Endogenous interferon-γ is required for efficient skeletal muscle regeneration

Abstract

The inflammatory response is thought to play important roles in tissue healing. The hypothesis of this study was that the inflammatory cytokine interferon (IFN)-gamma is produced endogenously following skeletal muscle injury and promotes efficient healing. We show that IFN-gamma is expressed at both mRNA and protein levels in skeletal muscle following injury, and that the time course of IFN-gamma expression correlated with the accumulation of macrophages, T-cells, and natural killer cells, as well as myoblasts, in damaged muscle. Cells of each type were isolated from injured muscle, and IFN-gamma expression was detected in each cell type. We also demonstrate that administration of an IFN-gamma receptor blocking antibody to wild-type mice impaired induction of interferon response factor-1, reduced cell proliferation, and decreased formation of regenerating fibers. IFN-gamma null mice showed similarly impaired muscle healing associated with impaired macrophage function and development of fibrosis. In vitro studies demonstrated that IFN-gamma and its receptor are expressed in the C2C12 muscle cell line, and that the IFN-gamma receptor blocking antibody reduced proliferation and fusion of these muscle cells. In summary, our results indicate that IFN-gamma promotes muscle healing, in part, by stimulating formation of new muscle fibers.

Growth factor and cytokine interactions in myogenesis. Part I. The effect of TNF-α and IFN-γ on IGF-I-dependent differentiation in mouse C2C12 myogenic cells

“…5), which resembles the activation of satellite cells in vivo by molecules released in skeletal muscle by rapidly infiltrating inflammatory cells following muscle injury (Goetsch et al 2003). IFN-γ and its receptor are expressed in the C2C12 muscle cell line and this cytokine has recently been found to be required for proliferation and fusion of C2C12 cells (Cheng et al 2008). It has been demonstrated that the IFN-γ receptor blocking antibody reduced proliferation and fusion of these myogenic cells, pointing to the role of this cytokine in the formation of new muscle fiber and muscle healing, which is in apparent contrast to our study indicating disturbances in myoblast differentiation.…”

“…It has been demonstrated that the IFN-γ receptor blocking antibody reduced proliferation and fusion of these myogenic cells, pointing to the role of this cytokine in the formation of new muscle fiber and muscle healing, which is in apparent contrast to our study indicating disturbances in myoblast differentiation. However, Cheng et al (2008) eliminated the effect of endogenous IFN-γ on proliferation and fusion of C2C12 cells by blocking the specific receptor, whereas in our study the effect of IFN-γ added to the differentiation medium was explored. Even thought IFN-γ seems to be required for efficient cell proliferation and fusion, an excess of this cytokine could impair the formation of muscle fibers.…”

Genetic Ablation of TWEAK Augments Regeneration and Post-Injury Growth of Skeletal Muscle in Mice

“…7 Similarly, interferon-␥ also promotes myofiber regeneration after injury. 8 In contrast, several pro-inflammatory cytokines (such as tumor necrosis factor [TNF]-␣, IL-1␤ and IL-6) while augmenting the proliferation of muscle progenitor cells, inhibit the terminal differentiation/fusion of myoblasts into mature myofibers. 9 -11 Injection of soluble TNF-␣ (henceforth TNF) protein at specific time points during regeneration delayed the appearance of regenerating fibers, without exacerbating fiber death following the initial trauma.…”

Cachexia – The Interplay Between the Immune System, Brain Control and Metabolism

“…Although IFN-was proposed as a pro-cachectic factor, it reversed the TNF--induced apoptotic activity (Tolosa et al, 2005). In line with this finding, Cheng et al (2008) have demonstrated that IFN-promotes muscle healing, in part, by stimulating formation of new muscle fibers. Administration of an IFNreceptor blocking antibody to wild-type mice impaired induction of IFN response factor-1, reduced cell proliferation, and decreased formation of regenerating fibers.…”

“…during exercise) but also by muscle fibers per se (Pajak et al, 2008). Among a wide group of myokines should be named pro-inflammatory cytokines such as TNF-, IL-1 , IL-6, IL-8, IL-15, IFN-, CNTF, LIF, or TGF- (Pajak et al, 2008;Hunt et al, 2011;Burks & Cohn, 2011;Stockli et al, 1989;Cheng et al, 2008;Pedersen & Febbraio, 2008). Cytokines act on skeletal muscle cells through the specific membrane receptors that may differ for each cytokine in their intracellular domains and thus mediate distinct cellular www.intechopen.com responses.…”