Mandel Erin R, Dunford Emily C, Abdifarkosh Ghoncheh, Turnbull Patrick C, Perry Christopher G R, Riddell Michael C, Haas Tara L
School of Kinesiology and Health Science and the Muscle Health Research Centre, York University, Toronto, Ontario, Canada.
Physiol Rep. 2017 May;5(10):e13243. doi: 10.14814/phy2.13243.
Sustained elevations in circulating glucocorticoids elicit reductions in skeletal muscle microvascular content, but little is known of the underlying mechanisms. We hypothesized that glucocorticoid-induced oxidative stress contributes to this phenomenon. In rats that were implanted with corticosterone (CORT) or control pellets, CORT caused a significant decrease in muscle glutathione levels and a corresponding increase in protein carbonylation, an irreversible oxidative modification of proteins. Decreased endothelial nitric oxide synthase and increased endothelin-1 mRNA levels were detected after 9 days of CORT, and blood flow to glycolytic muscles was diminished. Control and CORT rats were treated concurrently with drinking water containing the superoxide dismutase mimetic tempol (172 mg/L) or the -1 adrenergic receptor antagonist prazosin (50 mg/L) for 6 or 16 days. Both tempol and prazosin alleviated skeletal muscle protein carbonylation. Tempol failed to prevent CORT-mediated capillary rarefaction and was ineffective in restoring skeletal muscle blood flow. In contrast, prazosin blocked capillary rarefaction and restored skeletal muscle blood flow to control levels. The failure of tempol to prevent CORT-induced skeletal muscle microvascular rarefaction does not support a dominant role of superoxide-induced oxidative stress in this process. Although a decrease in protein carbonylation was observed with prazosin treatment, our data suggest that the maintenance of skeletal muscle microvascular content is related more closely with counteracting the CORT-mediated influence on skeletal muscle vascular tone.
循环糖皮质激素持续升高会导致骨骼肌微血管含量减少，但其潜在机制尚不清楚。我们推测糖皮质激素诱导的氧化应激是导致这一现象的原因。在植入皮质酮（CORT）或对照丸剂的大鼠中，CORT导致肌肉谷胱甘肽水平显著降低，蛋白质羰基化相应增加，蛋白质羰基化是一种不可逆的蛋白质氧化修饰。CORT处理9天后，检测到内皮型一氧化氮合酶减少，内皮素-1 mRNA水平增加，糖酵解肌的血流量减少。对照大鼠和CORT大鼠同时饮用含有超氧化物歧化酶模拟物tempol（172mg/L）或α-1肾上腺素能受体拮抗剂哌唑嗪（50mg/L）的水6天或16天。tempol和哌唑嗪均能减轻骨骼肌蛋白质羰基化。tempol未能预防CORT介导的毛细血管稀疏，也无法恢复骨骼肌血流量。相比之下，哌唑嗪可阻止毛细血管稀疏，并将骨骼肌血流量恢复到对照水平。tempol未能预防CORT诱导的骨骼肌微血管稀疏，这并不支持超氧化物诱导的氧化应激在此过程中起主导作用。尽管哌唑嗪治疗可观察到蛋白质羰基化减少，但我们的数据表明，骨骼肌微血管含量的维持与抵消CORT对骨骼肌血管张力的影响更为密切相关。
