Diaphragm muscle adaptation to sustained hypoxia: lessons from animal models with relevance to high altitude and chronic respiratory diseases

The diaphragm is the primary inspiratory pump muscle of breathing. Notwithstanding its critical role in pulmonary ventilation, the diaphragm like other striated muscles is malleable in response to physiological and pathophysiological stressors, with potential implications for the maintenance of respiratory homeostasis. This review considers hypoxic adaptation of the diaphragm muscle, with a focus on functional, structural, and metabolic remodeling relevant to conditions such as high altitude and chronic respiratory disease. On the basis of emerging data in animal models, we posit that hypoxia is a significant driver of respiratory muscle plasticity, with evidence suggestive of both compensatory and deleterious adaptations in conditions of sustained exposure to low oxygen. Cellular strategies driving diaphragm remodeling during exposure to sustained hypoxia appear to confer hypoxic tolerance at the expense of peak force-generating capacity, a key functional parameter that correlates with patient morbidity and mortality. Changes include, but are not limited to: redox-dependent activation of hypoxia-inducible factor (HIF) and MAP kinases; time-dependent carbonylation of key metabolic and functional proteins; decreased mitochondrial respiration; activation of atrophic signaling and increased proteolysis; and altered functional performance. Diaphragm muscle weakness may be a signature effect of sustained hypoxic exposure. We discuss the putative role of reactive oxygen species as mediators of both advantageous and disadvantageous adaptations of diaphragm muscle to sustained hypoxia, and the role of antioxidants in mitigating adverse effects of chronic hypoxic stress on respiratory muscle function.

Low valence cation doping of bulk Cr2O3: Charge compensation and oxygen vacancy formation

The different oxidation states of chromium allow its bulk oxide form to be reducible, facilitating the oxygen vacancy formation process, which is a key property in applications such as catalysis. Similar to other useful oxides such as TiO2, and CeO2, the effect of substitutional metal dopants in bulk Cr2O3 and its effect on the electronic structure and oxygen vacancy formation are of interest, particularly in enhancing the latter. In this paper, density functional theory (DFT) calculations with a Hubbard + U correction (DFT+U) applied to the Cr 3d and O 2p states, are carried out on pure and metal-doped bulk Cr2O3 to examine the effect of doping on the electronic and geometric structure. The role of dopants in enhancing the reducibility of Cr2O3 is examined to promote oxygen vacancy formation. The dopants are Mg, Cu, Ni, and Zn, which have a formal +2 oxidation state in their bulk oxides. Given this difference in host and, dopant oxidation states, we show that to predict the correct ground state two metal dopants charge compensated with an oxygen vacancy are required. The second oxygen atom removed is termed "the active" oxygen vacancy and it is the energy required to remove this atom that is related to the reduction process. In all cases, we find that substitutional doping improves the oxygen vacancy formation of bulk Cr2O3 by lowering the energy cost.