Heme Deficiency Causes Impaired Glycogen Synthesis in Skeletal Muscle Leading to Insulin Resistance

In vertebrates, the initial step in heme biosynthesis is the production of 5-aminolevulinic acid (ALA) by ALA synthase (ALAS). The ALAS1 gene encodes a ubiquitously expressed isozyme. Mice heterozygous null for ALAS1 (A1^+/-s) experience mitochondrial dysfunction in skeletal muscle, impaired glucose tolerance (IGT) and insulin resistance (IR) past 20-weeks of age (aged A1^+/-s) ¹⁾. IGT/IR in aged A1^+/-s was remedied by oral administration of ALA for 1-week¹⁾. By contrast, mitochondrial dysfunction required 6-weeks of ALA administration before improvements could be observed, indicating the phenotype of IGT/ IR is not due to mitochondrial dysfunction¹⁾. We found no remarkable change in expressions and phosphorylation of proteins related to insulin signalling such as Akt and GSK3β in skeletal muscle of aged A1^+/-s¹⁾. Rather, abnormal ultrastructure of glycogen granules and increased glycogen contents were observed in skeletal muscle of aged A1^+/-s unlike of less than 15-weeks-old A1^+/-s, and those abnormalities of glycogen were reversed after ALA-treatment for 1-week as well as IGT/IR. The quantification of glycogen contents showed that insulin-induced glycogen synthesis was impaired in skeletal muscle of aged A1^+/-s, and the reduced de novo glycogen synthesis was recovered in ALA-administrated aged A1^+/-s. Glycogen synthase (GS) activities were constitutively activated even at the low concentration of glucose 6-phosphate (G6P) and not augmented at the high concentration of G6P in extracts from skeletal muscle of aged A1^+/-s, suggesting that GS fails to respond to allosteric activation by G6P. While, GS activities were normally regulated in those of ALA-administered aged A1^+/-s. Taken together, our data suggest that impaired de novo glycogen synthesis in skeletal muscle is relevant to IGT/IR in aged A1^+/-s due to constitutively activated GS without allosteric activation by G6P. Ref. 1) Saitoh et al. PLOS ONE in press.