FDG uptake tracks the oxidative damage in diabetic skeletal muscle: An experimental study

Abstract

ObjectivesThe present study aims to verify the relationship between glucose consumption and uptake of 18F-2-deoxy-glucose (FDG) in the skeletal muscle (SM) of experimental models of streptozotocin-induced diabetes mellitus (STZ-DM).MethodsThe study included 36 Balb/c mice. Two weeks after intraperitoneal administration of saline (control group, n = 18) or 150 mg streptozotocin (STZ-DM group, n = 18), the two cohorts were submitted to an oral glucose tolerance test and were further subdivided into three groups (n = 6 each): untreated and treated with metformin (MTF) at low or high doses (10 or 750 mg/kg daily, respectively). Two weeks thereafter, all mice were submitted to dynamic micro–positron emission tomography (PET) imaging after prolonged fasting. After sacrifice, enzymatic pathways and response to oxidative stress were evaluated in harvested SM.ResultsOn PET imaging, the FDG uptake rate in hindlimb SM was significantly lower in nondiabetic mice as compared with STZ-DM–untreated mice. MTF had no significant effect on SM FDG uptake in untreated mice; however, its high dose induced a significant decrease in STZ-DM animals. Upon conventional analysis, the SM standard uptake value was higher in STZ-DM mice, while MTF was virtually ineffective in either control or STZ-DM models. This metabolic reprogramming was not explained by any change in cytosolic glucose metabolism. By contrast, it closely agreed with the catalytic function of hexose-6P-dehydrogenase (H6PD; i.e., the trigger of a specific pentose phosphate pathway selectively located within the endoplasmic reticulum). In agreement with this role, the H6PD enzymatic response to both STZ-DM and MTF matched the activation of the NADPH-dependent antioxidant responses to the increased generation of reactive oxygen species caused by chronic hyperglycemia. Ex vivo analysis of tracer kinetics confirmed that the enhanced SM avidity for FDG occurred despite a significant reduction in glucose consumption, while it was associated with increased radioactivity transfer to the endoplasmic reticulum.ConclusionsThese data challenge the current dogma linking FDG uptake to the glycolytic rate. They instead introduce a new model considering a strict link between the uptake of this glucose analog, H6PD reticular activity, and oxidative damage in diabetes, at least under fasting condition.

Mechanisms underlying the predictive power of high skeletal muscle uptake of FDG in Amyotrophic Lateral Sclerosis

“…activity, induced by SOD1 G93A mutation, that would rather suggest a deceleration in glycolytic ux combined with a constant rate of cytosolic PPP. However, the divergent response of tracer retention and glycolytic ux to SOD1 G93A mutation closely agrees with a series of previous observations [10][11][12][13][14] documenting a relative independence between FDG uptake and glucose consumption. According to this evidence, tracer accumulation rate largely re ects the activation of H6PD catalytic function within the ER as also con rmed by the selective localization of the FDG uorescent analog, 2-NBDG, within the ER of transgenic muscles.…”

“…Quadriceps muscle side was randomly selected. Ex vivo FDG uptake of quadriceps and hearts was evaluated using the Ligand-Tracer White ® instrument (Ridgeview, Uppsala, SE) according to our previously validated procedure [12,14,19]. Brie y, the device consists of a betaemission detector and a rotating platform harboring a standard Petri dish.…”

“…Slices (300 µm thick) of quadriceps or hearts were stuck in the outer ring of a Petri dish with octyl-cyanoacrylate (Dermabond, Ethicon, US) and covered with 3 mL solution collected from an input vial containing 4 mL of Dulbecco's Modi ed Eagle's Medium (DMEM) containing glucose and FDG at the concentration of 5.5 mM (1 g/L) and 2 MBq/mL, respectively. Time-activity curves were thus obtained by subtracting decay-corrected background counting rate from the corresponding target value, as previously described [12,14,[19][20]. After 40 min, an aliquot of 0.5 mL was sampled both from the input vial and from the Petri dish (output) to measure the radioactivity concentration using a dose calibrator with an activity resolution <10 KBq (Capintec CRC55).…”

“…FDG uptake is commonly considered an index of glucose consumption. Nevertheless, several studies recently challenged this classical assumption and reported a direct and strict link between tracer retention and the activation of a speci c pentose phosphate pathway (PPP) triggered by the "omnivore" enzyme hexose-6P-dehydrogenase (H6PD) within the endoplasmic reticulum (ER) of cancer cells [10][11], neurons and astrocytes [12], cardiomyocytes [13] and, more importantly, in skeletal muscles [14]. A major function of PPP is the reduction of NADP + to NADPH to fuel the glutathione-dependent antioxidant responses.…”

Mechanisms underlying the predictive power of high skeletal muscle uptake of FDG in Amyotrophic Lateral Sclerosis

“…Although FDG uptake is commonly considered an index of glucose consumption, several studies recently reported a direct and strict link between tracer retention and the response to redox stress involving a selective activation of pentose phosphate pathway (PPP) triggered by hexose-6Pdehydrogenase (H6PD) within the endoplasmic reticulum (ER) [10]. This correlation fits the capability of this enzyme to recognize a large number of hexoses (including FDG-6P) as substrates and was documented in cancer cells [10][11], neurons and astrocytes [12], cardiomyocytes [13] and, more importantly, in skeletal muscles [14].…”