Myeloid cell‐derived tumor necrosis factor‐alpha promotes sarcopenia and regulates muscle cell fusion with aging muscle fibers

Abstract

Sarcopenia is age‐related muscle wasting that lacks effective therapeutic interventions. We found that systemic ablation of tumor necrosis factor‐α (TNF‐α) prevented sarcopenia and prevented age‐related change in muscle fiber phenotype. Furthermore, TNF‐α ablation reduced the number of satellite cells in aging muscle and promoted muscle cell fusion in vivo and in vitro. Because CD68+ macrophages are important sources of TNF‐α and the number of CD68+ macrophages increases in aging muscle, we tested whether macrophage‐derived TNF‐α affects myogenesis. Media conditioned by TNF‐α‐null macrophages increased muscle cell fusion in vitro, compared to media conditioned by wild‐type macrophages. In addition, transplantation of bone marrow cells from wild‐type mice into TNF‐α‐null recipients increased satellite cell numbers and reduced numbers of centrally nucleated myofibers, indicating that myeloid cell‐secreted TNF‐α reduces muscle cell fusion. Transplanting bone marrow cells from wild‐type mice into TNF‐α‐null recipients also increased sarcopenia, although transplantation did not restore the age‐related change in muscle fiber phenotype. Collectively, we show that myeloid cell‐derived TNF‐α contributes to muscle aging by affecting sarcopenia and muscle cell fusion with aging muscle fibers. Our findings also show that TNF‐α that is intrinsic to muscle and TNF‐α secreted by immune cells work together to influence muscle aging.

3D-printed drug testing platform based on a 3D model of aged human skeletal muscle

“…Nucleation was also affected by the cytokine, since the number of nuclei per visible fiber was reduced from 9 to 5 for the concentration of 80 ng/mL ( Figure 3C). All these morphological changes were consistent with those related to sarcopenia induced by TNF-α 25,26,30,39,40 . In order to test whether functional changes were also compatible, we set the concentration of TNF-α to 40 ng/mL for the remaining experiments, since it was the concentration for which some effects could be observed without becoming too adverse.…”

“…Moreover, this behavior differs from that observed in 3D-bioengineered C2C12 cells, which only show a sustained tetanic contraction for frequencies higher than 10 Hz without an initial stroke 2 . TNF-α is a proinflammatory cytokine known to be related to sarcopenia, or loss of muscle mass and function in ageing, as well as reduction of cell fusion [25][26][27][28][29][30][31] . Hence, we examined whether addition of this cytokine could be used to model aged skeletal muscle tissue in our muscle platform.…”

“…TNF-α is the best known SASPs component in skeletal muscle tissues, whose expression increases with age. This cytokine has been described as one of the main drivers for the known morphological changes that take place in senescent muscles [23][24][25] , and has been linked to the development of sarcopenia affecting satellite cells 26 . In mouse cell lines, differences in TNF-α have been related to changes in calcium transients 27,28 and reduction of contractile force 25 .…”

Divergent Roles of Inflammation in Skeletal Muscle Recovery From Injury

“…TNFα concentrations rise substantially at the site of muscle injury due to its release from injured myofibers and infiltrating immune cells (De Bleecker et al, 1999). In vitro work has shown that TNFα intrinsic to satellite cells and myeloid cell-derived TNFα influence the myogenic response (Wang et al, 2018). The early increase in TNFα expression functions as a chemoattractant signal that stimulates myogenic cell migration to the site of injury (Torrente et al, 2003).…”

“…This occurs analogous to TWEAK through the activation of classical NF-κB signaling and downstream inhibition of MyoD mRNA and protein expression (Langen et al, 2004). An abundance of myeloid cell-derived TNFα also appears to reduce muscle cell fusion (Wang et al, 2018). While high concentrations of recombinant TNFα (≥0.5 ng/mL) inhibit the progression of myogenesis, low concentrations of TNFα (0.05 ng/mL) have been shown to enhance differentiation in cultured myoblasts (Chen et al, 2007).…”