Fig. 2

Mediators of acute respiratory distress syndrome (ARDS)-induced muscle dysfunction. Skeletal muscle atrophy is the most universal feature of the early phase, which is driven fundamentally by inflammation and disuse. Other factors such as neuropathic injury and medications can exacerbate atrophy (blue arrow) and independently cause muscle dysfunction. Therefore, inhibiting muscle protein degradation is the most promising potential early-phase therapy. The late phase is marked by cessation of inflammation-induced muscle proteolysis and therefore potential treatments at this time point will differ. Mediators of the late phase may involve persistence of some early-phase injuries or a failure to regain muscle homeostasis following the early phase. Late-phase dysfunction may be compounded by underlying pre-ARDS neuromuscular defects. NMJ, neuromuscular junction; SR Ca⁺, sarcoplasmic reticulum calcium; UPS, ubiquitin-proteasome system