Inflammation-Induced Acute Phase Response in Skeletal Muscle and Critical Illness Myopathy

Abstract

ObjectivesSystemic inflammation is a major risk factor for critical-illness myopathy (CIM) but its pathogenic role in muscle is uncertain. We observed that interleukin 6 (IL-6) and serum amyloid A1 (SAA1) expression was upregulated in muscle of critically ill patients. To test the relevance of these responses we assessed inflammation and acute-phase response at early and late time points in muscle of patients at risk for CIM.DesignProspective observational clinical study and prospective animal trial.SettingTwo intensive care units (ICU) and research laboratory.Patients/Subjects33 patients with Sequential Organ Failure Assessment scores ≥8 on 3 consecutive days within 5 days in ICU were investigated. A subgroup analysis of 12 patients with, and 18 patients without CIM (non-CIM) was performed. Two consecutive biopsies from vastus lateralis were obtained at median days 5 and 15, early and late time points. Controls were 5 healthy subjects undergoing elective orthopedic surgery. A septic mouse model and cultured myoblasts were used for mechanistic analyses.Measurements and Main ResultsEarly SAA1 expression was significantly higher in skeletal muscle of CIM compared to non-CIM patients. Immunohistochemistry showed SAA1 accumulations in muscle of CIM patients at the early time point, which resolved later. SAA1 expression was induced by IL-6 and tumor necrosis factor-alpha in human and mouse myocytes in vitro. Inflammation-induced muscular SAA1 accumulation was reproduced in a sepsis mouse model.ConclusionsSkeletal muscle contributes to general inflammation and acute-phase response in CIM patients. Muscular SAA1 could be important for CIM pathogenesis.Trial RegistrationISRCTN77569430.

The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill

“…Although this increase in inflammation-induced IL-6 myokine production is substantially smaller than in response to strenuous exercise (ϳ15-vs. 100-fold, respectively; Refs. 192,392), the results point towards a common denominator in a "muscle-immune system" axis where skeletal muscle feeds back to the proinflammatory response syndrome by tuning the onset of the CARS reaction (FIGURE 3B). However, since IL-6 also exerts potential detrimental effects on muscle such as muscle wasting, this may even become the more prominent effect in critical illness beyond a putative "tipping point" of IL-6 production such as suggested in FIGURE 3B.…”

“…It is attractive to speculate that systemic IL-6 produced in nonmuscle tissues by TNF-␣ and IL-1 may contribute to proinflammatory feedback while, once muscle secretes large amounts of IL-6 into the circulation, this would shift the response towards an anti-inflammatory feedback. This hypothesis still awaits experimental clarification, but at least one recent study shows that in mechanically ventilated ICU patients who developed myopathy, the inflammation-induced acute phase response resulted in a marked increase in IL-6 production in skeletal muscle, and also in immobilized muscle (392). Although this increase in inflammation-induced IL-6 myokine production is substantially smaller than in response to strenuous exercise (ϳ15-vs. 100-fold, respectively; Refs.…”

The Role of Local and Systemic Inflammation in the Pathogenesis of Intensive Care Unit-acquired Weakness

“…High serum acute phase protein levels [11][12][13][14] and plasma complement products [11] do not correlate with the presence of ICUacquired weakness. The vascular endothelium may be involved in the pathogenesis of ICU-acquired weakness, since cytokines, complement membrane attack complex (MAC) and antigen presenting molecules are found on the vascular endothelium in ICU-acquired weakness [1].…”

Intensive Care Unit Acquired Weakness (ICU-AW): a brief and practical review

“…Fiber atrophy is associated with myosin filament depolymerization that may be caused by increased expression of lysosomal enzymes and ubiquitin [71]. Patients who developed severe weakness after receiving high-dose steroids showed increased ubiquitin expression [72]. This suggests that the ubiquitin-ATP-dependent proteolytic system may be initiated by corticosteroid use.…”

“…This suggests that the ubiquitin-ATP-dependent proteolytic system may be initiated by corticosteroid use. Serum amyloid A1 transiently accumulates within the first few days in muscle of critical illness myopathy patients and is in vitro induced by interleukin 6 and tumor necrosis factor-alpha [72]. Upregulation of part of the apoptotic system, specifically TGF-beta/MAPK, has been found to be uniquely involved in CIM [74].…”