Acute spinal cord injury induces systemic muscle wasting by lesion-level dependent neuroendocrine tone

A limited mechanistic understanding of skeletal muscle wasting after acute spinal cord injury (SCI) precludes targeted molecular interventions. Here, we demonstrate marked systemic wasting also affecting neurologically intact non-paralyzed (supralesional) muscle early after SCI. Systemic muscle mass loss propagates muscle weakness, affects fast type 2 myofibers preferentially, and becomes exacerbated after high (T3) compared to low (T9) thoracic paraplegia indicating lesion-level dependent (“neurogenic”) mechanisms. The wasting of non-paralyzed muscle, its rapid onset and severity beyond what can be explained by disuse implies additional systemic drivers. Muscle transcriptome and biochemical analysis revealed a glucocorticoid-mediated catabolic signature of SCI-induced systemic muscle wasting that was mitigated i) by endogenous glucocorticoid ablation (adrenalectomy), ii) by pharmacological glucocorticoid receptor (GR) blockade, and was iii) completely prevented, relative to T9 SCI, by genetic muscle-specific GR deletion. We provide evidence of neurogenic hypercortisolism underlying a rapid systemic and functionally relevant muscle wasting syndrome after acute SCI. 4 to 6 replicates of sham, high-thoracic (T3), or low-thoracic (T9) spinal cord injuries from Gastrocnemius Muscle or Triceps Brachii Muscle