Oxygen regulation and limitation to cellular respiration in mouse skeletal muscle in vivo.
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 (Mo2) 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 Mo2. In vivo Mo2 in mouse skeletal muscle was increased by systemic treatment with 2 and 4 mg/kg body wt 2,4-dinitrophenol to partially uncouple mitochondria. Mo2 was not dependent on intracellular Po2 above 3 mmHg in the three groups despite a threefold increase in Mo2. These results indicate that Mo2 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.
Marcinek
David J
DJ
Department of Radiology, Box 357115, University of Washington, 1959 NE Pacific Avenue, Seattle, WA 98195-7115, USA. dmarc@u.washington.edu
Ciesielski
Wayne A
WA
Conley
Kevin E
KE
Schenkman
Kenneth A
KA
D019297:2,4-Dinitrophenol / Q000494:pharmacology; D000818:Animals; D019069:Cell Respiration / Q000502:physiology; D005260:Female; D006863:Hydrogen-Ion Concentration; D007511:Ischemia / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology*; D010725:Phosphocreatine / Q000378:metabolism; D010759:Phosphorus Isotopes; D010766:Phosphorylation; D014475:Uncoupling Agents / Q000494:pharmacology
D010759:Phosphorus Isotopes; D014475:Uncoupling Agents; D010725:Phosphocreatine; D019297:2,4-Dinitrophenol; D010100:Oxygen