Mitochondrial function adaptations to changed metabolic conditions

The skeletal muscle mitochondria play a decisive role for the metabolic capacity of the body. A capability to adapt to changed metabolic conditions and energy demands is crucial for weight control and physical exercise. The aim of this thesis was to describe how the mitochondria adapt its function to different environmental conditions and changed metabolic demands.

In study I, the aim was to evaluate mitochondrial adaptations to hypoxic exercise. The effect of one-legged cycle training at hypoxia was compared to equivalent normoxic training, performed at the same relative intensity. Eight untrained volunteers performed one-legged cycle training during 4 weeks. Muscle biopsies were taken before and after the exercise period. The leg trained during normoxia increased its mitochondrial population (+20.8%, P<0.05) and there was a trend towards increased respiratory capacity (+31.2%, P<0.08), while adaptations were absent in the hypoxically trained leg. Altitude training might thus be disadvantageous for mitochondrial adaptations and muscle oxidative function.

In study II, the aim was to investigate the effect of ultra endurance exercise on mitochondrial function. Elite ultra endurance athletes performed running, kayaking, and cycling at 60% of their maximal oxygen consumption for 24 h. Muscle biopsies were taken preexercise, postexercise, and after 28 h of recovery. We found that mitochondrial efficiency was reduced, while the mitochondrial capacity to utilize fat was up regulated (+40%, P<0.05) after exercise. This increase in fat oxidation was reflected at whole body level substrate utilization, thus it might benefit performance during prolonged exercise.

In study III and IV, the aims were to study mitochondrial function in obesity and effects of weight loss, respectively. Weight gain varies among individuals despite equal calorie overconsumption. Furthermore, weight loss resulting from low calorie diets is often less than expected and long-term success is low. This suggests differences and changes in metabolic efficiency and basal metabolism. Since mitochondrial uncoupling accounts for a substantial portion of the basal metabolic rate, we compared mitochondrial respiration in obese subjects to normal weight reference groups (study III). In study IV, we studied how mitochondrial capacity was affected by calorie restriction. Muscle biopsies were taken from 11 obese women, with an average BMI of 39 kg/m2, in conjunction with their gastric bypass surgery and at 6-months of follow-up.

We found that obese subjects had a decreased oxidative capacity (-47%, P<0.01) per mitochondrial volume, compared to the to normal weight reference groups. A low capacity for fuel oxidation could play a role in the predisposition for obesity. Six months after the gastric bypass surgery, the subjects had lost on average 25.5 kg of their body weight. Coupled, ADP generating respiration, had increased significantly (+69%, P≤0.01), while the uncoupled respiration was not significantly altered. Mitochondrial efficiency increased significantly. An increased mitochondrial efficiency could partly explain the reduced basal metabolism and thus the reduced inclination for weight loss at calorie restriction. The reduced capacity among the obese is thus suggested to rather be an effect of the obesity than a casual factor.

List of scientific papers

I. Bakkman L, Sahlin K, Holmberg HC, Tonkonogi M (2007). "Quantitative and qualitative adaptation of human skeletal muscle mitochondria to hypoxic compared with normoxic training at the same relative work rate." Acta Physiol (Oxf) 190: 243-251.
https://doi.org/10.1111/j.1748-1716.2007.01683.x

II. Fernström M, Bakkman L, Tonkonogi M, Shabalina IG, Rozhdestvenskaya Z, Mattsson CM, Enqvist JK, Ekblom B, Sahlin K (2007). "Reduced efficiency, but increased fat oxidation, in mitochondria from human skeletal muscle after 24-h ultraendurance exercise." J Appl Physiol 102: 1844-1849.
https://doi.org/10.1152/japplphysiol.01173.2006

III. BAKKMAN L, Fernström M, Loogna P, Rooyackers O, Brandt L, Trolle Lagerros Y (1970). "Reduced Respiratory Capacity in Muscle Mitochondria of Obese Subjects". [Accepted]
https://doi.org/10.1159/000320167

21196791

IV. BAKKMAN L, Fernström M, Loogna P, Rooyackers O, Svensson M, Jakobsson T, Brandt L, Trolle Lagerros Y (2010). "Increased muscle mitochondrial efficiency following calorie restriction in obese subjects". [Manuscript]