Understanding efficiency of human muscular movement exemplifies integrative and translational physiology.

This issue of The Journal of Physiology contains a paper by Mogensen et al (2006) that is an excellent example of integrative physiology, addressing questions both at the subcellular and whole body levels that have implications for basic muscle energetics as well as athletic performance. Within a given population, muscular efficiency and thus work rate typically vary by as much as 20–30% when comparing individuals with low vs. high efficiency individuals despite controlling for oxygen consumption, training status, diet and other factors (Coyle et al. 1992). This represents a large amount of biological difference between individuals, which directly influences physical stress and work productivity. Elucidating the factors that determine and influence the energetic efficiency of human muscular movement in vivo, as currently measured by cycling or work efficiency, remains an important, open and challenging question. Work efficiency represents the product of two phenomena: (a) the efficiency with which the chemical energy of glucose and/or fat is converted to ATP through oxidative phosphorylation; and (b) the efficiency with which the chemical energy of ATP hydrolysis is converted to work. Mogensen et al (2006) convincingly demonstrate that differences in the efficiency of human muscular movement (e.g. gross cycling efficiency) observed among people cannot be explained by their in vitro differences in efficiency of oxidative phosphorylation within leg muscle mitochondria. Furthermore, mitochondrial efficiency was not different in endurance trained versus untrained individuals. This implies that the large differences among individuals in cycling efficiency appear to be due largely to the efficiency of transferring the chemical energy from ATP hydrolysis into physical work. The authors provide a good road map for translational physiologists to follow, especially when, as in the present case, the results don't support the initial hypothesis. Contrary to the initial hypothesis, cycling efficiency of people in vivo was not related to mitochondrial respiratory efficiency (i.e. phosphorylation ratio; P/O ratio) measured in vitro within isolated skeletal muscle mitochondria. The authors display keen insight into the literature and wisdom as they reconstruct how molecules of UCP3 or myosin might translate into the muscle functions currently observed. These appear to be the first such measurements made in vitro on humans of skeletal muscle mitochondrial efficiency measured during submaximal respiration. For this purpose, the authors developed a physiologically appropriate method involving constant rate ADP infusion across multiple flux rates to calculated the P/O at a common 50% value. However, their hard earned and physiologically sound data failed to support their theory leading to a host of new questions. The main new finding in the present study was that cycling efficiency was correlated to UCP3 protein content. It is hypothesized that other factors such as muscle fibre type influence UCP3 and thus muscle efficiency in vivo. However, the authors recognize the limitations in concluding a cause and effect relationship between UCP3 protein content and efficiency and go on to present a balanced argument including discussion against a direct role of UCP3 in determining muscle efficiency. This study again shows that cross-sectional endurance training status does not relate to mitochondrial efficiency (Tonkonogi et al. 2000; Fernstrom et al. 2004). Although oxidative phosphorylation can have direct influence on cycling efficiency, the authors acknowledge that it represents only part of the equation for work or cycling efficiency. We are left with an emerging picture that cycling efficiency appears related to percentage MHC I and somehow to UCP3 protein content. This study has made clear the fact that solving this puzzle requires use of techniques at the molecular and whole body levels, both of which can only be interpreted when controlling for the relative work rate.