Increased myocardial 18F-FDG uptake as a marker of Doxorubicin-induced oxidative stress

Bauckneht, Matteo; Pastorino, Fabio; Castellani, Patrizia; Cossu, Vanessa; Orengo, Anna Maria; Piccioli, Patrizia; Emionite, Laura; Capitanio, Selene; Yosifov, Nikola; Bruno, Silvia; Lazzarini, Edoardo; Ponzoni, Mirco; Ameri, Pietro; Rubartelli, Anna; Ravera, Silvia; Morbelli, Silvia; Sambuceti, Gianmario; Marini, Cecilia

doi:10.1007/s12350-019-01618-x

Cited by 35 publications

(63 citation statements)

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“…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.…”

Section: Discussionsupporting

confidence: 91%

“…To assess lipid peroxidation, malondialdehyde (MDA) levels were evaluated, by the thiobarbituric acid reactive substances (TBARS) assay, with minor modi cations [13,25]. The activity assay of the Complex I was measured on 50μg of total protein as previously described [10,12,26].…”

Section: Enzymatic Assaymentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Marini

Cossu

Bonifacino

et al. 2020

Preprint

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Background. We recently reported that enhanced [18F]-fluorodeoxyglucose (FDG) uptake in skeletal muscles predicts disease aggressiveness in patients with amyotrophic lateral sclerosis (ALS). The present experimental study aimed to assess whether this predictive potential reflects the link between FDG uptake and redox stress that has been previously reported in different tissues and disease models. Methods. The study included 15 SOD1G93A mice (as experimental ALS model) and 15 wildtype mice (around 120-days-old). Mice were submitted to micro-PET imaging. Enzymatic pathways and response to oxidative stress were evaluated in harvested quadriceps and hearts by biochemical, immunohistochemical and immunofluorescence analysis. Colocalization between the endoplasmic reticulum (ER) and the fluorescent FDG analog 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxyglucose (2-NBDG) was performed in fresh skeletal muscle sections. Finally, mitochondrial ultrastructure and bioenergetics were evaluated in harvested quadriceps and hearts.Results. FDG retention was significantly higher in hindlimb skeletal muscles of symptomatic SOD1G93A mice with respect to control ones. This difference was not explained by any acceleration in glucose degradation through glycolysis or cytosolic pentose phosphate pathway (PPP). Similarly, it was independent of inflammatory infiltration. Rather, the high FDG retention in SOD1G93A skeletal muscle was associated with an accelerated generation of reactive oxygen species. This redox stress selectively involved the ER and the local PPP triggered by hexose-6P-dehydrogenase. ER involvement was confirmed by the colocalization of the 2-NBDG with a vital ER tracker. The oxidative damage in transgenic skeletal muscle was associated with a severe impairment in the crosstalk between ER and mitochondria combined with alterations in mitochondrial ultrastructure and fusion/fission balance. The expected respiratory damage was confirmed by a deceleration in ATP synthesis and oxygen consumption rate. These same abnormalities were represented to a markedly lower degree in the myocardium, as a sample of non-voluntary striated muscle.Conclusion. Skeletal muscle of SOD1G93A mice reproduces the increased FDG uptake observed in ALS patients. This finding reflects the selective activation of the ER-PPP in response to significant redox stress associated with alterations of mitochondrial ultrastructure, networking, and connection with the ER itself. This scenario is less severe in cardiomyocytes suggesting a relevant role for either communication with synaptic plaque or contraction dynamics.

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Section: Discussionsupporting

confidence: 91%

Section: Enzymatic Assaymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Marini

Cossu

Bonifacino

et al. 2020

Preprint

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“…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].…”

Section: Introductionmentioning

confidence: 72%

“…Serum glucose level was tested and FDG (3-4 MBq) was injected through a tail vein. Forty minutes later, mice were positioned in a dedicated micro-PET system (Albra, Bruker, USA) whose dual ring configuration allows the acquisition of the whole mouse body by static acquisition lasted ten minutes [10,13]. After its completion mice were immediately euthanized by cervical dislocation.…”

Section: Experimental Micro-pet Imagingmentioning

confidence: 99%

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

Marini

Cossu

Bonifacino

et al. 2020

Preprint

Self Cite

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BackgroundUsing a computational approach to PET/CT images, we recently reported that enhanced 18F-fluorodeoxyglucose (FDG) uptake in skeletal muscles predicts aggressiveness and outcome in patients with amyotrophic lateral sclerosis (ALS). The present experimental study aimed to assess the mechanisms underlying the predictive potential of this metabolic shift in SOD1G93A mice as a model of ALS.Methods.The study included 15 SOD1G93A mice and 15 wild-type mice (around 120-days-old). Mice were submitted to micro-PET imaging. Enzymatic pathways and response to oxidative stress were evaluated in harvested quadriceps and hearts by biochemical, immunohistochemical and immunofluorescence analysis. Colocalization between the endoplasmic reticulum (ER) and the fluorescent FDG analog 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxyglucose (2-NBDG) were performed in fresh skeletal muscle sections. Finally, mitochondrial ultrastructure and bioenergetic evaluation were evaluated in harvested quadriceps and hearts.ResultsFDG retention was significantly higher in hindlimb skeletal muscles of symptomatic SOD1G93A mice with respect to control ones. This difference was not explained by any acceleration in cytosolic glucose degradation through glycolysis or pentose phosphate pathway (PPP). Similarly, it was independent of inflammatory infiltration. Rather, the high FDG retention in SOD1G93A skeletal muscle was associated with an accelerated generation of reactive oxygen species. This redox stress selectively involved the ER and the local PPP triggered by hexose-6P-dehydrogenase. ER involvement was confirmed by the colocalization of the 2-NBDG with a vital ER tracker. The oxidative damage in transgenic skeletal muscle was associated with a severe impairment in the crosstalk between ER and mitochondria combined with alterations in mitochondrial ultrastructure and fusion/fission balance. The expected respiratory damage was confirmed by a deceleration in ATP synthesis and oxygen consumption rate. These same abnormalities were represented to markedly lower degree in the myocardium, as a sample of non-voluntary skeletal muscle.ConclusionSkeletal muscle of SOD1G93A mice reproduces the increased FDG uptake observed in ALS patients. This finding reflects the selective activation of the ER-PPP in response to a significant redox stress associated with alterations of mitochondrial ultrastructure, networking and connection with the ER itself. This scenario is less severe in cardiomyocytes suggesting a relevant role for either communication with synaptic plaque or contraction dynamics.

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Nuclear Medicine Tools for Cardiac Damage Diagnosis in Oncology

2021

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Increased myocardial 18F-FDG uptake as a marker of Doxorubicin-induced oxidative stress

Cited by 35 publications

References 29 publications

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

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

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

Nuclear Medicine Tools for Cardiac Damage Diagnosis in Oncology

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