medical Center, Columbus, OH 43210, USA – sequence: 2 givenname: Angela R orcidid: 0000-0003-1493-3197 surname: Filous fullname: Filous, Angela R organization: Belford Center for Spinal Cord Injury, Ohio State University, Wexner Medical Center, Columbus, OH 43210, USA – sequence: 3 givenname: Christopher P orcidid: 0009-0004-2640-4035 surname: Vadala fullname: Vadala, Christopher P organization: Belford Center for Spinal Cord Injury, Ohio State University, Wexner Medical Center, Columbus, OH 43210, USA – sequence: 4 givenname: Amy surname: Webb fullname: Webb, Amy organization: Department of Biomedical Informatics, College of Medicine, Ohio State University, Wexner Medical Center, Columbus, OH 43210, USA – sequence: 5 givenname: Maciej orcidid: 0000-0001-5768-7884 surname: Pietrzak fullname: Pietrzak, Maciej organization: Department of Biomedical Informatics, College of Medicine, Ohio State University, Wexner Medical Center, Columbus, OH 43210, USA – sequence: 6 givenname: Zarife surname: Sahenk fullname: Sahenk, Zarife organization: Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH 43205, USA – sequence: 7 givenname: Harald orcidid: 0000-0002-8283-7976 surname: Prüss fullname: Prüss, Harald organization: German Center for Neurodegenerative Diseases (DZNE), 10117 Berlin, Germany – sequence: 8 givenname: Peter J orcidid: 0000-0003-3677-4211 surname: Reiser fullname: Reiser, Peter J organization: Division of Biosciences, College of Dentistry, Ohio State University, Columbus, OH 43210, USA – sequence: 9 givenname: Phillip G orcidid: 0000-0003-1329-7395 surname: Popovich fullname: Popovich, Phillip G organization: Department of Neuroscience, Ohio State University, Wexner Medical Center, Columbus, OH 43210, USA – sequence: 10 givenname: W David orcidid: 0000-0001-9889-7036 surname: Arnold fullname: Arnold, W David organization: Department of Physical Medicine and Rehabilitation, University of Missouri, Columbia, MO 65212, USA – sequence: 11 givenname: Jan M orcidid: 0000-0001-6784-4919 surname: Schwab fullname: Schwab, Jan M organization: Department of Physical Medicine and Rehabilitation, Ohio State University, Wexner Medical Center, Columbus, OH 43210, USA |
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SubjectTerms | Animals Glucocorticoids Mice Muscle, Skeletal - metabolism Spinal Cord - metabolism Spinal Cord Injuries - pathology |
Title | Lesion level-dependent systemic muscle wasting after spinal cord injury is mediated by glucocorticoid signaling in mice |
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