COX-2, cyclooxygenase; CXCR4, CXC chemokine receptor 4; ECM, extracellular matrix; ELAM-1, endothelial leukocyte adhesion molecule 1; eNOS, endothelial nitric oxide synthase; GC, guanylyl cyclase; HIF-1, hypoxia-inducible factor-1; HUVECs, human umbilical vascular endothelial cells; IL-33, cytokine interleukin-33; iNOS, inducible nitric oxide synthase; MAPK, mitogen-activated protein kinase; MMP, matrix metalloproteinase; nNOS, neuronal nitric oxide synthase; NO•, nitric oxide; NO•-NSAIDs, nitric oxide-releasing non-steroidal anti-inflammatory drugs; NOS, nitric oxide synthase; PCNA, proliferating cell nuclear antigen; PKC, protein kinase C; QUER, quercetin; TPA, 12-O-tetradecanoylphorbol 13-acetate; t-PTER, trans-pterostilbene; VEGF-C, vascular endothelial growth factor-C

Po2 cycling, often referred to as intermittent hypoxia, involves exposing tissues to brief cycles of low oxygen environments immediately followed by hyperoxic conditions. After experiencing long-term hypoxia, muscle can be damaged during the subsequent reintroduction of oxygen, which leads to muscle dysfunction via reperfusion injury. The protective effect and mechanism behind Po2 cycling in skeletal muscle during reoxygenation have yet to be fully elucidated. We hypothesize that Po2 cycling effectively increases muscle fatigue resistance through reactive oxygen species (ROS), protein kinase B (Akt), extracellular signal-regulated kinase (ERK), and certain mitochondrial channels during reoxygenation. Using a dihydrofluorescein fluorescent probe, we detected the production of ROS in mouse diaphragmatic skeletal muscle in real time under confocal microscopy. Muscles treated with Po2 cycling displayed significantly attenuated ROS levels (n = 5; P < 0.001) as well as enhanced force generation compared with controls during reperfusion (n = 7; P < 0.05). We also used inhibitors for signaling molecules or membrane channels such as ROS, Akt, ERK, as well as chemical stimulators to close mitochondrial ATP-sensitive potassium channel (KATP) or open mitochondrial permeability transition pore (mPTP). All these blockers or stimulators abolished improved muscle function with Po2 cycling treatment. This current investigation has discovered a correlation between KATP and mPTP and the Po2 cycling pathway in diaphragmatic skeletal muscle. Thus we have identified a unique signaling pathway that may involve ROS, Akt, ERK, and mitochondrial channels responsible for Po2 cycling protection during reoxygenation conditions in the diaphragm.

No abstract

No abstract