DOI: 10.1097/ccm.0000000000007288 ISSN: 0090-3493

Rethinking Muscle Wasting in Critical Illness: A Systematic Review and Meta-Analysis of Myofiber Size and Protein Turnover

Felipe González-Seguel, Cayla M. Robinson, Camilo Caceres-Parra, Cecilia Villablanca, Catalina Olave, Felipe Muñoz-Muñoz, Owen Gustafson, Madeline Cavallaro, Zoe Calulo Rivera, Selina M. Parry, Yuan Wen, Benjamin F. Miller, Kirby P. Mayer, Esther E. Dupont-Versteegden
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Objectives:

To identify biological findings underlying skeletal muscle dysfunction in adults with critical illness and meta-analyze myofiber cross-sectional area and protein turnover variables.

Data Sources:

Six databases were electronically searched from inception to January 2025.

Study Selection:

We included original studies reporting biological findings obtained from skeletal muscle biopsies of adults with critical illness.

Data Extraction:

Bibliometrics, characteristics of the patients/controls, and biological findings were extracted in duplicate. Descriptive statistics of biological findings were performed. Random-effects meta-analyses investigated mean differences (MDs) in myofiber cross-sectional area and protein turnover compared with controls.

Data Synthesis:

From 22,035 titles screened, 75 studies ( n = 2,023 patients; n = 642 controls) published between 1988 and 2024 were included, with 48 unique patient datasets. Biopsies were mainly collected from vastus lateralis (64 [85%] studies) during the first ICU week (50% of studies) and post-ICU (9%). Biological findings included predominant type II myofiber atrophy with necrosis and structural degeneration, mitochondrial dysfunction, inflammatory/fibrotic changes, and upregulated ubiquitin-proteasome/autophagy pathways. Data from six studies ( n = 100 patients; 193 controls) indicated that cross-sectional area was 22% lower in patients with critical illness before (MD, –689 µm 2 ; 95% CI, –1265 to –113 µm 2 ; p = 0.02) and after (MD, –775 µm 2 ; 95% CI, –1512 to –37 µm 2 ; p = 0.04) ICU discharge. Across seven studies ( n = 126 patients; 61 controls) protein synthesis was not significantly different in patients with critical illness compared with controls (MD, 0.007%/hr; 95% CI, –0.010 to 0.027; p = 0.36). Protein degradation pathway markers were significantly higher (standardized MD ranging, 0.5–1.7) in data from 11 studies ( n = 439 patients; 163 controls).

Conclusions:

Muscle wasting during critical illness reflects multifaceted biological disturbances. While myofiber size is significantly lower in patients with critical illness, pooled analyses show no significant differences in muscle protein synthesis compared with non-ICU controls, whereas protein degradation markers are consistently higher.

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