Mitochondrial content and function decrease in mouse diaphragm after chronic hypoxia

Abstract

Loss of aerobic capacity induced by chronic hypoxia (i.e. diminished mitochondrial content) has been partially attributed to reduced physical activity. That is true for the limb muscles; however, hypoxia increases the workload on the diaphragm and other respiratory muscles. Thus, we hypothesized that mitochondrial content and function would not change in the mouse diaphragm following chronic hypoxia. Male C57BL/6J mice were kept in normoxia (FiO2=21%, control) or normobaric hypoxia (FiO2=10%, hypoxia) for 4 weeks. Then, mice were killed and the diaphragm and triceps surae were collected for analysis. In the diaphragm the content of electron transport chain (ETC) proteins was significantly reduced after 4 weeks of hypoxia (decreases of 25 to 30% compared to control). Mitochondrial volume density decreased after 4 weeks of hypoxia (control 33.6±5.5% vs. hypoxia 26.8±6.7%, p=0.013). A significant reduction of the ADP‐stimulated mitochondrial respiration (state 3) was also observed in the hypoxia group (159.0±28.8 vs. 112.2±38.9 nmolO2/min/mg protein, p=0.017). By contrast, no change was found in ETC protein content in triceps surae. However, chronic hypoxia decreased respiration states 2 (control 41.2±4.1 vs. hypoxia 33.2±6.7 nmolO2/min/mg protein, p=0.033) and 3 (control 196.6±32.6 vs. hypoxia 135±43.1 nmolO2/min/mg protein, p=0.018). These results disprove our initial hypothesis. Despite the increased work on ventilation, chronic hypoxia is more detrimental to mitochondrial content and function in the diaphragm than in limb muscles.Supported by NIH/NIGMS F31 GM084665