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The exact mechanism of selective motor neuron death in amyotrophic lateral sclerosis (ALS) remains still unclear. In the present study, we performed in vivo capillary imaging, directly measured spinal blood flow (SBF) and glucose metabolism, and analyzed whether if a possible flow-metabolism coupling is disturbed in motor neuron degeneration of ALS...
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... WT mice, SBF of GM was much higher than that of WM, and was slightly increased with normal aging from 12 to 19 W (Table 2; Figures 2E, 2I, 2M, and 3A-3I). Anterior horn showed a trend toward higher SBF than DH in cervical, thoracic, and lumbar regions ( Table 2). ...
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... WT mice, SBF of GM was much higher than that of WM, and was slightly increased with normal aging from 12 to 19 W (Table 2; Figures 2E, 2I, 2M, and 3A-3I). Anterior horn showed a trend toward higher SBF than DH in cervical, thoracic, and lumbar regions ( Table 2). As compared with age-matched WT mice, significant reduction of SBF was found in GM of Tg mice as early as 12 W, especially AH of cervical (À20%, **P < 0.01 in AH; À15%, **P < 0.01 in DH), thoracic (À16%, *P < 0.05 in AH), and lumbar cord (À24%, **P < 0.01 in AH; À18%, **P < 0.01 in DH), except for dorsal region of thoracic cord (Table 2; Figures 2F, 2J, 2N, 3A, 3D, and 3G). ...
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... horn showed a trend toward higher SBF than DH in cervical, thoracic, and lumbar regions ( Table 2). As compared with age-matched WT mice, significant reduction of SBF was found in GM of Tg mice as early as 12 W, especially AH of cervical (À20%, **P < 0.01 in AH; À15%, **P < 0.01 in DH), thoracic (À16%, *P < 0.05 in AH), and lumbar cord (À24%, **P < 0.01 in AH; À18%, **P < 0.01 in DH), except for dorsal region of thoracic cord (Table 2; Figures 2F, 2J, 2N, 3A, 3D, and 3G). In contrast, there were no significant changes of SBF in any region of WM at 12 W. ...
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... contrast, there were no significant changes of SBF in any region of WM at 12 W. At 16 W of Tg mice, the reduction of SBF was progressively exacerbated in GM, and the reduction rate of SBF was prominent in AH (À39%, À32%, and À45% in cervical, thoracic, and lumbar cord, respectively, **P < 0.01 in each), and not so prominent in DH (À23%, À20%, and À32% in cervical, thoracic, and lumbar cord, respectively, **P < 0.01 in each), resulting in dis- sociative reduction of SBF between AH and DH (Table 2; Figures 2G, 2K, 2O, 3B, 3E, and 3H). There was no significant difference of SBF in WM too at this 16 W. ...
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... was no significant difference of SBF in WM too at this 16 W. At 19 W of Tg mice, the reduction of SBF in GM was further aggravated in cervical (À52%, **P < 0.01 in AH; À48%, **P < 0.01 in DH), thoracic (À41%, **P < 0.01 in AH; À35%, **P < 0.01 in DH), and lumbar cord (À56%, **P < 0.01 in AH; À50%, **P < 0.01 in DH) (Table 2; Figures 2H, 2L, 2P, 3C, 3F, and 3I). At this 19 W, SBF was only slightly reduced in WM especially lateral funiculus of cervical (À22%, **P < 0.01) and lumbar cord (À23%, **P < 0.01). ...
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... significant difference of LSGU was observed in GM of thoracic cord, or WM of all spinal cord regions at 12 W. In Tg mice at 16 W, significant reductions of LSGU were observed in GM regions of cervical (À23%, **P < 0.01 in AH; À35%, **P < 0.01 in DH) and lumbar spinal cord (À28%, **P < 0.01 in AH; À33%, **P < 0.01 in DH) (Table 3; Figures 2S, 2W, 2AA, 3T, 3W, and 3Z). There was no significant change in GM of thoracic cord and WM of all levels of spinal cord. ...
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... mice initially showed a significant increase of LSGU at 12 W in GM of cervical and lumbar cords (Table 3; Figures 2Q-AB and Figures 3J-3R). How- ever, LSGU now turned a progressive decrease from 16 to 19 W ( Figures 3J-3R, black bars). ...
