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

Mieradilijiang Abudupataer,Zhiwei Zhang,Weihong Zou,Jinmiao Chen,Xiangdong Yang,Chunsheng Wang,Hui Li,Suling Ding,Junbo Ge,Tao Hong,Zheliang Zhou,Weiwei Zhang

doi:10.1111/jcmm.14720

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.

Highlights

Skeletal muscle regeneration after ischaemic injury involves multiple processes, the inflammatory response, an‐ giogenesis and tissue regeneration
Given that we found that the expression of Igf‐1 and Igf‐1 receptor mRNA decreased in the injured muscle of Hdc−/− mice relative to WT mice, we aimed to clarify the relationship between the histamine/HR pathway and the IGF‐1R/phosphatidylinositol 3‐kinase (PI3K)/AKT pathway during muscle regeneration
We show that histamine deficiency (Hdc−/−) interrupts the regenerative microenvironment leading to impaired muscle regeneration

Summary

| INTRODUCTION

Skeletal muscle regeneration after ischaemic injury involves multiple processes, the inflammatory response, an‐ giogenesis and tissue regeneration. The growth factors and cytokines released from the injured blood vessels, muscle fibres and infiltrated immune cells have multiple effects on the proliferation and differentiation of myoblasts in re‐ sponse to muscle fibre damage. Injured muscle fibres can increase the infiltration of immune cells in injured muscle, and myoblasts have been demonstrated to release factors that attract macrophages and monocytes This indicates that myoblasts, immune cells and IGF‐1 can interact with each other and influence their func‐ tion, resulting in the formation of a microenvironment that regulates muscle regeneration co‐ordinately.[15,16]. Histamine is involved in the regula‐ tion of inflammation, hematopoiesis, immune cell differentiation, embryonic development and wound healing, but its roles in the proliferation and differentiation of muscle stem cells and tissue regeneration have not been fully studied. We report that histamine deficiency promotes inflammation, re‐ duces limb perfusion and represses myoblast proliferation, leading to delayed muscle regeneration after ischaemic injury of skeletal muscle

| MATERIALS AND METHODS

| DISCUSSION

Findings

CONFLICT OF INTEREST