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.