Skeletal muscle displays a robust regenerative response upon injury where muscle stem cells (satellite cells) exit quiescence, undergo activation, proliferation and fuse to form newly regenerating myofibers [1
]. This process is accompanied by inflammation, e.g. infiltration of immune cells, primarily macrophages, at the site of muscle injury [3
]. While it has been shown that inflammation generally increases with aging, which has been attributed to impaired immune response [4
], several previous studies have demonstrated that in the young animals inflammatory macrophages play a positive role in clearing the wound and promoting muscle regeneration [7
Muscle regenerative potential declines with aging, which is largely due to the changes in the microenvironment of muscle stem cells, but a role of an altered immune response in the age-specific decline of muscle repair is not well understood in cellular or molecular terms [14
]. With advancing age and in certain pathologies, such as muscular dystrophy, chronic and increased inflammation impairs tissue regeneration [5
] and in normal aged human skeletal muscle, exercise induced injury results in a different cytokine profile as compared to young tissue [4
]. However, while the published data suggests that altered inflammatory response by untimely or sustained higher production of cytokines might contribute to the decline in the regenerative properties of muscle stem cells in the old, this has not been directly shown or explained at molecular level.
OPN, a pleiotropic cytokine (also known as Spp1), is expressed in variety of tissues including macrophages and bodily fluids and broadly regulates cell migration, adhesion, immune responses and inflammation [18
]. It has also been shown to play a key role in a number of pathophysiological conditions such as, Duchene muscular dystrophy, autoimmune diseases, cancer, tissue injury, fibrosis and delayed wound healing [18
]. It was suggested that transient up-regulation of OPN after muscle injury plays a positive role in overall regeneration [26
]; however, in cultured myoblasts OPN has been shown to inhibit cell migration and differentiation under some experimental conditions [27
] and in pathologically inflamed muscle of MDX mice (animal model of DMD), OPN was shown to inhibit muscle regeneration [24
]. Also, mice lacking OPN are healthy and normal, including skeletal muscle, and are protected against inflammatory disorders, which suggest that the absence of OPN does not influence myogenesis negatively [28
Considering these interesting and somewhat contradictory data on the role of OPN in myogenesis compounded by the lack of information on the age-specific effects of inflammatory cytokines on muscle repair, we investigated a potential involvement of OPN in the acquired decline of muscle regeneration in the old. We found that as compared to young, OPN become over-pronounced in macrophages that infiltrate old injured muscle (at both protein and mRNA levels). Very interestingly, OPN is also elevated in the blood serum of old mice, and only if animals are injured, suggesting that this cytokine can potentially deregulate regenerative responses not only at the site of the injury, but systemically. Furthermore, we found that physiological OPN directly inhibits the regenerative responses of old muscle stem cells and ectopic OPN is able to inhibit myogenic capacity of young muscle stem cells. Notably, regeneration of old injured muscle was significantly enhanced by the neutralization of OPN and young intramuscular CD11b+ macrophages also enhanced the myogenic responses of old satellite cells in the presence of old myofibers and old serum, suggesting that secretome of young inflammatory cells is capable of negating the inhibitory influence of old stem cell niches. Summarily, this work improves our understanding of the role of inflammation in tissue aging and introduces new avenues for restoration of muscle repair in the old.