DS have been reported to stimulate cell regeneration in skin cells, neurons, and b cells. Here, we supply additional evidence that increases in muscle strength with DS supplementation are associated with muscle regeneration, evidenced by increased centronucleation. Inflammation is required for muscle fiber turnover in rodents and humans. Proinflammatory interventions, such as delivery of myotoxic agents or glucose, have been shown to increase muscle regeneration and improve muscle strength. In this study, increased IL-10 mRNA expression and CD163+ M2 macrophage localization in skeletal muscle with DS supplementation are consistent with the observed increase in centronucleation. IL-10 is highly expressed in M2 macrophages, which are known to promote muscle regeneration. Taken together, increased cell turnover is expected to reduce average cell age in skeletal muscle, which may underlie the increased resilience of skeletal muscle after long-term DS supplementation. Though DS supplementation appears to potentiate inflammatory signaling in skeletal muscle, injured fibers and EE-induced oxidative damage were absent in rats with long-term, low-dose DS supplementation. This is consistent with reduced M1 macrophage infiltration, a primary source of NO production during inflammation. M1 macrophage infiltration into tissues typically occurs with cell injury, particularly after traumatic challenge or during cell aging. Longterm DS supplementation may shorten the length of time required for this muscle regeneration program to produce a younger and healthier muscle fiber population. In previous studies, Panax ginseng extract supplementation has been shown to reduce nitric oxide and muscle damage levels in untrained exercise. Our results suggest that DS may be the active component of ginseng that contributes to the putative ergogenic effect reported in previous studies. In the present study, our data show that DS supplementation significantly increased oxidative stress at rest. Free radicals are a required mediator for perpetuating inflammatory responses and stem cell recruitment. Oxidative stress generated during inflammation amplifies the inflammatory responses mediated by activation of NFkB and MAPK signaling to increase gene expression of pro-inflammatory mediators, e.g., iNOS, eNOS, COX-2 and cytokines. However, EE-induced NFkB/MAPK signaling, M1 macrophage infiltration, and gene expression of inflammatory mediators were attenuated in the skeletal muscle of DS-treated rats. Thus, early renewal of muscle fiber populations by potentiating inflammatory signaling with long-term DS supplementation may explain the protective effect of DS against a muscle-damaging exercise. Whether or not the inflammatory potentiation effects of increasing DS dosage can produce adverse outcome in humans BAY 43-9006 demands further clinical investigation. The NFkB/MAPK signaling system is also known to enhance expression of antioxidant enzymes. The duration and degree of free radical surge during inflammatory processes can be controlled by alterations in antioxidant levels.