Rac1 Is a Novel Regulator of Contraction-Stimulated Glucose Uptake in Skeletal Muscle

Abstract

In skeletal muscle, the actin cytoskeleton-regulating GTPase, Rac1, is necessary for insulin-dependent GLUT4 translocation. Muscle contraction increases glucose transport and represents an alternative signaling pathway to insulin. Whether Rac1 is activated by muscle contraction and regulates contraction-induced glucose uptake is unknown. Therefore, we studied the effects of in vivo exercise and ex vivo muscle contractions on Rac1 signaling and its regulatory role in glucose uptake in mice and humans. Muscle Rac1-GTP binding was increased after exercise in mice (∼60–100%) and humans (∼40%), and this activation was AMP-activated protein kinase independent. Rac1 inhibition reduced contraction-stimulated glucose uptake in mouse muscle by 55% in soleus and by 20–58% in extensor digitorum longus (EDL; P < 0.01). In agreement, the contraction-stimulated increment in glucose uptake was decreased by 27% (P = 0.1) and 40% (P < 0.05) in soleus and EDL muscles, respectively, of muscle-specific inducible Rac1 knockout mice. Furthermore, depolymerization of the actin cytoskeleton decreased contraction-stimulated glucose uptake by 100% and 62% (P < 0.01) in soleus and EDL muscles, respectively. These are the first data to show that Rac1 is activated during muscle contraction in murine and human skeletal muscle and suggest that Rac1 and possibly the actin cytoskeleton are novel regulators of contraction-stimulated glucose uptake.

Rho GTPases in insulin-stimulated glucose uptake

“…For instance, a GEF other than FLJ00068 may be responsible for contraction-stimulated Rac1 activation. Additionally, it was reported that Rac1 activation in response to contraction is not mediated by AMPK 71 . This may be an unexpected result, taking into consideration that AMPK has been implicated in contraction-dependent glucose uptake as described above, and AMPK can stimulate Rac1 (see below).…”

“…A pivotal role of Rac1 in contraction-stimulated glucose uptake in skeletal muscle has been clarified by using muscle-specific rac1 knockout mice 71 . The activation of Rac1 was observed after exercise in both mice and humans, and contraction-stimulated glucose uptake was abrogated in rac1 knockout mouse skeletal muscle.…”

Ca2+signals promote GLUT4 exocytosis and reduce its endocytosis in muscle cells

“…The paramount intracellular signal triggered by changes in the AMP/ATP ratio is activation of the AMP-activated protein kinase (AMPK). Signals triggered by mechanical stretch include the small G protein Rac1 and its downstream effector kinases PAK1/2 (8,42). These pathways may also intersect one another to affect glucose uptake, as exemplified by the activation of AMPK by CaMKK (22,49).…”

Regulation of NADPH oxidases in skeletal muscle

“…Consistent with this notion, Nox2 knockout mice have higher baseline levels of plasma glucose and insulin compared to wild type animals [161]. Muscle contraction and stretch stimulate glucose transport in a ROS-dependent manner [176, 177], and recent studies have indicated that Rac1 is required for contraction- and stretch-stimulated glucose uptake in skeletal muscle [76, 178]. These findings suggest Nox2-derived ROS as potential mediators of skeletal muscle glucose transport.…”