Histamine deficiency delays ischaemic skeletal muscle regeneration via inducing aberrant inflammatory responses and repressing myoblast proliferation

Histidine decarboxylase (HDC) catalyses the formation of histamine from L‐histidine. Histamine is a biogenic amine involved in many physiological and pathological processes, but its role in the regeneration of skeletal muscles has not been thoroughly clarified. Here, using a murine model of hindlimb ischaemia, we show that histamine deficiency in Hdc knockout (Hdc(−/−)) mice significantly reduces blood perfusion and impairs muscle regeneration. Using Hdc‐EGFP transgenic mice, we demonstrate that HDC is expressed predominately in CD11b(+)Gr‐1(+) myeloid cells but not in skeletal muscles and endothelial cells. Large amounts of HDC‐expressing CD11b(+) myeloid cells are rapidly recruited to injured and inflamed muscles. Hdc(−/−) enhances inflammatory responses and inhibits macrophage differentiation. Mechanically, we demonstrate that histamine deficiency decreases IGF‐1 (insulin‐like growth factor 1) levels and diminishes myoblast proliferation via H3R/PI3K/AKT‐dependent signalling. These results indicate a novel role for HDC‐expressing CD11b(+) myeloid cells and histamine in myoblast proliferation and skeletal muscle regeneration.