High exercise capacity is associated with lower risk for cardiovascular diseases and better outcome in disease. Aging is associated with decreasing exercise capacity and increasing incidence of diseases. Mitochondrial function is central in ageing and additionally associated with exercise capacity. In the model of rats with inherited high (HCR) or low (LCR) intrinsic exercise capacity, life expectancy is about 1/3 lower in LCR. We aimed to assess, if lower life expectancy is related to mitochondrial dysfunction.

We examined exercise capacity and cardiac function in HCR and LCR at 15 and 100 weeks (end of LCR lifespan). In addition, we assessed HCR at 130 weeks (end of HCR lifespan). Mitochondria from cardiac and skeletal muscle were functionally assessed and isolated complex activities determined. Furthermore, we measured mitochondrial ROS production, antioxidative capacity as well as oxidative damage.

Independent of age, exercise capacity was lower in LCR. Cardiac contractile function decreased with age but was comparable in HCR and LCR (fractional shortening [%]: HCR 15 weeks – 42.6 ± 2.5, HCR 100 weeks – 31.2 ± 2.5, HCR 130 weeks – 33.2 ± 3.5, LCR 15 weeks – 53.6 ± 2.6, LCR 100 weeks – 43.7 ± 2.9). Cardiac mitochondrial function also decreased with age and there was again no difference between HCR and LCR. In skeletal muscle, mitochondrial maximal respiratory capacity was higher in 15 weeks old HCR compared to 15 weeks old LCR. With age, respiration decreased more in LCR compared to HCR (pyruvate/malate [natomsO/min/mg protein]: HCR 15 weeks - 280 ± 33, HCR 100 weeks - 185 ± 13, LCR 15 weeks - 173 ± 12, LCR 100 weeks - 100 ± 11). At 130 weeks, HCR showed an additional impairment of mitochondrial respiration leading to same low levels as found in 100 weeks old LCR (pyruvate/malate [natomsO/min/mg protein]: HCR 130 weeks - 109 ± 11, LCR 100 weeks - 100 ± 11; refer to figure 1). Isolated complex activities in skeletal muscle were higher in 15 weeks old HCR compared to 15 weeks old LCR and decreased with age. 130 weeks old HCR presented with the same low levels as found in 100 weeks old LCR, reflecting the changes seen in respiration. Neither mitochondrial ROS production nor oxidative damage indicated differences between HCR and LCR.

Differences in life expectancy in HCR and LCR correlate with maximal respiratory capacity of skeletal muscle mitochondria of both, HCR and LCR. Thus, skeletal muscle mitochondrial function may be a unifying phenotypic feature for life expectancy in HCR and LCR.

Figure 1: Maximal respiratory capacity with pyruvate/malate of skeletal muscle mitochondria in rats with inherited high (HCR) and low (LCR) exercise capacity with different age (HCR: 15 + 100 + 130 weeks, LCR: 15 + 100 weeks), * p<0.05 indicates significant difference between HCR and LCR same age