Mitochondrial content and distribution changes specific to mouse diaphragm after chronic normobaric hypoxia

Jorge L. Gamboa, Francisco H. Andrade

Research output: Contribution to journalArticlepeer-review

50 Scopus citations


Chronic hypoxia reduces aerobic capacity (mitochondrial content) in limb skeletal muscles, and one of the causes seems to be decreased physical activity. Diaphragm and other respiratory muscles, however, may have a different pattern of adaptation as hypoxia increases the work of breathing. Thus, we hypothesized that chronic hypoxia would not reduce mitochondrial content in mouse diaphragm. Adult male C57BL/6J mice were kept in normoxia (FIO2 = 21%, control) or normobaric hypoxia (FIO2 = 10%, hypoxia) for 1, 2, and 4 wk. Mice were then killed, and the diaphragm and gastrocnemius muscles collected for analysis. In the diaphragm, cytochrome c oxidase histochemistry showed less intense staining in the hypoxia group. The total content of subunits from the electron transport chain, pyruvate dehydrogenase kinase 1 (PDK1), and voltage-dependent anion channel 1 (VDAC1) was evaluated by Western blot. These proteins decreased by 25-30% after 4 wk of hypoxia (P < 0.05 vs. control for all comparisons), matching a comparable decrease in diaphragmatic mitochondrial volume density (control 33.6 ± 5.5% vs. hypoxia 26.8 ± 6.7%, P = 0.013). Mitochondrial volume density or protein content did not change in gastrocnemius after hypoxia. Hypoxia decreased the content of peroxisome proliferator-activated receptor gamma (PPARγ) and PPARγ cofactor 1-alpha (PGC-1α) in diaphragm but not in gastrocnemius. PGC-1α mRNA levels in diaphragm were also reduced with hypoxia. BCL2/adenovirus E1B interacting protein 3 (BNIP-3) mRNA levels were upregulated after 1 and 2 wk of hypoxia in diaphragm and gastrocnemius, respectively; BNIP-3 protein content increased only in the diaphragm after 4 wk of hypoxia. Contrary to our hypothesis, these results show that chronic hypoxia decreases mitochondrial content in mouse diaphragm, despite the increase in workload. A combination of reduced mitochondrial biogenesis and increased mitophagy seems to be responsible for the decrease in mitochondrial content in the mouse diaphragm after hypoxia.

Original languageEnglish
Pages (from-to)R575-R583
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Issue number3
StatePublished - Mar 2010


  • Autophagy
  • Metabolism
  • Mitochondrial biogenesis
  • Respiratory muscles

ASJC Scopus subject areas

  • General Medicine


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