Salah, Heba

Key points Critical illness myopathy (CIM) is a frequently observed negative consequence of modern critical care. Chronic Janus kinase (JAK)/signal transducer and activator of transcription activation impairs muscle size and function and is prominent following mechanical ventilation. We identify pSTAT‐3 activation in tibialis anterior of CIM patients, before examining the potential benefits of JAK1/2 inhibition in an experimental model of CIM, where muscle mass and function are impaired. CIM activates complement cascade and increased monocyte infiltration in the soleus muscle, which was ameliorated by JAK1/2 inhibition, leading to reduced muscle degeneration and improved muscle force. Here, we demonstrate that JAK1/2 inhibition augments CIM muscle function through regulation of the complement cascade. AbstractCritical illness myopathy (CIM) is frequently observed in response to modern critical care with negative consequences for patient quality of life, morbidity, mortality and healthcare costs. Janus kinase (JAK)/signal transducer and activator of transcription (STAT) activation is observed in limb muscles following controlled mechanical ventilation. Chronic JAK/STAT activation promotes loss of muscle mass and function. Thus, we hypothesized that JAK1/2 inhibition would improve muscle outcomes for CIM. Following 12 days of intensive care unit conditions, pSTAT‐3 levels increased in tibialis anterior muscle of CIM patients (P = 0.0489). The potential of JAK1/2 inhibition was assessed in an experimental model of CIM, where soleus muscle size and force are impaired. JAK1/2 inhibition restores soleus force (P < 0.0001). CIM activated muscle complement cascade, which was ameliorated by JAK1/2 inhibition (P < 0.05, respectively). Soleus macrophage number corresponded with complement activity, leading to reduced muscle degeneration and augmented muscle function (P < 0.05). Thus, JAK/STAT inhibition improves soleus function by modulating the complement cascade and muscle monocyte infiltration. Collectively, we demonstrate that JAK/STAT inhibition augments muscle function in CIM.

AbstractAimMuscle wasting is one of the factors most strongly predicting mortality and morbidity in critically ill intensive care unit (ICU). This muscle wasting affects both limb and respiratory muscles, but the understanding of underlying mechanisms and muscle‐specific differences remains incomplete. This study aimed at investigating the temporal expression and phosphorylation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway in muscle wasting associated with the ICU condition to characterize the JAK/STAT proteins and the related changes leading or responding to their activation during exposure to the ICU condition.MethodsA novel experimental ICU model allowing long‐term exposure to the ICU condition, immobilization and mechanical ventilation, was used in this study. Rats were pharmacologically paralysed by post‐synaptic neuromuscular blockade and mechanically ventilated for durations varying between 6 hours and 14 days to study muscle‐specific differences in the temporal activation of the JAK/STAT pathway in plantaris, intercostal and diaphragm muscles.ResultsThe JAK2/STAT3 pathway was significantly activated irrespective of muscle, but muscle‐specific differences were observed in the temporal activation pattern between plantaris, intercostal and diaphragm muscles.ConclusionThe JAK2/STAT3 pathway was differentially activated in plantaris, intercostal and diaphragm muscles in response to the ICU condition. Thus, JAK2/STAT3 inhibitors may provide an attractive pharmacological intervention strategy in immobilized ICU patients, but further experimental studies are required in the study of muscle‐specific effects on muscle mass and function in response to both short‐ and long‐term exposure to the ICU condition prior to the translation into clinical research and practice.