Human macrophages rescue myoblasts and myotubes from apoptosis through a set of adhesion molecular systems

Abstract

The mechanisms underlying stromal cell supportive functions are incompletely understood but probably implicate a mixture of cytokines, matrix components and cell adhesion molecules. Skeletal muscle uses recruited macrophages to support post-injury regeneration. We and others have previously shown that macrophages secrete mitogenic factors for myogenic cells. Here, we focused on macrophage-elicited survival signals. We demonstrated that: (1) macrophage influx is temporally correlated with the disappearance of TUNEL-positive apoptotic myogenic cells during post-injury muscle regeneration in mice; (2) direct cell-cell contacts between human macrophages and myogenic cells rescue myogenic cells from apoptosis, as assessed by decreased annexin V labelling and caspase-3 activity, and by increased DIOC-6 staining, Bcl-2 expression and phosphorylation of Akt and ERK1/2 survival pathways; (3) four pro-survival cell-cell adhesion molecular systems detected by DNA macroarray are expressed by macrophages and myogenic cells in vitro and in vivo - VCAM-1-VLA-4, ICAM-1-LFA-1, PECAM-1-PECAM-1 and CX3CL1-CX3CR1; (4) macrophages deliver anti-apoptotic signals through all four adhesion systems, as assessed by functional analyses with blocking antibodies; and (5) macrophages more strongly rescue differentiated myotubes, which must achieve adhesion-induced stabilisation of their structure to survive. Macrophages could secure these cells until they establish final association with the matrix.

Transplanted Mesoangioblasts Require Macrophage IL-10 for Survival in a Mouse Model of Muscle Injury

“…Notably, macrophages secrete both signals such as TNF-a that worsen muscle wasting via activation of the FOXO transcription factor (66, 67) and molecules that have an opposite function, such as IGF-1, a central regulator of muscle regeneration (7,56,57), or IL-10 (59, 68, 69). The activation of distinct pathways in muscle cells depending on macrophage activation leading to growth or differentiation had been described and characterized in elegant earlier studies (12,(70)(71)(72)(73)(74)(75)(76)(77).…”

Skeletal muscle regeneration involves macrophage-myoblast bonding

“…al provided evidence for the expression of a set of adhesion molecules that deliver survival signals to myogenic cells. 7 These adhesion molecules were only detected by DNA microarray and then visualized by in vivo immunolabelling. However, in situ ultrastructural details of direct intercellular contacts have not been investigated so far.…”

The Role of the Innate and Adaptive Immunity in Exercise Induced Muscle Damage and Repair

“…Once the repair process has been resolved, the number of tissue resident macrophages returns to base line levels. Tissue resident macrophages can directly affect resident fibro-adipogenic precursors (FAPs) in the muscle, that promote their differentiation to stimulate extracellular matrix (ECM) formation [44, 47,48]. In addition, macrophages can also induce effects on muscle progenitor cells through secretion of cytokines such as IL-1, IL-6, TNFα and vascular endothelial growth factor (VEGF) [49].…”