Critical illness impairs coordinated myogenesis: a prospective longitudinal study of skeletal muscle progenitor cell biology using serial muscle biopsies (SATELLITE study)

BACKGROUND: Critical illness often causes prolonged weakness, possibly due to impaired skeletal muscle regeneration, but the timing and nature of satellite cell (SC) dysfunction remain unclear. We aimed to determine whether SC depletion and dysfunction are detectable early after intensive care unit admission and describe their pathophysiological nature. METHODS: In this prospective single-centre observational cohort study, mechanically ventilated adults underwent paired vastus lateralis biopsies within 72 h of ICU admission and again after 7 and 180 days. Isolated satellite cells were studied for proliferation, differentiation and fusion, mitochondrial morphology, respiratory function, substrate oxidation, and selected signalling proteins. RESULTS: We enrolled 20 healthy control subjects and 33 ICU patients. Twenty three ICU patients survived to day 7 with a repeat biopsy. During 7 days in ICU, the patient developed profound weakness (MRC score 16 [0-32]) and insulin resistance (whole body glucose disposal 4.0 [3.5-5.1] versus 13.8 [8.8-16.1] mg/kg/min in controls). Satellite cell number per fibre was similar in controls and patients at admission (0.106 [0.085-0.129] vs. 0.098 [0.056-0.125]) and after 7 days (0.084 [0.066-0.117]; paired p = 0.784). SC proliferation was lower in older patients (ρ=-0.68 and - 0.49) and associated with lower muscle strength (ρ = 0.55 and 0.62). Myogenic differentiation was transiently impaired at day 0 (fusion index 68.9% [66.3-71.7] vs. 74.0% [70.3-77.1] in controls; p = 0.029). Satellite cell bioenergetics and substrate preferences were broadly preserved. In contrast, a more fragmented mitochondrial phenotype was associated with lower proliferation, lower respiratory performance, and worse muscle strength (ρ≈-0.6 to -0.8), whereas more interconnected morphology was associated with better function (ρ ≈ 0.6-0.7). Out of 10 ICU survivors at day 180, only 7 attended follow up. In those, impaired SF-36 physical score (62.5 [55.0 to 75.0]) and SC proliferation capacity (~50 %), contrasted with improved insulin sensitivity and SC number per fiber (~71 % and ~95% of control values, respectively). CONCLUSIONS: Critical illness was associated with disturbed satellite cell regenerative programming and altered mitochondrial remodelling rather than early depletion of the satellite cell pool or overt bioenergetic failure. Age was a stronger predictor of early satellite cell dysfunction than disease severity. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05671614. Registered 4 January 2023.