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

Abstract

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.