Strain differences in response to acute hypoxia: CD-1 versus C57BL/6J mice

Some mammals respond to hypoxia by lowering metabolic demand for oxygen and others by maximizing efficiency of oxygen usage: the former strategy is generally held to be the more effective. We describe within the same species one outbred strain ( CD-1) that lowers demand and another inbred strain ( C57BL/6J) that maximizes oxygen efficiency to markedly extend hypoxic tolerance. Unanesthetized adult male mice ( Mus musculus, CD-1 and C57BL/6J) between 20 and 35 g were used. Sham-conditioned ( SC) C57BL/6J mice survived severe hypoxia ( 4.5% O-2, balance N-2) roughly twice as long as SC CD-1 mice ( median 211 and 93.5 s, respectively; P < 0.0001). Following acute hypoxic conditioning ( HC), C57BL/6J mice survived subsequent hypoxia 10 times longer than HC CD-1 mice ( median 2,198 and 238 s respectively; P < 0.0001). Therefore, C57BL/6J mice are both naturally more tolerant to hypoxia and show a greater increase in hypoxic tolerance in response to hypoxic conditioning. Indirect calorimetry indicates that CD-1 mice lower mass-specific oxygen consumption ( V'O-2 in ml O2 . kg(-1) . min(-1)) and carbon dioxide production ( V'CO2 in ml CO2 . kg(-1) . min < 1) in response to HC ( P = 0.002 and P < 0.0001, respectively), but C57BL/6J mice maintain V'O-2 and V'CO2 after HC. Respiratory exchange ratio and fluorometric assay of plasma ketones suggest that C57BL/6J mice rapidly switch to ketone metabolism, a more efficient substrate, while CD-1 mice reduce overall metabolic activity. We conclude that under severe hypoxia in mice, switching fuel, possibly to ketones, while maintaining V'O-2, may confer a greater survival advantage than simply lowering demand.