Is contraction-stimulated glucose transport feedforward regulated by Ca2+?

New Findings What is the topic of this review? The article critically reviews the role of sarcoplasmic reticulum (SR) Ca2+ as a feedforward regulator of glucose uptake in skeletal muscle. What advances does it highlight? We highlight recent findings suggesting that stimulation of glucose transport in muscle can be completely uncoupled from Ca2+ release from the SR and weigh these data against the previous literature supporting a key role of Ca2+ in regulation of glucose transporter4 translocation and glucose transport. A revised working model for contraction-regulated glucose transport is proposed. In many cell types, Ca2+ signals to increase the movement and surface membrane insertion of vesicles. In skeletal muscle, Ca2+ is predominantly released from the sarcoplasmic reticulum (SR) to initiate contraction. Sarcoplasmic reticulum Ca2+ release is widely believed to be a direct feedforward regulator of the translocation of glucose transporter4 to the cell surface to facilitate transmembrane glucose transport. This review summarizes the evidence supporting the Ca2+ feedforward model and its proposed signalling links to regulation of glucose transport in skeletal muscle and other cell types. The literature is contrasted against our recent findings suggesting that SR Ca2+ release is neither essential nor adequate to stimulate glucose transport in muscle. Instead, feedback signals through AMPK and mechanical stress are likely to account for most of contraction-stimulated glucose transport. A revised working model is proposed, in which muscle glucose transport during contraction is not directly regulated by SR Ca2+ release but rather responds exclusively to feedback signals activated secondary to cross-bridge cycling and tension development.