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... diameter, density, and RBC velocity are important parameters of SBF. Our in vivo optical study strongly suggests that such an SBF reduction (Table 2; Figures 2E-2P) was closely related to the decrease of capillary diameter, density, and RBC velocity (Figure 1), and the early SBF reduction from the presymptomatic stage at 12 W might provide chronic and progressive ischemic stress to the affected spinal cord as implicated by early increase of Hif-1a and vascular endothelial growth factor ( Murakami et al, 2003;Xu et al, 2011). ...
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Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is an adult onset neurodegenerative disorder characterised by the degeneration of cortical and spinal cord motor neurons, resulting in progressive muscular weakness and death. Increasing evidence supports mitochondrial dysfunction and oxidative DNA damage in ALS motor ne...
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... Reduced GLUT1 expression in spinal cord astrocytes indicates decreased glucose uptake, while diminished glucose transport is observed in motor cortex synaptosomes during the early symptomatic and end stages of ALS. These findings suggest limitations in glucose transport and altered metabolism in ALS progression [87][88][89][90][91][92]. ...
... Reduced GLUT1 expression in spinal cord astrocytes indicates decreased glucose uptake, while diminished glucose transport is observed in motor cortex synaptosomes during ALS's early symptomatic and end stages. These findings suggest limitations in glucose transport and altered metabolism in ALS progression [87][88][89][90][91][92]. ...
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressive loss of motor neurons. Emerging evidence suggests a potential link between metabolic dysregulation and ALS pathogenesis. This study aimed to investigate the relationship between metabolic hormones and disease progression in ALS patients. A cross-sectional study was conducted involving 44 ALS patients recruited from a tertiary care center. Serum levels of insulin, total amylin, C-peptide, active ghrelin, GIP (gastric inhibitory peptide), GLP-1 active (glucagon-like peptide-1), glucagon, PYY (peptide YY), PP (pancreatic polypeptide), leptin, interleukin-6, MCP-1 (monocyte chemoattractant protein-1), and TNFα (tumor necrosis factor alpha) were measured, and correlations with ALSFRS-R, evolution scores, and biomarkers were analyzed using Spearman correlation coefficients. Subgroup analyses based on ALS subtypes, progression pattern of disease, and disease progression rate patterns were performed. Significant correlations were observed between metabolic hormones and ALS evolution scores. Insulin and amylin exhibited strong correlations with disease progression and clinical functional outcomes, with insulin showing particularly robust associations. Other hormones such as C-peptide, leptin, and GLP-1 also showed correlations with ALS progression and functional status. Subgroup analyses revealed differences in hormone levels based on sex and disease evolution patterns, with male patients showing higher amylin and glucagon levels. ALS patients with slower disease progression exhibited elevated levels of amylin and insulin. Our findings suggest a potential role for metabolic hormones in modulating ALS progression and functional outcomes. Further research is needed to elucidate the underlying mechanisms and explore the therapeutic implications of targeting metabolic pathways in ALS management.
... In rodent and fly models of ALS, reduced metabolic flexibility or metabolic reprogramming, which is defined by alterations in glucose or fatty acid uptake and/or oxidation in the CNS [148][149][150][151][152][153] and skeletal muscle 65,136,137,154,155 , has been increasingly reported. In addition, defects in mitochondrial respiration and function 115,[156][157][158][159][160] have been observed. ...
Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease that is classically thought to impact the motor system. Over the past 20 years, research has started to consider the contribution of non-motor symptoms and features of the disease, and how they might affect ALS prognosis. Of the non-motor features of the disease, nutritional status (for example, malnutrition) and metabolic balance (for example, weight loss and hypermetabolism) have been consistently shown to contribute to more rapid disease progression and/or earlier death. Several complex cellular changes observed in ALS, including mitochondrial dysfunction, are also starting to be shown to contribute to bioenergetic failure. The resulting energy depletion in high energy demanding neurons makes them sensitive to apoptosis. Given that nutritional and metabolic stressors at the whole-body and cellular level can impact the capacity to maintain optimal function, these factors present avenues through which we can identify novel targets for treatment in ALS. Several clinical trials are now underway evaluating the effectiveness of modifying energy balance in ALS, making this article timely in reviewing the evidence base for metabolic and nutritional interventions.
... A recent study reported that glycolytic muscles in SOD1 G93A mice and myotubes from ALS patients show increased dependence on fatty acid oxidation [31]. In addition, a study using a SOD1 G86R mouse model performed gene expression profiling and demonstrated a fuel preference switch from glycolysis to fatty acid oxidation in the fast-twitch tibialis anterior muscle [69]. This study also showed that promoting glycolytic capacity by administering dichloroacetate improved muscle strength [69]. ...
