Skeletal Muscle Myokine Expression in Critical Illness, Association With Outcome and Impact of Therapeutic Interventions

Abstract

Context Muscle expresses and secretes several myokines that bring about benefits in distant organs. Objective We investigated impact of critical illness on muscular expression of irisin, kynurenine-aminotransferases and amylase; association with clinical outcome; and impact of interventions that attenuate muscle wasting/weakness. Design/Setting We studied critically ill patients who participated in two RCTs (EPaNIC/NESCI) and documented time profiles in critically ill mice. Patients/other participants 174 intensive-care-unit (ICU) patients (day 8 ± 1) vs 19 matched controls, 60 mice subjected to surgery/sepsis vs 60 pair-fed healthy mice. Interventions Seven-days neuromuscular electrical stimulation (NMES), withholding parenteral-nutrition in the first ICU-week (late-PN) vs early-PN. Main outcome measures FNDC5 (irisin-precursor), KYAT1, KYAT3 and amylase mRNA-expression in skeletal-muscle. Results Critically ill patients showed a 34-80% lower mRNA-expression of FNDC5, KYAT1 and amylases compared with controls (p < 0.0001). Critically ill mice showed time-dependent reductions in all mRNAs compared with healthy mice (p ≤ 0.04). The lower FNDC5 expression in patients was independently associated with a higher ICU-mortality (p = 0.015) and ICU-acquired weakness (p = 0.012), whereas the lower amylase expression in ICU survivors was independently associated with a longer ICU-stay (p = 0.0060). A lower amylase expression was independently associated with a lower risk of death (p = 0.048) and a lower KYAT1 expression with a lower risk of weakness (p = 0.022). NMES increased FNDC5 expression compared with unstimulated muscle (p = 0.016), and late-PN patients had a higher KYAT1 expression than early-PN patients (p = 0.022). Conclusions Expression of the studied myokines was affected by critical illness and associated with clinical outcomes, with limited effects of interventions that attenuate muscle wasting or weakness.