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Oxygen regulation and limitation to cellular respiration in mouse skeletal muscle in vivo

Departments of ¹Radiology, ²Physiology and Biophysics and Bioengineering, and ³Pediatrics, Anesthesiology, and Bioengineering, University of Washington Medical Center, Seattle 98195; and ⁴Children's Hospital and Regional Medical Center, Seattle, Washington 98105

Submitted 11 March 2003 ; accepted in final form 27 May 2003

In skeletal muscle, intracellular PO₂ can fall to as low as 2–3 mmHg. This study tested whether oxygen regulates cellular respiration in this range of oxygen tensions through direct coupling between phosphorylation potential and intracellular PO₂. Oxygen may also behave as a simple substrate in cellular respiration that is near saturating levels over most of the physiological range. A novel optical spectroscopic method was used to measure tissue oxygen consumption (O₂) and intracellular PO₂ using the decline in hemoglobin and myoglobin saturation in the ischemic hindlimb muscle of Swiss-Webster mice. ³¹P magnetic resonance spectroscopic determinations yielded phosphocreatine concentration ([PCr]) and pH in the same muscle volume. Intracellular PO₂ fell to <2 mmHg during the ischemic period without a change in the muscle [PCr] or pH. The constant phosphorylation state despite the decline in intracellular PO₂ rejects the hypothesis that direct coupling between these two variables results in a regulatory role for oxygen in cellular respiration. A second set of experiments tested the relationship between intracellular PO₂ and O₂. In vivo O₂ in mouse skeletal muscle was increased by systemic treatment with 2 and 4 mg/kg body wt 2,4-dinitrophenol to partially uncouple mitochondria. O₂ was not dependent on intracellular PO₂ above 3 mmHg in the three groups despite a threefold increase in O₂. These results indicate that O₂ and the phosphorylation state of the cell are independent of intracellular PO₂ throughout the physiological range of oxygen tensions. Therefore, we reject a regulatory role for oxygen in cellular respiration and conclude that oxygen acts as a simple substrate for respiration under physiological conditions.

oxygen limitation; critical PO₂; ATPase rate; oxygen consumption; oxygen tension

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