... In addition, a study using a SOD1 G86R mouse model performed gene expression profiling and demonstrated a fuel preference switch from glycolysis to fatty acid oxidation in the fast-twitch tibialis anterior muscle [69]. This study also showed that promoting glycolytic capacity by administering dichloroacetate improved muscle strength [69]. These findings are consistent with another study that used Ranolazine, an inhibitor of fatty acid oxidation used to promote glycolysis, which improved muscle strength and ATP content in the muscle [49]. ...
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects motor neurons, leading to muscle weakness, paralysis, and eventual death. Research from the past few decades has appreciated that ALS is not only a disease of the motor neurons but also a disease that involves systemic metabolic dysfunction. This review will examine the foundational research of understanding metabolic dysfunction in ALS and provide an overview of past and current studies in ALS patients and animal models, spanning from full systems to various metabolic organs. While ALS-affected muscle tissue exhibits elevated energy demand and a fuel preference switch from glycolysis to fatty acid oxidation, adipose tissue in ALS undergoes increased lipolysis. Dysfunctions in the liver and pancreas contribute to impaired glucose homeostasis and insulin secretion. The central nervous system (CNS) displays abnormal glucose regulation, mitochondrial dysfunction, and increased oxidative stress. Importantly, the hypothalamus, a brain region that controls whole-body metabolism, undergoes atrophy associated with pathological aggregates of TDP-43. This review will also cover past and present treatment options that target metabolic dysfunction in ALS and provide insights into the future of metabolism research in ALS.
... A previous arterial spin labeled MR study demonstrated hypoperfusion in ALS patients compared to healthy subjects in the frontal, medial, middle cingulate cortices, and precuneus (Rule et al., 2010). In correspondence with clinical findings, spinal blood flow was progressively decreased at preand post-symptomatic stages in SOD1 G93A mice, as detected by in vivo capillary imaging (Miyazaki et al., 2012). In this study, no significant age or group-related differences in basal CBF were observed in cerebral motor regions. ...
Currently TAR DNA binding protein 43 (TDP-43) pathology, underlying Amyotrophic Lateral Sclerosis (ALS), remains poorly understood which hinders both clinical diagnosis and drug discovery efforts. To better comprehend the disease pathophysiology, positron emission tomography (PET) and multi-parametric magnetic resonance imaging (mp-MRI) provide a non-invasive mode to investigate molecular, structural, and neurochemical abnormalities in vivo. For the first time, we report the findings of a longitudinal PET-MR study in the TDP-43 A315T ALS mouse model, investigating disease-related changes in the mouse brain. 2-deoxy-2-[ 18 F]fluoro-D-glucose [ 18 F]FDG PET showed significantly lowered glucose metabolism in the motor and somatosensory cor-tices of TDP-43 A315T mice whereas metabolism was elevated in the region covering the bilateral substantia nigra, reticular and amygdaloid nucleus between 3 and 7 months of age, as compared to non-transgenic controls. MR spectroscopy data showed significant changes in glutamate + glutamine (Glx) and choline levels in the motor cortex and hindbrain of TDP-43 A315T mice compared to controls. Cerebral blood flow (CBF) measurements, using an arterial spin labelling approach, showed no significant age-or group-dependent changes in brain perfusion. Diffusion MRI indices demonstrated transient changes in different motor areas of the brain in TDP-43 A315T mice around 14 months of age. Cytoplasmic TDP-43 proteinaceous inclusions were observed in the brains of symptomatic , 18-month-old mice, but not in non-symptomatic transgenic or wild-type mice. Our results reveal that disease-and age-related functional and neurochemical alterations, together with limited structural changes, occur in specific brain regions of transgenic TDP-43 A315T mice, as compared to their healthy counterparts. Altogether these findings shed new light on TDP-43 A315T disease pathogenesis and may prove useful for clinical management of ALS.
... 432,433 The dysregulation of EPO and VEGF accompanied by vascular changes, and blood flow disorder contributes to the pathogenesis of ALS, resulting in the hypoxia of the tissue. 434,435 Hypoxia in tissues increases ROS production, leading to cell death. 436 Thus, the uncontrolled hypoxia pathway is responsible for motor neuron death in ALS. ...
