Spinal cord hypermetabolism extends to skeletal muscle in amyotrophic lateral sclerosis: a computational approach to [18F]-fluorodeoxyglucose PET/CT images

Bauckneht, Matteo; Lai, Rita; Miceli, Alberto; Schenone, Daniela; Cossu, Vanessa; Donegani, Maria Isabella; Raffa, Stefano; Borra, Anna; Marra, Stefano; Campi, Cristina; Orengo, Anna Maria; Massone, Anna Maria; Tagliafico, Alberto; Caponnetto, Claudia; Cabona, Corrado; Cistaro, Angelina; Chiò, Adriano; Morbelli, Silvia; Nobili, Flavio; Sambuceti, Gianmario; Piana, Michele; Marini, Cecilia

doi:10.1186/s13550-020-0607-5

Cited by 22 publications

(17 citation statements)

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“…The present study confirms that the increased skeletal muscle FDG uptake observed in ALS patients also occurs in the SOD1 G93A experimental model [9]. The increase in FDG accumulation rate was observed in living mice, under fasting conditions and in the presence of normal glucose levels.…”

Section: Discussionsupporting

confidence: 89%

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Mechanisms underlying the predictive power of high skeletal muscle uptake of FDG in amyotrophic lateral sclerosis

et al. 2020

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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 SOD1 G93A 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.

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Section: Discussionsupporting

confidence: 89%

“…The apparent metabolic activation of this nervous district faced an opposite pattern in the brain cortex that showed a generalized reduction in tracer uptake [8]. By contrast, it extended to the psoas muscles of the same patients, suggesting a link between the metabolic pattern of the second motoneuron and its effector [9].…”

Section: Introductionmentioning

confidence: 92%

Mechanisms underlying the predictive power of high skeletal muscle uptake of FDG in amyotrophic lateral sclerosis

et al. 2020

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“…The present study confirms that the metabolic activation of skeletal muscle, observed in ALS patients, also occurs in the SOD1 G93A experimental model [9]. The increase in FDG accumulation rate was observed in living mice, under fasting conditions and in the presence of normal glucose levels.…”

Section: Discussionsupporting

confidence: 89%

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

Marini

Cossu

Bonifacino

et al. 2020

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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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“…The present study con rms that the increased skeletal muscle FDG uptake observed in ALS patients also occurs in the SOD1 G93A experimental model [9]. The increase in FDG accumulation rate was observed in living mice, under fasting conditions and in the presence of normal glucose levels.…”

Section: Discussionsupporting

confidence: 84%

Section: Introductionmentioning

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

View full text Add to dashboard Cite

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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Spinal cord hypermetabolism extends to skeletal muscle in amyotrophic lateral sclerosis: a computational approach to [18F]-fluorodeoxyglucose PET/CT images

Cited by 22 publications

References 36 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

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

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