Platelet-derived chemokines promote skeletal muscle regeneration by guiding neutrophil recruitment to injured muscles

Abstract

Skeletal muscle regeneration involves coordinated interactions between different cell types. Injection of platelet-rich plasma is circumstantially considered an aid to muscle repair but whether platelets promote regeneration beyond their role in hemostasis remains unexplored. Here, we find that signaling via platelet-released chemokines is an early event necessary for muscle repair in mice. Platelet depletion reduces the levels of the platelet-secreted neutrophil chemoattractants CXCL5 and CXCL7/PPBP. Consequently, early-phase neutrophil infiltration to injured muscles is impaired whereas later inflammation is exacerbated. Consistent with this model, neutrophil infiltration to injured muscles is compromised in male mice with Cxcl7-knockout platelets. Moreover, neo-angiogenesis and the re-establishment of myofiber size and muscle strength occurs optimally in control mice post-injury but not in Cxcl7ko mice and in neutrophil-depleted mice. Altogether, these findings indicate that platelet-secreted CXCL7 promotes regeneration by recruiting neutrophils to injured muscles, and that this signaling axis could be utilized therapeutically to boost muscle regeneration.

Signaling roles of platelets in skeletal muscle regeneration

“…[25] Further confirming the important role of neutrophils in muscle regeneration downstream of platelet-induced chemokine signaling, we found that antibody-based depletion of neutrophils similarly reduces myofiber size and muscle force production post-injury. [25] Altogether, this study identifies a key role of platelets in regenerating muscle by guiding the infiltration of neutrophils into injured muscles (Figure 1).…”

“…Our study now indicates that platelets are necessary to recruit neutrophils to injured muscles and that this occurs via the secretion of platelet‐specific chemokines with potent neutrophil chemoattractant activities. [ 25 ] In particular, we found that neutrophil infiltration, which occurs by day 1 after injury, is significantly reduced by platelet depletion. Cytokine arrays indicate that the intramuscular protein levels of the neutrophil chemoattractants CXCL5 and CXCL7/PPBP, which are chemokines specifically expressed by platelets, [ 27 ] are high at day 1 after injury but that their levels are significantly reduced by platelet depletion.…”

“…[1,23,24] We have recently found that platelets are the first responders that mount the regenerative response of skeletal muscle. [25] By virtue of their hemostatic functions, platelet clusters are found within the muscle blood vessels at the site of injury. [25] Although capillaries may not be directly damaged by myotoxic agents, it was previously reported that the blood vessel network is indirectly disrupted because of myofiber necrosis.…”

“…[25] Because platelets typically release their granules upon clotting and activation, any ensuing effect on myogenesis in vivo may be the indirect result of the effects of platelets on earlier steps of regeneration (such as neutrophil recruitment, inflammation, and neo-angiogenesis, as discussed in the paragraphs above and below). Although no effect of platelet depletion was found on myogenesis in vivo, based on the assessment of eMHC, [25] it is possible that exogenous (therapeutic) application of the PR may indeed boost several aspects of myogenesis, as observed in cell culture systems. [29][30][31]33] In agreement with this possibility, an interesting study found that intraperitoneal injection of the PR from wild-type platelets can rescue the muscle regeneration deficits of ApoE knockout mice, at least in part by promoting myoD and myogenin expression in differentiating myoblasts, and by promoting the growth of newly formed myofibers.…”

“…[37] At day 1 after injury (a time point at which the myofibers are necrotic), we found that platelet depletion reduces the intramuscular levels of VEGF. [25] Because myofibers are necrotic on day 1 after injury and because both platelets and neutrophils are highly present in injured muscles at that stage [25] and are both known sources of VEGF, [38][39][40][41] neutrophils and platelets appear to be the major source of VEGF at this early stage of regeneration. [25] Moreover, the high levels of MMP9 and other metalloproteases expressed by neutrophils release additional VEGF from the extracellular matrix, further increasing VEGF bioavailability.…”