Disruption of the purine nucleotide cycle by inhibition of adenylosuccinate lyase produces skeletal muscle dysfunction.

Abstract

Abstract. Controversy exists as to whether the purine nucleotide cycle is important in normal skeletal muscle function. Patients with disruption of the cycle from a deficiency of AMP deaminase exhibit variable degrees of muscle dysfunction. An animal model was used to examine the effect of inhibition of the purine nucleotide cycle on muscle function. When the compound 5-amino-4-imidazolecarboxamide riboside (AICAriboside) is phosphorylated to the riboside monophosphate in the myocyte it is an inhibitor of adenylosuccinate lyase, one of the enzymes of the purine nucleotide cycle. AICAriboside was infused in 28 mice, and 22 mice received saline. Gastrocnemius muscle function was assessed in situ by recording isometric tension developed during stimulation. The purine nucleotide content of the muscle was measured before and after stimulation.Disruption of the purine nucleotide cycle during muscle stimulation was evidenced by a greater accumulation of adenylosuccinate, the substrate for adenylosuccinate lyase, in the animals receiving AICAriboside (0.60±0.10 vs. 0.05±0.01 nmol/Mmol total creatine, P

Biochemical and structural analysis of 14 mutant adsl enzyme complexes and correlation to phenotypic heterogeneity of adenylosuccinate lyase deficiency

“…ADSL acts in two pathways of purine nucleotide metabolism: the de novo purine synthesis pathway and the purine nucleotide cycle. Although both pathways are constitutively active during development and throughout life [Flanagan et al, 1986;Swain et al, 1984;Van den Berghe et al, 1992;Watts, 1983], their activity must be precisely regulated and coordinated to meet the entirely different nucleotide demands of dividing, differentiating and fully differentiated cells. The regulation of purine metabolism certainly takes place at various levels as demonstrated by the distinct compartmentalization of the purinosome within cells and the entirely different downstream regulatory effects of various intermediates of both of the pathways.…”

Activation of glycogen phosphorylase and glycogenolysis in rat skeletal muscle by AICAR — an activator of AMP‐activated protein kinase

“…These concentrations are equivalent to a muscle content of between 0.7 to 1.4 ~mollg wet wt. During infusion of 8 millimoles of AICAR to dogs over 40 rain the peak concentration of AICAR in the plasma at the end of infusion is 0.336 mM [22,23]. ZMP content reached a maximum of 0.032 ~mol/g wet wt.…”

Acadesine activates AMPK and induces apoptosis in B-cell chronic lymphocytic leukemia cells but not in T lymphocytes

“…9 The precursor of nucleotide biosynthesis acadesine or 5-aminoimidazole-4-carboxamide (AICA) riboside has various effects in several types of eukaryotic cells. These effects include inhibition of growth and depletion of pyrimidine nucleotide pools in fibroblasts, 10,11 accelerated repletion of purine nucleotide pools in heart, 12 reduction of endurance in skeletal muscle, 13 inhibition of fatty acid, sterol synthesis, and gluconeogenesis in hepatocytes, and increase in glucose uptake in muscle. 14 Acadesine is phosphorylated to AICA ribotide (ZMP), which mimics 5Ј-adenosine monophosphate (AMP) and activates both AMP-activated protein kinase (AMPK) and AMPK kinase (AMPKK).…”