Electrical Stimulated Glut4 Trafficking Reduces Critical Illness-Associated Muscle Wasting.

Critical illness myopathy (CIM) is a debilitating condition characterized by the preferential loss of the motor protein myosin. CIM is a consequence of critical care, impairs recovery and provides long-term complications, and mortality. CIM pathophysiology is complex and remains incompletely understood, however loss of mechanical stimuli appears central to critical illness associated muscle atrophy and weakness. Passive mechanical loading (ML) and electrical stimulation (ES) augment muscle mass and function, however the mechanisms underpinning these therapies are less known. Here we aimed to assess the hypothesis that chronic supramaximal ES would ameliorate CIM in a unique experimental rat model of critical care. Rats were subjected to deep sedation, controlled mechanical ventilation, and immobilization with and without direct soleus ES for 8 days. Critical care reduced soleus muscle mass, cross-sectional area (CSA), Myosin: Actin ratio and single muscle fibre specific force. ES reduced the loss of soleus muscle fibre CSA and Myosin: Actin ratio yet failed to effect specific force. Insulin signalling gene pathway was downregulated following critical care and GLUT4 trafficking was reduced leading to muscle glycogen depletion. ES promoted phosphofructokinase and insulin signalling pathways and maintained GLUT4 translocation and glycogen levels. ES evoked AMPK, but not AKT, signalling pathway, where the downstream target TBC1D4 and AMPK-specific P-TBC1D4 levels tended to be increased. Reduced muscle protein degradation promoted soleus CSA, as ES reduced E3 ligases Atrogin-1 and MuRF1 downstream of AMPK-FoxO3. These results demonstrate chronic supramaximal ES reduces critical care associated muscle wasting, preserved glucose signalling and reduced muscle protein degradation in CIM.