Monocyte/Macrophage-derived IGF-1 Orchestrates Murine Skeletal Muscle Regeneration and Modulates Autocrine Polarization

Abstract

Insulin-like growth factor 1 (IGF-1) is a potent enhancer of tissue regeneration, and its overexpression in muscle injury leads to hastened resolution of the inflammatory phase. Here, we show that monocytes/macrophages constitute an important initial source of IGF-1 in muscle injury, as conditional deletion of the IGF-1 gene specifically in mouse myeloid cells (ϕIGF-1 CKO) blocked the normal surge of local IGF-1 in damaged muscle and significantly compromised regeneration. In injured muscle, Ly6C+ monocytes/macrophages and CD206+ macrophages expressed equivalent IGF-1 levels, which were transiently upregulated during transition from the inflammation to repair. In injured ϕIGF-1 CKO mouse muscle, accumulation of CD206+ macrophages was impaired, while an increase in Ly6C+ monocytes/macrophages was favored. Transcriptional profiling uncovered inflammatory skewing in ϕIGF-1 CKO macrophages, which failed to fully induce a reparative gene program in vitro or in vivo, revealing a novel autocrine role for IGF-1 in modulating murine macrophage phenotypes. These data establish local macrophage-derived IGF-1 as a key factor in inflammation resolution and macrophage polarization during muscle regeneration.

Highly Dynamic Transcriptional Signature of Distinct Macrophage Subsets during Sterile Inflammation, Resolution, and Tissue Repair

“…hi macrophages fulfill the designation of restorative macrophages given their ability to produce proregenerative factors (e.g., insulin-like growth factor-1 [29]) and their contribution to muscle regeneration by acting on both myogenic (13) and fibroadipogenic (48) precursors.…”

“…The expression pattern of a series of molecules secreted by macrophages and involved in myogenesis (insulin-like growth factors, urokinase plasminogen activator, platelet-derived growth factor a, hepatocyte growth factor, bone morphogenetic protein 2 [24][25][26][27][28][29]) was increased with time of regeneration, and particularly in Ly6C neg macrophages (Fig. 3C).…”

Macrophages in Tissue Repair, Regeneration, and Fibrosis

“…Knuever and colleagues have shown that myeloid cell-restricted insulin and IGF-1 receptor deficiency protects mice from skin inflammation by decreasing pro-inflammatory cytokine production from epidermal cells (Knuever et al, 2015). Monocyte and macrophage-derived IGF-1 has also been identified as a critical factor in skeletal muscle repair (Tonkin et al, 2015). Finally, anti-inflammatory macrophages also regulate the development and maintenance of IL-10 and TGF-β1 producing Treg cells, which contribute to the resolution of tissue-damaging inflammatory responses in multiple tissues (Soroosh et al, 2013).…”

Redox Control of Skeletal Muscle Regeneration

“…Insulin growth factor-1 (IGF-1), which is a master regulator of myogenesis and skeletal muscle growth, is expressed mainly by macrophages during muscle regeneration and is required for their skewing in an autocrine way (324). One study reported that ROS suppression (UK-134 and a-lipoic acid) restores IGF-1 sensitivity of diabetic fibroblasts and improves their healing functions both in vitro and in vivo (37).…”