Remote neuromuscular electrical stimulation upregulates MDK to enhance macrophage efferocytosis

Neuromuscular electrical stimulation (NMES) is a well-established therapeutic approach for chronic wounds. Conventionally, NMES involves direct electrode contact with wounds or adjacent healthy skin; however, it is limited by the need for wound exposure and by increased pain. Our preliminary study demonstrated the innovative application of remote NMES (rNMES) to the skeletal muscle of the distal calf, which showed the potential to accelerate wound healing in remote areas. rNMES was effective in human clinical trials in our previous work, although the underlying mechanisms remain unclear. As rNMES is often used to stimulate muscle contraction in long-term bedridden patients, we analyzed data from the Gene Expression Omnibus (GEO) database and found that exercise promotes midkine (MDK) expression in muscle. MDK is a small secreted heparin-binding protein that interacts with multiple cell surface receptors to promote growth. In the present study, we found that MDK significantly enhanced macrophage efferocytosis in a low-density lipoprotein receptor-related protein 1 (LRP1)-dependent manner. Our findings demonstrate that rNMES upregulates MDK expression in skeletal muscles through the AMPK-ERK axis, facilitating its delivery to wounds through the circulatory system and promoting LRP1-mediated efferocytosis of apoptotic cells, thereby expediting wound healing.