Integrated Single-Fiber Multi-Omics in ICU-acquired weakness

ABSTRACT: Skeletal muscle dysfunction is a pervasive complication of critical illness that worsens survival and recovery, yet remains poorly explained by current clinical or molecular markers. To directly connect disease-associated molecular states to the contractile machinery, this study combined sequential functional, transcriptomic, and proteomic profiling of the same single human rectus femoris myofibers from critically ill patients in the intensive care unit with acquired weakness (ICU-AW) and controls. Despite marked donor-level heterogeneity, integrated analysis revealed a subtle yet conserved myofiber state enriched in ICU-AW, characterized by inflammatory and chemotactic gene programs, intracellular structural remodeling, and bioenergetic adaptation. Nineteen features were significantly altered at both RNA and protein levels from the same myofiber, linking an inflammatory transcriptional landscape to a proteomic shift toward mitochondrial and translational machinery and away from membrane-associated signaling. Functionally, fibers within this state displayed selectively disrupted myosin dynamics, attested by prolonged ATP turnover time of myosin heads in their super-relaxed conformation, implicating altered myosin energetics as a contributor to muscle dysfunction under systemic stress. These findings define a discrete, disease-associated myofiber state and establish an integrative single-fiber framework for connecting multi-omic heterogeneity to molecular motor function in complex human disease.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Skeletal Muscle Fiber, Rectus Femoris

DISEASE(S): Critical Illness Polyneuropathy

SUBMITTER: Alexandra Winant  

LAB HEAD: Julien Ochala

PROVIDER: PXD073993 | Pride | 2026-10-20

REPOSITORIES: Pride