Intensive Care Unit Acquired Weakness Is Associated with Rapid Changes to Skeletal Muscle Proteostasis

Abstract

Intensive care unit (ICU)-acquired weakness is a frequent consequence of critical illness that impacts both the limb and respiratory muscles. The cause of ICU-acquired weakness is multifactorial, but both prolonged limb muscle inactivity and mechanical ventilation are risk factors for muscle wasting, which predisposes ICU patients to both short-term complications and long-term disabilities resulting from muscle weakness. Unfortunately, the current research does not provide a detailed understanding of the cellular etiology of ICU-acquired weakness, and no standard treatment exists. Therefore, improving knowledge of the mechanisms promoting muscle atrophy in critically ill patients is essential to developing therapeutic strategies to protect against ICU-induced skeletal muscle wasting. To advance our understanding of the mechanism(s) responsible for ICU-acquired weakness, we tested the hypothesis that ICU-induced muscle inactivity promotes a rapid decrease in anabolic signaling/protein synthesis and accelerates proteolysis in both limb and respiratory muscles. To investigate ICU-induced changes in skeletal muscle proteostasis, adult Sprague Dawley rats were anesthetized and mechanically ventilated for 12 h to simulate ICU care. Measurements of anabolic signaling, protein synthesis, and proteolytic activity in the limb muscles (plantaris and soleus) and respiratory muscles (parasternal and intercostal) revealed ICU-induced reductions in both anabolic signaling (i.e., AKT/mTOR pathway) and muscle protein synthesis. Moreover, simulated ICU care resulted in increased biomarkers of accelerated proteolysis in both limb and respiratory muscles. These novel findings reveal that disturbances in limb and respiratory muscle proteostasis occur rapidly during ICU-induced muscle inactivity, irrespective of the muscle function or muscle fiber type.