OBJECTIVE: Tumor necrosis factor-alpha (TNF-α) is a multifunctional proinflammatory cytokine that plays a critical role in mediating inflammatory and immunological responses. TNF-α has been shown to elicit both beneficial and detrimental biological effects by acting through its two receptors, TNFR1/p55 and TNFR2/p75. Previous studies from this laboratory have shown that TNF-TNFR2/p75 signaling plays a critical role in ischemia-induced neovascularization in muscle and heart tissues. However, the role of TNF-TNFR2/p75 signaling in ischemia induced inflammation and muscle regeneration remains to be characterized. METHODS: To evaluate ischemia induced inflammation responses, young wild type (WT) and young TNFR2/p75 knockout (p75KO) mice were subjected to unilateral hind limb ischemia (HLI) surgery. Operated hind limb tissue samples were collected at 1, 3, 7, and 10 days post-HLI surgery and studied for neutrophil (myeloperoxidase-1 positive cells) and macrophage (F4/80 positive cells) infiltration as well as satellite-cell activation (neural cell adhesion molecule positive cells) at each time point. To determine possible synergistically negative roles of tissue aging and the absence of TNFR2/p75 in either the tissue or bone marrow (BM), two chimeric BM transplantation (BMT) models were generated where young Green Fluorescent Protein (GFP) positive (+) p75KO and WT BM-derived cells were transplanted into adult p75KO mice. HLI surgery was performed one month post-BMT, after confirming complete engraftment of the recipient BM with GFP donor cells. Operated hind limb tissue samples were evaluated up to 28 days post-surgery to examine proliferation and apoptosis of BM-derived cells in ischemic tissue. RESULTS: Ischemia induced significant and long-lasting inflammation associated with a considerable decrease in satellite-cell activation in p75KO muscle tissue 1-10 days post-HLI surgery. For the BMT studies, in adult p75KO with the WT-BMT, proliferative (Ki67+) cells were detected only by day 28 and were exclusively GFP (+), suggesting delayed contribution of young WT-BM cell to adult p75KO ischemic tissue recovery. No GFP (+) young p75KO BM cells survived in adult p75KO tissue. CONCLUSION: The data demonstrate that: (1) ischemia-induced recovery in skeletal muscle tissue is impaired in young p75KO mice; (2) inflammatory responses are significantly increased and long-lasting in p75KO mice; (3) in the absence of TNFR2/p75 signaling, satellite-cell activation is affected in p75KO mice; (4) during post-ischemic recovery, tissue aging combined with decreased/absent TNFR2/p75 signaling may have synergistically negative roles on survival and proliferation in the damaged tissue.