Glucose 6-P Dehydrogenase-An Antioxidant Enzyme with Regulatory Functions in Skeletal Muscle during Exercise

Abstract

Hypomorphic Glucose 6-P dehydrogenase (G6PD) alleles, which cause G6PD deficiency, affect around one in twenty people worldwide. The high incidence of G6PD deficiency may reflect an evolutionary adaptation to the widespread prevalence of malaria, as G6PD-deficient red blood cells (RBCs) are hostile to the malaria parasites that infect humans. Although medical interest in this enzyme deficiency has been mainly focused on RBCs, more recent evidence suggests that there are broader implications for G6PD deficiency in health, including in skeletal muscle diseases. G6PD catalyzes the rate-limiting step in the pentose phosphate pathway (PPP), which provides the precursors of nucleotide synthesis for DNA replication as well as reduced nicotinamide adenine dinucleotide phosphate (NADPH). NADPH is involved in the detoxification of cellular reactive oxygen species (ROS) and de novo lipid synthesis. An association between increased PPP activity and the stimulation of cell growth has been reported in different tissues including the skeletal muscle, liver, and kidney. PPP activity is increased in skeletal muscle during embryogenesis, denervation, ischemia, mechanical overload, the injection of myonecrotic agents, and physical exercise. In fact, the highest relative increase in the activity of skeletal muscle enzymes after one bout of exhaustive exercise is that of G6PD, suggesting that the activation of the PPP occurs in skeletal muscle to provide substrates for muscle repair. The age-associated loss in muscle mass and strength leads to a decrease in G6PD activity and protein content in skeletal muscle. G6PD overexpression in Drosophila Melanogaster and mice protects against metabolic stress, oxidative damage, and age-associated functional decline, and results in an extended median lifespan. This review discusses whether the well-known positive effects of exercise training in skeletal muscle are mediated through an increase in G6PD.

Keywords: G6PD; NADPH; aging; pentose phosphate pathway; physical training; skeletal muscle.

Figure 1

The pentose phosphate pathway and its interrelation with glycolysis. Blue and orange arrows show reversible and irreversible reactions, respectively. Enzyme names are shown in blue and orange boxes. Glycolysis metabolites obtained through the PPP are shown in red squares. G6P—glucose 6-phosphate; F6P—fructose 6-phosphate; F1,6P—fructose 1,6-biphosphate; DHAP—dihydroxyacetone phosphate; G3P—glyceraldehyde 3-phosphate; 1,3 BPG—1,3-bisphosphoglycerate; 3PG—3-phosphoglycerate; 2PG—2-phosphoglycerate; PEP—phosphoenolpyruvate; 6PG—6-phosphogluconate; HK—hexokinase; PGI—phosphoglucoisomerase; PFK—phosphofructokinase; FBA—fructose-1,6-bisphosphate aldolase; TPI—triose-phosphate isomerase; GAPDH—glyceraldehyde 3-phosphate dehydrogenase; PGK—phosphoglycerate kinase; PGM—phosphoglycerate mutase; G6PD—glucose 6-phosphate dehydrogenase; 6PGD—6-phosphogluconate dehydrogenase; RPE—ribulose-phosphate 3-epimerase; RPI—ribose-5-phosphate isomerase; TKL—transketolase; TAL: transaldolase.

Figure 2

NADPH-dependent enzymes. NOs—nitric oxide synthases; NOx—NADPH-oxidase enzymes; DHFR—dihydrofolate reductase.

Figure 3

Pentose phosphate pathway regulation depends on cellular needs. MODE 1: This mode dominates when the need for R5P is higher than that for NADPH, for instance, in proliferative cells. In this situation, the glycolytic metabolites 3GP and F6P can be converted in R5P through the reversible non-oxidative PPP. The oxidative PPP and its associated NADPH formation are bypassed. MODE 2: This mode occurs when the needs for NADPH and R5P are balanced. Then, ideally, from one molecule of G6P two molecules of NADPH and a molecule of R5P can be obtained with no generation of glycolytic metabolite. MODE 3: This mode is adopted when the cellular need for NADPH exceeds that for R5P and ATP, for instance, during fatty acid synthesis in adipocytes. The non-oxidative phase of the pathway leads to the conversion of ribulose 5-phosphate to fructose 6-phosphate (F6P) and glyceraldehyde 3-phosphate (G3P). Then, these glycolytic metabolites—through gluconeogenesis reactions—form G6P, which can enter again into the PPP to produce more NADPH. MODE 4: In this scenario, the cellular need for NADPH and ATP is higher than that for R5P. As described in PPP mode 3, ribulose 5-P is transformed into G3P and F5P through the non-oxidative branch of the PPP; however, in mode 4, these molecules are metabolized to pyruvate through glycolysis, which is associated with ATP formation.