Divergent physiological responses in laboratory rats and mice raised at high altitude

Abstract

Ecological studies show that mice can be found at high altitude (HAup to 4000 m) while rats are absent at these altitudes, and there are no data to explain this discrepancy. We used adult laboratory rats and mice that have been raised for more than 30 generations in La Paz, Bolivia (3600 m), and compared their hematocrit levels, right ventricular hypertrophy (index of pulmonary hypertension) and alveolar surface area in the lungs. We also used whole-body plethysmography, indirect calorimetry and pulse oxymetry to measure ventilation, metabolic rate (O 2 consumption and CO 2 production), heart rate and pulse oxymetry oxygen saturation (p O2,sat ) under ambient conditions, and in response to exposure to sea level P O2 (32% O 2 =160 mmHg for 10 min) and hypoxia (18% and 15% O 2 =90 and 75 mmHg for 10 min each). The variables used for comparisons between species were corrected for body mass using standard allometric equations, and are termed mass-corrected variables. Under baseline, compared with rats, adult mice had similar levels of p O2,sat , but lower hematocrit and hemoglobin levels, reduced right ventricular hypertrophy and higher mass-corrected alveolar surface area, tidal volume and metabolic rate. In response to sea level P O2 and hypoxia, mice and rats had similar changes of ventilation, but metabolic rate decreased much more in hypoxia in mice, while p O2,sat remained higher in mice. We conclude that laboratory mice and rats that have been raised at HA for >30 generations have different physiological responses to altitude. These differences might explain the different altitude distribution observed in wild rats and mice.

HIF1α and physiological responses to hypoxia are correlated in mice but not in rats

“…Overall, these results seem to indicate that responses to hypoxia are more efficient in FVB mice than in SD rats. This is line with our previous findings obtained in the HA colonies of FVB mice and SD rats (Jochmans-Lemoine et al, 2015), in which we concluded that the specific physiological traits observed in laboratory mice at HA could explain why mice are commonly found at HA. By contrast, and as also presented in the Introduction, it is less common to find rats at HA.…”

“…We previously compared the physiological adjustments to HA in laboratory Sprague Dawley (SD) rats and FVB mice that have been bred and raised at 3600 m above SL (La Paz, Bolivia) for more than 20 years and over 30 generations. Compared with rats, mice had lower hematocrit and hemoglobin levels, reduced right ventricular hypertrophy (a sign of reduced pulmonary hypertension), increased alveolar surface area and lung volume, higher tidal volume and metabolic rate (Jochmans-Lemoine et al, 2015). Along with the data obtained at HA, we also reported values obtained at SL under normoxic conditions showing that rats and mice had similar lung volume, total alveolar surface area and metabolic rate (JochmansLemoine et al, 2015).…”

“…Interestingly, in the present study, the respiratory exchange ratio increased in response to hypoxia in rats (although this was only significant at 15% O 2 compared with normoxia). Taken together, these results likely underlie a general response strategy in rats that rely on glycolytic pathways when exposed to hypoxia, while species considered as being adapted to HA can rely on other sources of metabolic fuels (Cheviron et al, 2012;Jochmans-Lemoine et al, 2015). Finally, we did not observed specific increase of Pdk1 in rats or in mice, despite its well-known induction by HIF-1α, and its role to inhibit pyruvate dehydrogenase and limit the conversion of pyruvate to acetyl-CoA, the entry point of the Krebs cycle (Prabhakar and Semenza, 2012).…”

“…As previously described (Jochmans-Lemoine et al, 2015) we used allometric scaling to compare physiological and morphological variables between mice and rats. Each specific variable A is reported relative to body mass (M, in g) to the exponent b (A/M b ), and we used the scaling variables calculated by Stahl (1967), which are: b=0.8 for minute ventilation, b=1.04 for tidal volume, b=−0.25 for respiratory frequency and b=0.76 for O 2 consumption and CO 2 production.…”

“…Because SD rats and FVB mice had different respiratory and metabolic responses at HA (Jochmans-Lemoine et al, 2015), we tested the hypothesis that at SL, SD rats and FVB mice have different ventilatory and metabolic responses to hypoxia which could be releated to a different expression of HIF-1α in the brainstem, the main region harboring respiratory neurons. To answer these questions, the animals were exposed for 6 h to normoxia (21% O 2 ) or two levels of hypoxia (15 and 12% O 2 ).…”