Department of Neurology, Spinal Cord Injury Division (Paraplegiology), College of Medicine, Ohio State University, Wexner Medical Center, Columbus, OH 43210, USA.
Medical Scientist Training Program, College of Medicine, Ohio State University, Wexner Medical Center, Columbus, OH 43210, USA.
Sci Transl Med. 2023 Dec 20;15(727):eadh2156. doi: 10.1126/scitranslmed.adh2156.
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.
脊髓损伤 (SCI) 后早期对骨骼肌萎缩的不完全机制理解阻碍了有针对性的分子干预。在这里，我们在 SCI 小鼠模型中证实了全身性的肌肉消耗，这种消耗也影响了有神经支配的非瘫痪（上位）肌肉，并在 SCI 后 1 周内出现。全身性肌肉消耗导致肌肉无力，优先影响快型 2 肌纤维，并且在高（T3）位而非低位（T9）截瘫后恶化，表明存在与损伤部位相关的（“神经源性”）机制。非瘫痪肌肉的消耗及其快速发生和严重程度超出了废用所解释的范围，暗示存在未知的全身性驱动因素。肌肉转录组和生化分析显示，T3 SCI 后早期存在糖皮质激素介导的分解代谢特征。通过（i）内源性糖皮质激素消除（肾上腺切除术）和（ii）药理学糖皮质激素受体 (GR) 阻断，可减轻 SCI 诱导的全身性肌肉消耗，并且（iii）通过肌肉特异性 GR 缺失可完全预防 T3 相对于 T9 SCI 后的肌肉消耗。这些结果表明，神经源性高皮质醇血症导致小鼠截瘫 SCI 后早期出现快速的全身性和具有功能相关性的肌肉消耗综合征。
