Muscle satellite cell dysfunction in critical illness: niche biology, regenerative failure, and implications for recovery

Abstract

Adult skeletal muscle can regenerate. After muscle injury, muscle stem cells (satellite cells) can generate new muscle fibers. Under normal conditions, satellite cells are mitotically quiescent and located beneath the basal lamina of muscle fibers. In response to regenerative stimuli, satellite cells activate and proliferate as myogenic precursor cells. After several rounds of cell division, these precursor cells differentiate and fuse to form new muscle fibers. A subset of proliferating myogenic precursor cells returns to a quiescent state to replenish the satellite cell pool through self-renewal. Intensive care unit–acquired weakness (ICU-AW) affects many critically ill patients partly due to acute muscle loss. It is a major physical component of post-intensive care syndrome. Current explanations of ICU-AW focus on rapid protein breakdown and impaired energy metabolism during the early catabolic phase, but these mechanisms do not fully explain why some survivors fail to rebuild muscle once the initial catabolic stress has subsided. In this review, we argue that persistent weakness may also reflect defective muscle regeneration, with satellite cell dysfunction and niche abnormalities as plausible contributors. Recent serial-biopsy studies suggest that dysfunction can occur without stem-cell depletion: satellite cell number can be preserved even when differentiation or later proliferative capacity is impaired in culture. We first review the normal satellite cell niche, including the parent fiber, microvasculature and perivascular cells, extracellular matrix, resident immune and interstitial cells, and systemic signals, with separate consideration of the diaphragm. We then examine how critical illness affects these compartments and how cell-intrinsic defects may additionally impair regeneration. We use this evidence to develop three working hypotheses (niche-detached activation, abortive myogenesis, and niche locking) and treat them as testable models rather than recognized mechanisms. Finally, we consider how future studies might measure, target, and test these processes.