Abstract
In this study, we investigated the effects and mechanisms of the pro-inflammatory cytokines IL-1β and TNF-α on the proliferation and commitment phases of myoblast differentiation. C2C12 mouse myoblast cells were cultured to reach a proliferated or committed status and were incubated with these cytokines for the evaluation of cell proliferation, cyclooxygenase 2 (COX-2) expression, release of prostaglandins (PGs) and myokines, and activation of myogenic regulatory factors (MRFs). We found that inhibition of the IL-6 receptor reduced IL-1β- and TNF-α-induced cell proliferation, and that the IL-1β effect also involved COX-2-derived PGs. Both cytokines modulated the release of the myokines myostatin, irisin, osteonectin, and IL-15. TNF-α and IL-6 reduced the activity of Pax7 in proliferated cells and reduced MyoD and myogenin activity at both proliferative and commitment stages. Otherwise, IL-1β increased myogenin activity only in committed cells. Our data reveal a key role of IL-6 and COX-2-derived PGs in IL-1β and TNF-α-induced myoblast proliferation and support the link between TNF-α and IL-6 and the activation of MRFs. We concluded that IL-1β and TNF-α induce similar effects at the initial stages of muscle regeneration but found critical differences between their effects with the progression of the process, bringing new insights into inflammatory signalling in skeletal muscle regeneration.
Highlights
Skeletal muscle is a dynamic tissue with the ability to regenerate successfully following injury and to adapt in response to growth or exercise
Since several myokines are endogenously secreted in response to muscular efforts and are involved in the growth and repair of damaged myofibers [31], we investigated the effect of the inflammatory cytokines IL-1β and tumour necrosis factor-α (TNF-α) on the release of these myokines by myoblast cells at the proliferation stage
We report that TNF-α and IL-1β use similar mechanisms to induce the proliferation of myoblast cells in culture, but they regulate the transitory phase of myoblast differentiation through distinct mechanisms
Summary
Skeletal muscle is a dynamic tissue with the ability to regenerate successfully following injury and to adapt in response to growth or exercise. Named satellite cells, are the main drivers of the plasticity, maintenance, and regeneration of skeletal muscle [1,2,3]. Under resting conditions, these cells are mitotically and physiologically quiescent, but in response to increased physiological muscle loading or injury, they are activated and re-enter the cell cycle to generate satellite cell-derived myoblasts. IL-1β has been reported to be a pivotal mediator, especially early in the regeneration process, in damaged muscle tissues, acting (i) by amplifying chemoattractants and recruiting immune cells to the site of injury and (ii) by directly influencing the intrinsic capabilities of myoblasts [7,8]. A series of in vitro experiments using satellite cells from IL-1α/β double-knockout (IL-1KO) mice revealed that IL-1KO myoblasts have impairments in terms of both proliferation and differentiation that were reversed by exogenous IL-1β administration in culture [11]
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