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.


O. Nakajima: None. S. Saitoh: Research Support; Spouse/Partner; Japan Society for the Promotion of Science, SBI Pharmaceuticals Co.,Ltd.. T. Kimura: None. T. Osaki: None. K.P. Vincent: Research Support; Self; Kora Healthcare. K. Takahashi: None. T. Tanaka: None. M. Nakajima: None.

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