In their study, de Wendt et al. (1) present evidence to suggest that the full effect of contraction on muscle glucose uptake is regulated by a framework of proteins consisting of AMPK, TBC1D1, TBC1D4, and Rac1. Their work is based on experiments performed in isolated and incubated skeletal muscle from a novel mouse model deficient in muscle AMPK combined with whole-body knockout of TBC1D1 and TBC1D4. From a mechanistic point of view, the experimental ex vivo mouse muscle model used is strong, as it permits accurate assessment of glucose uptake in isolated muscle during contraction in the absence of confounding factors that may persist in the intact animal model (2).
A limitation of the study by de Wendt et al. (1) resides in the inability to accurately define “contraction-mediated glucose uptake.” This likely creates bias in their conclusion. As described in their methods section, muscle glucose uptake was measured during a 20-min period that included 10 min during which the muscle contracted and 10 min in recovery from the contraction stimulus. With the assumption that the molecular mechanisms responsible for regulating glucose uptake during contraction and in the immediate period after contraction are similar, the authors concluded that AMPK and TBC1D1 are part of a framework regulating contraction-mediated glucose uptake. The assumption made, however, may not be valid because the importance of the various molecular mechanisms responsible for regulating glucose uptake during and after contraction is not the same. Indeed, we recently demonstrated the importance of both AMPK and TBC1D1 in regulating glucose uptake in the period after, but not during, muscle contraction (3). These observations were also supported by a thorough evaluation of the literature, which showed that the majority of studies reporting impaired contraction-mediated glucose uptake in muscle from AMPK- and TBC1D1-deficient mice had been measuring glucose uptake in the period after contraction (3). These observations led us to propose the idea that the AMPK–TBC1D1 signaling axis acts by inhibiting endocytosis of GLUT4-containing vesicles, thereby maintaining GLUT4 at the plasma membrane and, thus, glucose transport in the period after contraction. Although the AMPK–TBC1D1 axis is also activated during contraction, it likely is not important for GLUT4 translocation or glucose transport because signaling promoting GLUT4 exocytosis dominates during this period (4,5).
While we deeply appreciate the great amount of work and exciting data provided by de Wendt et al. (1) to delineate the molecular mechanisms regulating contraction-mediated glucose uptake in muscle, we believe that the data fail to accurately describe the role of AMPK and TBC1D1 in this process because measurements of glucose uptake are reported as the combined uptake of glucose during and after contraction. Therefore, we would like to emphasize that defining the accurate period for measuring glucose transport is of the utmost importance to avoid bias in the interpretation of data on contraction-mediated glucose transport.
Duality of Interest. No potential conflicts of interest relevant to this article were reported.