Muscle endurance and mitochondrial function after chronic normobaric hypoxia: Contrast of respiratory and limb muscles

Skeletal muscle adaptation to chronic hypoxia includes loss of oxidative capacity and decrease in fiber size. However, the diaphragm may adapt differently since its activity increases in response to hypoxia. Thus, we hypothesized that chronic hypoxia would not affect endurance, mitochondrial function, or fiber size in the mouse diaphragm. Adult male mice were kept in normoxia (control) or hypoxia (hypoxia, FIO ₂ = 10%) for 4 weeks. After that time, muscles were collected for histological, biochemical, and functional analyses. Hypoxia soleus muscles fatigued faster (fatigue index higher in control, 21.5 ± 2.6% vs. 13.4 ± 2.4%, p < 0.05), but there was no difference between control and hypoxia diaphragm bundles. Mean fiber cross-sectional area was unchanged in hypoxia limb muscles, but it was 25% smaller in diaphragm (p < 0.001). Ratio of capillary length contact to fiber perimeter was significantly higher in hypoxia diaphragm (28.6 ± 1.2 vs. 49.3 ± 1.4, control and hypoxia, p < 0.001). Mitochondrial respiration rates in hypoxia limb muscles were lower: state 2 decreased 19%, state 3 31%, and state 4 18% vs. control, p < 0.05 for all comparisons. There were similar changes in hypoxia diaphragm: state 3 decreased 29% and state 4 17%, p < 0.05. After 4 weeks of hypoxia, limb muscle mitochondria had lower content of complex IV (cytochrome c oxidase), while diaphragm mitochondria had higher content of complexes IV and V (F ₁/F ₀ ATP synthase) and less uncoupling protein 3 (UCP-3). These data demonstrate that diaphragm retains its endurance during chronic hypoxia, apparently due to a combination of morphometric changes and optimization of mitochondrial energy production.