Cannon 2021 Respir Physiol Neurobiol
| Cannon DT, Nogueira L, Gutierrez-Gonzalez AK, Gilmore NK, Bigby TD, Breen EC (2021) Role of IL-33 receptor (ST2) deletion in diaphragm contractile and mitochondrial function in the Sugen5416/hypoxia model of pulmonary hypertension. Respir Physiol Neurobiol 295:103783. |
Cannon Daniel T, Nogueira Leonardo, Gutierrez-Gonzalez Alma K, Gilmore Natalie K, Bigby Timothy D, Breen Ellen C (2021) Respir Physiol Neurobiol
Abstract: Pulmonary arterial hypertension (PAH) is a progressive disease of the pulmonary vasculature that leads to right ventricular failure. Skeletal muscle maladaptations limit physical activity and may contribute to disease progression. The role of alarmin/inflammatory signaling in PAH respiratory muscle dysfunction is unknown. We hypothesized that diaphragm mitochondrial and contractile functions are impaired in SU5416/hypoxia-induced pulmonary hypertension due to increased systemic IL-33 signaling. We induced pulmonary hypertension in adult C57Bl/6 J (WT) and ST2 (IL1RL1) gene ablated mice by SU5416/hypoxia (SuHx). We measured diaphragm fiber mitochondrial respiration, inflammatory markers, and contractile function ex vivo. SuHx reduced coupled and uncoupled permeabilized myofiber respiration by βΌ40 %. During coupled respiration with complex I substrates, ST2-/- attenuated SuHx inhibition of mitochondrial respiration (genotype Γ treatment interaction F[1,67] = 3.3, p = 0.07, Ξ·2 = 0.04). Flux control ratio and coupling efficiency were not affected by SuHx or genotype. A higher substrate control ratio for succinate was observed in SuHx fibers and attenuated in ST2-/- fibers (F[1,67] = 5.3, p < 0.05, Ξ·2 = 0.07). Diaphragm TNFΞ±, but not IL-33 or NFkB, was increased in SuHx vs. DMSO in both genotypes (F[1,43] = 4.7, p < 0.05, Ξ·2 = 0.1). Diaphragm force-frequency relationships were right-shifted in SuHx vs. WT (F[3,440] = 8.4, p < 0.05, Ξ·2 = 0.0025). There was no effect of ST2-/- on the force-frequency relationship. Force decay during a fatigue protocol at 100 Hz, but not at 40 Hz, was attenuated by SuHx vs. DMSO in both genotypes (F[1,41] = 5.6, p < 0.05, Ξ·2 = 0.11). SuHx mice exhibit a modest compensation in diaphragm contractility and mitochondrial dysfunction during coupled respiration; the latter partially regulated through ST2 signaling. β’ Keywords: Diaphragm, Mitochondria, Pulmonary hypertension, Respirometry, SU5416 β’ Bioblast editor: Plangger M β’ O2k-Network Lab: US CA San Diego Cannon DT, US CA La Jolla Hogan MC
Labels: MiParea: Respiration
Pathology: Cardiovascular
Organism: Mouse Tissue;cell: Skeletal muscle Preparation: Permeabilized tissue
Coupling state: LEAK, OXPHOS, ET
Pathway: N, S, NS, ROX
HRR: Oxygraph-2k
2021-09
