학술논문
Programmed myofibre necrosis in critical illness acquired muscle wasting
Document Type
Academic Journal
Author
Source
JCSM Rapid Communications. July 2023, Vol. 6 Issue 2, p111, 121 p.
Subject
Language
English
Abstract
Introduction Skeletal muscle wasting during critical illness, and its impact on patients and the healthcare system is well described.[sup.1,2] Intramuscular inflammation and altered protein homeostasis contribute to a reduction in [...]
: Background: Acute skeletal muscle wasting during critical illness is common and causes significant morbidity and functional limitation. Myofibre necrosis is a major histological finding but is often considered an unprogrammed by‐product of muscle inflammation. This study sought to evaluate if a form of programmed necrosis, necroptosis, is activated in skeletal muscle during critical illness. Methods: A cohort of 28 patients from the MUSCLE‐UK study (ClinicalTrials.gov: NCT01106300) with serum and skeletal muscle biopsy samples were identified. Samples were available from ICU admission (T1) and between day 7–10 post admission (T2). Skeletal muscle was stratified by a histopathologist in the original study as necrotic (NEC, N = 14) or non‐necrotic (NONEC, N = 14) using haematoxylin and eosin staining. We used phosphorylated mixed‐lineage kinase domain‐like (pMLKL) protein (a key terminal effector protein) and receptor‐interacting protein kinase 3 (RIPK3) as markers of necroptosis activation using Western blotting and immunohistochemistry. Results: We show that pMLKL expression is significantly higher in the NEC group [NEC: T2:T1 expression; 9.1 (IQR 3.9–22.3) vs. NONEC: T2:T1 expression; 0.9 (IQR 0.6–1.1), P = 0.003]. We then confirm this upregulation and describe co‐localization with receptor interacting protein kinase 3 (RIPK3) in skeletal muscle using immunohistochemistry. We show that both RIPK3 and pMLKL are present within intact myofibres at the intermediate timepoint day 3 without cellular infiltrate. At T2, pMLKL is also present in the interstitial space where there is infiltrate of CD68 positive immune cells. The observed necroptosis may originate from both internal and infiltrating sources. These findings were absent in samples from patients who did not exhibit histopathological features of necrosis. Conclusions: We show that necroptosis machinery, RIPK3 and pMLKL, are associated with conventional histopathological features of myonecrosis in a critically ill cohort.
: Background: Acute skeletal muscle wasting during critical illness is common and causes significant morbidity and functional limitation. Myofibre necrosis is a major histological finding but is often considered an unprogrammed by‐product of muscle inflammation. This study sought to evaluate if a form of programmed necrosis, necroptosis, is activated in skeletal muscle during critical illness. Methods: A cohort of 28 patients from the MUSCLE‐UK study (ClinicalTrials.gov: NCT01106300) with serum and skeletal muscle biopsy samples were identified. Samples were available from ICU admission (T1) and between day 7–10 post admission (T2). Skeletal muscle was stratified by a histopathologist in the original study as necrotic (NEC, N = 14) or non‐necrotic (NONEC, N = 14) using haematoxylin and eosin staining. We used phosphorylated mixed‐lineage kinase domain‐like (pMLKL) protein (a key terminal effector protein) and receptor‐interacting protein kinase 3 (RIPK3) as markers of necroptosis activation using Western blotting and immunohistochemistry. Results: We show that pMLKL expression is significantly higher in the NEC group [NEC: T2:T1 expression; 9.1 (IQR 3.9–22.3) vs. NONEC: T2:T1 expression; 0.9 (IQR 0.6–1.1), P = 0.003]. We then confirm this upregulation and describe co‐localization with receptor interacting protein kinase 3 (RIPK3) in skeletal muscle using immunohistochemistry. We show that both RIPK3 and pMLKL are present within intact myofibres at the intermediate timepoint day 3 without cellular infiltrate. At T2, pMLKL is also present in the interstitial space where there is infiltrate of CD68 positive immune cells. The observed necroptosis may originate from both internal and infiltrating sources. These findings were absent in samples from patients who did not exhibit histopathological features of necrosis. Conclusions: We show that necroptosis machinery, RIPK3 and pMLKL, are associated with conventional histopathological features of myonecrosis in a critically ill cohort.