Increase in Carbohydrate Utilization in High-Altitude Andean Mice

Abstract

The low oxygen levels at high altitude are a potent and unavoidable physiological stressor to which highland mammals must adapt. One hypothesized adaptation to high altitude is an increased reliance on carbohydrates to support aerobic activities. Based on stoichiometries of combustion, ATP yield per mole of oxygen from carbohydrates is approximately 15% higher than from lipids (observed difference closer to 30%), and increased carbohydrate use represents an important oxygen-saving strategy that may be under high selective pressure. Although this hypothesis was first proposed nearly 30 years ago, the in vivo patterns of whole-body fuel use during exercise remain undefined for any highland mammal (including humans). Here we use a powerful multispecies approach to show that wild-caught high-altitude (4,000-4,500 m) native species of mice (Phyllotis andium and Phyllotis xanthopygus) from the Peruvian Andes use proportionately more carbohydrates and have higher oxidative capacities of cardiac muscles compared to closely related low-altitude (100-300 m) native counterparts (Phyllotis amicus and Phyllotis limatus). These results strongly infer that highland Phyllotis have evolved a metabolic strategy to economize oxygen when performing energy-demanding tasks at altitude. This study provides compelling evidence of adjustments in fuel use as an adaptation to high-altitude hypoxia in mammals.

Patterns of fuel use during locomotion in mammals revisited: the importance of aerobic scope

“…Calculations and statistical analyses V · O2 , V · CO2 and rates of carbohydrate and lipid oxidation were calculated as previously described (Withers et al, 1977;Schippers et al, 2012) using the indirect calorimetry equations of Frayn (Frayn, 1983). We used raw data obtained from previously published studies on rats (McClelland et al, 1998), dogs and goats (Roberts et al, 1996) and for comparison, means obtained for moderately trained humans (men) during treadmill running (Table 1) because fuel use differs between bicycle and treadmill exercise in humans (Achten et al, 2003).…”

“…Outbred male CD-1 mice were obtained at 6 weeks of age (Charles-River, Wilmington, MA, USA). Mice (N=12) were kept under a 12 h:12 h light:dark cycle with the lights coming on at 07:00 h. All mice were subjected to the following in vivo experimental measurements using a respirometry system and metabolic chamber as previously described (Schippers et al, 2012): (1) V · O2,max , and after at least 48 h recovery, (2) rates of oxygen consumption (V · O2 ) and carbon dioxide production (V · CO2 ) at rest in a 600 ml metabolic chamber or during exercise at 65 and 80% of individual V · O2,max in a rodent treadmill (~800 ml) using a flow-through respirometry system (Sables Systems, Las Vegas, NV, USA) as previously described (Schippers et al, 2012). These submaximal exercise measurements were performed in a random order between 12:00 and 19:00 h following a 6 h fast.…”

“…Exercise and resting protocols for mice V · O2,max was determined using criteria previously described (Schippers et al, 2012) by increasing the speed of the treadmill by 3 m min −1 every 2 min from an initial speed of 7 m min −1 at a constant angle of 10 deg. Submaximal exercise intensities were determined from the relationship between V · O2 and speed but also by adjusting treadmill speed in real time to maintain the target V · O2 .…”

“…Yet, prior to our recent study on wild Andean mice (genus Phyllotis) (Schippers et al, 2012), fuel selection patterns had not been described in a mammal smaller than a rat. Because mass-specific resting metabolic rate increases as body size decreases (Kleiber, 1932), mice and other small mammals have a smaller aerobic scope (increase in oxidative metabolism from resting rates to V · O 2 ,max ) compared with larger mammals of comparable aerobic capacities (Bishop, 1999).…”

“…Extending the mammalian fuel use model to small mammals would provide a valuable hypothesis-testing tool for many popular experimental models including laboratory and wild rodents. For example, species of wild mice, especially those native to different altitudes (genera Peromyscus and Phyllotis), represent unique systems to investigate appropriate allocation of metabolic fuels and other metabolic adaptations to extreme environments of low pressure and temperature (Cheviron et al, 2014;Hayes and O'Connor, 1999;Nespolo et al, 2003;Russell et al, 2008;Schippers et al, 2012;Storz, 2007). In addition, a more comprehensive fuel use model could be used to test predictions regarding fuel use without the confounding influence of exercise intensity.…”