Skeletal muscle myokine expression in critical illness, association with outcome and impact of therapeutic interventions

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.