Abstract
Myogenic differentiation is triggered, among other situations, in response to muscle damage for regenerative purposes. It has been shown that during myogenic differentiation, myotubes release extracellular vesicles (EVs) which participate in the signalling pattern of the microenvironment. Here we investigated whether EVs released by myotubes exposed or not to mild oxidative stress modulate the behaviour of targeted differentiating myoblasts and macrophages to promote myogenesis. We found that EVs released by oxidatively challenged myotubes (H2O2-EVs) are characterized by an increased loading of nucleic acids, mainly DNA. In addition, incubation of myoblasts with H2O2-EVs resulted in a significant decrease of myotube diameter, myogenin mRNA levels and myosin heavy chain expression along with an upregulation of proliferating cell nuclear antigen: these effects collectively lead to an increase of recipient myoblast proliferation. Notably, the EVs from untreated myotubes induced an opposite trend in myoblasts, that is, a slight pro-differentiation effect. Finally, H2O2-EVs were capable of eliciting an increased interleukin 6 mRNA expression in RAW264.7 macrophages. Notably, this is the first demonstration that myotubes communicate with surrounding macrophages via EV release. Collectively, the data reported herein suggest that myotubes, depending on their conditions, release EVs carrying differential signals which could contribute to finely and coherently orchestrate the muscle regeneration process.
Highlights
Skeletal muscle is a highly plastic tissue capable of adapting to different stresses, in part due to its remarkable regenerative capacity
Incubation of myoblasts with H2O2-extracellular vesicles (EVs) resulted in a significant decrease of myotube diameter, myogenin mRNA levels and myosin heavy chain expression along with an upregulation of proliferating cell nuclear antigen: these effects collectively lead to an increase of recipient myoblast proliferation
The aim of this study was to investigate whether the release of extracellular vesicles from oxidatively challenged myotubes in the microenvironment could modify the behaviour of surrounding myoblasts and macrophages, two of the key players in the muscle niche
Summary
Skeletal muscle is a highly plastic tissue capable of adapting to different stresses, in part due to its remarkable regenerative capacity This feature is largely attributable to the presence of satellite cells, which are undifferentiated mononucleated muscle precursors located beneath the basal lamina of myofibers [1,2]. Regeneration represents a highly coordinated process in which satellite cells are activated to maintain and preserve tissue structure and function. Many factors, such as local or systemic growth factors and inflammatory mediators, have been shown to be involved in the regulation of myoblasts’ proliferation and differentiation to promote muscle repair or regeneration [4]
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