Molecular oxygen (O2) is essential for most biological reactions in mammalian cells. When the intracellular oxygen content decreases, it is called hypoxia. The process of hypoxia is linked to several biological processes, including pathogenic microbe infection, metabolic adaptation, cancer, acute and chronic diseases, and other stress responses. The mechanism underlying cells respond to oxygen changes to mediate subsequent signal response is the central question during hypoxia. Hypoxia-inducible factors (HIFs) sense hypoxia to regulate the expressions of a series of downstream genes expression, which participate in multiple processes including cell metabolism, cell growth/death, cell proliferation, glycolysis, immune response, microbe infection, tumorigenesis, and metastasis. Importantly, hypoxia signaling also interacts with other cellular pathways, such as phosphoinositide 3-kinase (PI3K)- mammalian target of rapamycin (mTOR) signaling, nuclear factor kappa-B (NF-κB) pathway, extracellular signal-regulated kinases (ERK) signaling, and endoplasmic reticulum (ER) stress. This paper systematically reviews the mechanisms of hypoxia signaling activation, the control of HIF signaling, and the function of HIF signaling in human health and diseases. In addition, the therapeutic targets involved in HIF signaling to balance health and diseases are summarized and highlighted, which would provide novel strategies for the design and development of therapeutic drugs.
... Remarkably, discriminant analyses of these datasets could distinguish ALS patients from controls with up to 95% accuracy, suggesting that the pattern of cerebral glucose utilization could serve as a diagnostic or prognostic marker for ALS. Unsurprisingly, the SOD1 G93A mouse model also exhibits a progressive decline of glucose metabolism during disease progression [99]. Furthermore, carriers of the ALS/FTD-linked C9orf72 repeat expansion mutation exhibit cortical glucose hypometabolism up to 10 years prior to symptom onset, suggesting that decreases in glucose uptake may be an early and critical disease modifier event, particularly in the case of the C9orf72 [5,100]. ...
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that primarily affects motor neurons and causes muscle atrophy, paralysis, and death. While a great deal of progress has been made in deciphering the underlying pathogenic mechanisms, no effective treatments for the disease are currently available. This is mainly due to the high degree of complexity and heterogeneity that characterizes the disease. Over the last few decades of research, alterations to bioenergetic and metabolic homeostasis have emerged as a common denominator across many different forms of ALS. These alterations are found at the cellular level (e.g., mitochondrial dysfunction and impaired expression of monocarboxylate transporters) and at the systemic level (e.g., low BMI and hypermetabolism) and tend to be associated with survival or disease outcomes in patients. Furthermore, an increasing amount of preclinical evidence and some promising clinical evidence suggests that targeting energy metabolism could be an effective therapeutic strategy. This review examines the evidence both for and against these ALS-associated metabolic alterations and highlights potential avenues for therapeutic intervention.
... In the spinal cord, in-vivo capillary imaging measuring spinal blood flow (SBF) and glucose metabolism showed early and progressive reduction in glucose usage [162]. However, spinal cord mitochondrial defects were only detectable at the symptomatic stage [87]. ...
Amyotrophic lateral sclerosis (ALS) patients show a myriad of energetic abnormalities, such as weight loss, hypermetabolism, and dyslipidaemia. Evidence suggests that these indices correlate with and ultimately affect the duration of survival. This review aims to discuss ALS metabolic abnormalities in the context of autophagy, the primordial system acting at the cellular level for energy production during nutrient deficiency. As the primary pathway of protein degradation in eukaryotic cells, the fundamental role of cellular autophagy is the adaptation to metabolic demands. Therefore, autophagy is tightly coupled to cellular metabolism. We review evidence that the delicate balance between autophagy and metabolism is aberrant in ALS, giving rise to intracellular and systemic pathophysiology observations. Understanding the metabolism autophagy crosstalk can lead to the identification of novel therapeutic targets for ALS.
... Defective glucose metabolism has also been shown in the cortex and spinal cord of SOD1 mouse models of ALS [26,96]. Reduced glucose utilization before the onset of symptoms (60 days of age) was observed in motor regions of the cerebral cortex of mutant SOD1 G93A mice and this hypometabolism extended to the spinal cord at 120 days of age [26]. ...
... Reduced glucose utilization before the onset of symptoms (60 days of age) was observed in motor regions of the cerebral cortex of mutant SOD1 G93A mice and this hypometabolism extended to the spinal cord at 120 days of age [26]. In the spinal cord, glucose metabolism appeared to be reduced at early symptomatic and end stages of the disease in SOD1 G93A mice, but was increased before disease onset [96]. Recently, Weerasekera et al. used simultaneous 18 F-FDG PETmagnetic resonance imaging and showed that glucose metabolism is decreased in the motor and somatosensory cortices of TDP-43 A315T mice while it was increased in midbrain region between 3 and 7 months of age, as compared to WT controls [97]. ...
