Figure 9. Glucose pathways and their alterations in MHS muscle.

Glycogen, resident in the intermyofibrillar space in the form of granules or SR-bound, is synthesized from transported glucose or broken down to glucose-1-phosphate (Glc-1-P). In MHS, [Ca²⁺]_cyto is elevated (López Padrino, 1994) as a consequence (Rios, 2012) of an increased leak from the SR that results in a lower resting free SR calcium level. The lower [Ca²⁺]_SR promotes influx via SOCE or other pathways (Eltit et al., 2013) resulting in higher [Ca²⁺]_cyto. The change has two effects: (i) PhK activation that increases phosphorylation of GP and GS, to respectively enhance the breakdown and decrease the synthesis of glycogen. The resulting increase in Glc-1-P, Glc-6-P and glucose (Glc) hampers passive entry of glucose. (ii) Decrease of the basal activation by AMPK of the expression and membrane insertion of the glucose transporter GLUT4 (61), which contributes to reducing glucose entry. Concurrently, PhK, GPa, GSa and GDE move towards the intermyofibrillar space (not shown). Question marks indicate stages where evidence is lacking or conflicting. They include the site of interaction of PhK with its substrates, the location of GPa (whether in granules or attached to TC) and the possible effects of elevated [Ca²⁺] on GLUT4.