Ghrelin ameliorates sepsis-induced acute skeletal muscle wasting via hypothalamic JAK2/STAT3-AgRP pathway

Sepsis-induced acute skeletal muscle wasting would impede critical patients' recovery. The underlying mechanism for this metabolic disorder has not been fully elucidated. Here, we tested the hypothesis that circulating hormone ghrelin could regulate sepsis-induced acute skeletal muscle wasting via hypothalamic Janus Kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3) and agouti-related protein (AgRP) pathway.

Cecal ligation and puncture (CLP) was used to establish the model of sepsis-induced acute skeletal muscle wasting in rats. Ghrelin was administrated subcutaneously and in third ventricle (3V) to evaluate its effect on muscle wasting and hypothalamic molecules. Regulated AgRP expression by adenovirus vector approach and modulated hypothalamic JAK2/STAT3 activation by AG490 and colivelin injection were employed to study their role on muscle wasting. The effects of enteral nutrition (EN) on muscle wasting and hypothalamic molecules were also tested.

Both peripheral and 3V ghrelin administration could decrease atrophy genes expression, increase hypothalamic growth hormone secretagogue receptor-1a and AgRP gene expression, and lower hypothalamic JAK2/STAT3 pathway activation in septic model rats. Inhibiting AgRP expression has little effect on atrophy genes expression and hypothalamic JAK2/STAT3 pathway activity in sepsis, but it would mitigate the protective effect of ghrelin on muscle wasting. Inhibiting hypothalamic JAK2/STAT3 pathway partially restored AgRP expression, reduced hypothalamic IL-1β expression, and attenuated muscle wasting caused by sepsis. Of note, activate hypothalamic JAK2/STAT3 pathway evoked hypothalamic inflammation and neuropeptides alteration, as well as muscle wasting in sham subjects. Although AgRP over-expression could mitigate sepsis-induced muscle wasting, it has little effect on hypothalamic JAK2/STAT3 pathway activity and inflammation. EN could ameliorate sepsis-induced muscle wasting, but requiring AgRP expression.

Ghrelin could regulate sepsis-induced acute skeletal muscle wasting via hypothalamic JAK2/STAT3 and AgRP pathway. The protective effect of EN on muscle wasting was mediated by ghrelin and AgRP.