Skeletal muscle is the tissue most responsible for basal and exercise induced energy expenditure and is commonly investigated to provide insights into human physical performance and disease, such as obesity and diabetes. Uncoupling protein-3 (UCP3) has been shown, in rodent mitochondria, to uncouple mitochondrial oxidative phosphorylation. Intuitively, this would result in an increase in energy expenditure and a decrease in the efficiency of aerobic ATP production. UCP3 expression is decreased under conditions where mitochondrial ATP production rate (MAPR) is improved, such as after long term endurance training. In contrast, UCP3 is increased in situations where MAPR is reduced, such as with muscle disuse. Additionally, we have observed that UCP3 content is greater in mouse subsarcolemmal (SS) than in intermyofibrillar (IMF) mitochondria. The aim of our project is a better understanding of the biological role of UCP3. To achieve this, we wish to determine whether changes in UCP3 content within the different mitochondrial populations with exercise or with muscle disuse, reflect changes in mitochondrial uncoupling and MAPR. We propose first to extend preliminary findings that mouse UCP3 is increased in IMF, but not in SS mitochondria after bouts of swimming exercise. From this experiment we will measure mitochondrial uncoupling and MAPR in the SS and IMF mitochondrial populations after 1 h of swimming exercise. This study will allow us to test the hypothesis that an increased UCP3 content will increase mitochondrial uncoupling and reduce the MAPR.
We also propose two human studies in collaboration between the University of Geneva and the Clinique romande de réadaptation (CRR) SUVA Care Sion. We will investigate the effects of 10 days of endurance training on human UCP3 content, mitochondrial uncoupling and MAPR in SS and IMF mitochondria. It is hypothesised that endurance training will reduce UCP3 content and mitochondrial uncoupling with a resulting increase in the MAPR. Finally, at the CRR, patients suffering from muscle disuse injuries ranging from paraplegia to broken limbs, who stay at the clinic and undergo treatment for 1-6 months, will be sollicited as volunteers for a prospective study over 6 months which should allow us to investigate the effect of muscle disuse and physical therapy treatment on UCP3 content and mitochondrial
uncoupling and MAPR in both SS and IMF mitochondria.
