Histamine Deficiency Delays Ischemic Skeletal Muscle Regeneration Via Inducing Aberrant Inflammatory Responses and Repressing Myoblast Proliferation

Abstract

Histidine decarboxylase (HDC) catalyzes the formation of histamine from L-histidine. Histamine is a biogenic amine being involved in many physiological and pathological processes, but its role in the regeneration of skeletal muscles has not been thoroughly clarified. Here we show that histamine deficiency in Hdc-knockout (Hdc-/-) mice significantly reduces blood perfusion and impairs muscle regeneration using a murine model of hind limb ischemia. 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. A large amount of HDC-expressing CD11b myeloid cells are recruited rapidly to the injured and inflamed muscles. Hdc-/- enhances inflammatory responses and inhibits macrophage differentiation. Mechanically, we show that histamine deficiency decreases IGF-1 level and diminishes myoblast proliferation via H3R/PI3K/AKT dependent signal. These results indicate a novel role for HDC-expressing CD11b myeloid cells and histamine in myoblast proliferation and skeletal muscle regeneration. Funding Statement: This work was supported by the National Key Research and Development Program (No. 2016YFC1101102) and the National Natural Science Foundation of China (81370402, 91439121, 81521001, 81500262). Xiangdong Yang was also supported by Grants (13JC1401701, and 20130071110042). Declaration of Interests: The authors declare no conflicts of interest relevant to what we wrote. Ethics Approval Statement: The protocol was approved by the Committee on the Ethics of Animal Experiments of Fudan University (approval reference number: SY2014.2.001.002).