title: Specialization of mitochondrial and vascular oxidant modulated VEGFR in the denervated skeletal muscle.
abstract: 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.
authors.affiliation: Department of Integrative Medicine and Neurobiology, National Key Lab of Medical Neurobiology, Institute of Brain Sciences, Fudan University, Shanghai, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhao
authors.forename: Han-Wei
authors.initials: HW
authors.lastname: Huang
authors.forename: Jun-Guo
authors.initials: JG
authors.lastname: Wu
authors.forename: Pei-Yan
authors.initials: PY
authors.lastname: Huang
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D019409:Interleukin-15 / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D009121:Muscle Denervation; D018482:Muscle, Skeletal / Q000293:injuries / Q000294:innervation / Q000378:metabolism*; D009469:Neuromuscular Junction / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D011950:Receptors, Cholinergic / Q000235:genetics / Q000378:metabolism; D012584:Sciatic Nerve / Q000293:injuries / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism*; D014969:Xanthine Oxidase / Q000235:genetics / Q000378:metabolism
chemical_list: D019409:Interleukin-15; D053583:Interleukin-1beta; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D011950:Receptors, Cholinergic; D014157:Transcription Factors; D014969:Xanthine Oxidase; C475048:MuSK protein, rat; D020794:Receptor Protein-Tyrosine Kinases; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; C516610:Ptpn1 protein, rat
keywords: Mitochondria; Muscle denervation; VEGFR-1; VEGFR-2; XO pathway