Specialization of mitochondrial and vascular oxidant modulated VEGFR in the denervated skeletal muscle

Denervation of skeletal muscles results in timely muscular inflammation and muscle-T cell interaction, the cellular events might orchestrate a local circuit involved with IL-1β and IL-15. In the present study, by a combination assay of nerve–muscle preparation, western blot, immuno-precipitation, and radioactive of enzyme activity, we confirmed that mitochondrial and vascular oxidants were considerably up-regulated following gastrocnemius denervation, which was due to gradual decay in mitochondrial biogenesis and XO pathway and accompanied by strengthened IL-1β-VEGFR-2 and IL-15-VEGFR-1 signaling. Intriguingly, these alterations could be triggered by the early established muscular inflammation. In contrast, with prolonged muscle denervation, settings of organelle interconnection were ultimately conveyed by ER bound PTP1B, which promoted VEGFR-1 signaling and contributed to VEGFR-2 activation, and the process could be modulated by mitochondrial and vascular oxidant. Importantly, VEGFR-2 could rescue the disruption of MuSK activity and AchR cluster exerted by IL-1β and IL-15, with PGC-1α and XO involvement. Altogether, extensive network centered on VEGFR-2 signaling was essentially contributed to early recovery processes regarding muscle denervation. Increasing knowledge of this mechanism might open up a conduit for functional response to muscle atrophy, and enable the development of better agents to combat the related disorders. [Display omitted] •Muscle denervation initiated rapid mitochondrial and vascular oxidant production.•Muscle denervation initiated timely IL-1β-VEGFR2 and IL-15-VEGFR1 signaling.•Mitochondrial and vascular oxidant involved in both VEGFR1/2 signaling.•VEGFR1/2 signaling within NMJ could be modulated by PGC-1α and OX pathway.•VEGFR2 signaling could rescue the NMJ disruption of by IL-1β or IL-15.