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

Abstract

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, FIO2= 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 (F1/F0 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.

Effects of sustained hypoxia on sternohyoid and diaphragm muscle during development

“…Respiratory muscle remodelling following sustained hypoxia has been reported in adult rats and differential effects of sustained hypoxia on airway dilator and thoracic pump muscles have been noted [9,12]. Of interest, diaphragm muscle is either resistant to [10][11][12] or even shows improved endurance [9] following sustained hypoxia. A recent study by GAMBOA and ANDRADE [10] highlights the potential importance of a downregulation in uncoupling protein-3 in hypoxic adaptation in respiratory muscle.…”

“…Of interest, diaphragm muscle is either resistant to [10][11][12] or even shows improved endurance [9] following sustained hypoxia. A recent study by GAMBOA and ANDRADE [10] highlights the potential importance of a downregulation in uncoupling protein-3 in hypoxic adaptation in respiratory muscle. This adaptation may be unique to the diaphragm, as sustained hypoxia causes limb muscle fatigue [10,14,15] and fatigue is also reported for the adult sternohyoid muscle in one [12] but not another [9] study.…”

“…A recent study by GAMBOA and ANDRADE [10] highlights the potential importance of a downregulation in uncoupling protein-3 in hypoxic adaptation in respiratory muscle. This adaptation may be unique to the diaphragm, as sustained hypoxia causes limb muscle fatigue [10,14,15] and fatigue is also reported for the adult sternohyoid muscle in one [12] but not another [9] study. The present study extends these observations showing that 1 week of sustained hypoxia is sufficient to cause sternohyoid muscle dysfunction in neonatal rats when the exposure occurs early in life.…”

“…Skeletal muscle has the capacity to adapt to sustained hypoxia by way of modulation of skeletal muscle vasculature [1,2], muscle enzyme activities [3][4][5][6], muscle fibre size and distribution [7][8][9][10] and contractile performance [11][12][13]. Moreover, sustained hypoxia has been shown to elicit functional plasticity in respiratory muscles [9,10] in a manner that differs from the phenotypic changes occurring in limb muscles [10,14,15].…”

“…Moreover, sustained hypoxia has been shown to elicit functional plasticity in respiratory muscles [9,10] in a manner that differs from the phenotypic changes occurring in limb muscles [10,14,15].…”