Many pathways are called! Many may be chosen!

Since the early work of Rachmiel Levine and colleagues, investigators have attempted to decipher the molecules, metabolic pathways and signalling intermediates that may be responsible for the increase in glucose transport during and following exercise (Goldstein et al. 1953). While considerable progress and seminal observations have been procured in these diverse areas of investigation, the coordinate networking of metabolic control of hexose transport during and after muscle contraction remains underdefined. In the current issue of The Journal of Physiology, Sandstrom et al. (2006) have proposed that endogenously produced reactive oxygen species (ROS) play an important role in contraction-mediated activation of glucose transport in skeletal muscle. This report is not only novel but it is also timely. The investigation of ROS in the control of glucose metabolism during and/or after exercise has received relatively little attention despite similar investigations examining reactive nitrogen species, muscle contraction and glucose transport (Balon & Nadler, 1997). In the 1980s, a number of different laboratories observed that under certain experimental conditions, the effects of prior exercise and insulin exposure were additive on the enhancement of skeletal muscle glucose transport, thus suggesting that either different pools of glucose transporters were recruited or different signalling pathways were activated. While slightly more than a decade ago it was shown that a unique pool of glucose transporters are preferentially recruited by exercise (Coderre et al. 1995), divergent opinions have persisted about the relative importance of different signalling pathways and their upstream modulators in the control of augmented glucose transport during and after exercise (reviewed by Rose & Richter, 2005). Sandstrom et al. (2006) undertook a unique approach toward the delineation of the involvement of ROS in contraction-mediated glucose transport using an incubated skeletal muscle system in conjunction with mice over-expressing the Mn2+-dependent isoform of superoxide dismutase in combination with maximally effective concentrations of N-acetylcysteine (NAC) and hydrogen peroxide (H2O2). Within the limitation(s) of their model of mimicking in vivo exercise by electrical stimulation in vitro, they have presented an exciting possibility that a 5′AMP-activated protein kinase (AMPK) dependent–antioxidant-mediated and an AMPK-dependent–antioxidant-independent pathway for the modulation of glucose transport may exist. Along with the previously described insulin-sensitive, hypoxia-mediated and nitric oxide-dependent pathways, which may have both cyclic guanosine 3′,5′-monophosphate (cGMP)-dependent and cGMP-independent arms, exercise biochemists have plenty of pathways to examine and validate. The possibility that these pathways may diverge and may later converge or may exhibit cross-talk or redundancy under certain experimental conditions but be operative in vivo remains untested. This paper should serve as an impetus for the authors and other groups to conduct further experiments investigating ROS as a mediator of exercise-enhanced glucose transport. Following the adage often attributed to Yogi Berra, ‘If you come to a fork in the road take it’, the science community will hopefully examine these pathways under a variety of conditions that make the forks or paths in the signalling network physiologically relevant. The examination of muscles of various predominating fibre types along with exposure to physiological concentrations of insulin and different concentrations of H2O2 and NAC will be critical variables for future experimentation. Implementation of different animal models such as AMPK transgenic mice or diabetic animal models in conjunction with direct assessment of the exercise-regulative GLUT-4 transporter pool will be helpful in defining the relative importance of ROS in contraction-mediated glucose transport. Ultimately, understanding the signalling mechanisms linking exercise with increased glucose transport will have significant clinical value in the management of diabetes, insulin resistance and the design of new therapeutic interventions.