... Possible mechanisms for these changes may include reduced cerebral blood flow, and/or defects in glucose transport mechanisms or hexokinase activities. Reductions in cerebral blood flow that may affect provision of energy substrates to the brain have been shown in some CNS regions in animal models and patients with ALS [96,98,99]. Moreover, reduced expression of GLUT1 in the endothelial cells of lumbar and cervical spinal cord in SOD1 G93A mice indicate that glucose uptake could be decreased as lowered GLUT1 expression may limit glucose transport [100]. ...
Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disorder primarily characterized by selective degeneration of both the upper motor neurons in the brain and lower motor neurons in the brain stem and the spinal cord. The exact mechanism for the selective death of neurons is unknown. A growing body of evidence demonstrates abnormalities in energy metabolism at the cellular and whole-body level in animal models and in people living with ALS. Many patients with ALS exhibit metabolic changes such as hypermetabolism and body weight loss. Despite these whole-body metabolic changes being observed in patients with ALS, the origin of metabolic dysregulation remains to be fully elucidated. A number of pre-clinical studies indicate that underlying bioenergetic impairments at the cellular level may contribute to metabolic dysfunctions in ALS. In particular, defects in CNS glucose transport and metabolism appear to lead to reduced mitochondrial energy generation and increased oxidative stress, which seem to contribute to disease progression in ALS. Here, we review the current knowledge and understanding regarding dysfunctions in CNS glucose metabolism in ALS focusing on metabolic impairments in glucose transport, glycolysis, pentose phosphate pathway, TCA cycle and oxidative phosphorylation. We also summarize disturbances found in glycogen metabolism and neuroglial metabolic interactions. Finally, we discuss options for future investigations into how metabolic impairments can be modified to slow disease progression in ALS. These investigations are imperative for understanding the underlying causes of metabolic dysfunction and subsequent neurodegeneration, and to also reveal new therapeutic strategies in ALS.
... The LDH activity after dropping at the first onset of the disease increases its activity at the terminal stage of ALS. A similar observation was previously described by Miyazaki et al. [38], who showed that in the spinal cord of SOD1-G93A mice, glucose metabolism appeared to be reduced at early symptomatic and end stages of the disease but was increased before disease onset. Recently, another study used simultaneous [ 18 F]-FDG PET magnetic resonance imaging and showed that glucose metabolism is decreased in the motor and somatosensory cortices of TDP-43 (A315T) mice, while at the same time, it was increased in the midbrain region between at pre-symptomatic age, as compared to WT controls [39]. ...
(1) Background: Amyotrophic lateral sclerosis (ALS) is an incurable, neurodegenerative disease. In some cases, ALS causes behavioral disturbances and cognitive dysfunction. Swimming has revealed a neuroprotective influence on the motor neurons in ALS. (2) Methods: In the present study, a SOD1-G93A mice model of ALS were used, with wild-type B6SJL mice as controls. ALS mice were analyzed before ALS onset (10th week of life), at ALS 1 onset (first symptoms of the disease, ALS 1 onset, and ALS 1 onset SWIM), and at terminal ALS (last stage of the disease, ALS TER, and ALS TER SWIM), and compared with wild-type mice. Swim training was applied 5 times per week for 30 min. All mice underwent behavioral tests. The spinal cord was analyzed for the enzyme activities and oxidative stress markers. (3) Results: Pre-symptomatic ALS mice showed increased locomotor activity versus control mice; the swim training reduced these symptoms. The metabolic changes in the spinal cord were present at the pre-symptomatic stage of the disease with a shift towards glycolytic processes at the terminal stage of ALS. Swim training caused an adaptation, resulting in higher glutathione peroxidase (GPx) and protection against oxidative stress. (4) Conclusion: Therapeutic aquatic activity might slow down the progression of ALS.
... ALS causes muscle weakness and atrophy, which affects all of the muscles, ultimately resulting in death due to respiratory failure (Lechtzin et al., 2018). ALS pathogenesis is characterized by pronounced vascular changes and blood flow disturbances, accompanied by decreased expressions of EPO and VEGF (Miyazaki et al., 2011;Pronto-Laborinho et al., 2014), which result in tissue hypoxia. Decreased oxygen levels in tissues lead to excessive ROS production and cell death (Tafani et al., 2016). ...
Hypoxia is one of the most common pathological conditions, which can be induced by multiple events, including ischemic injury, trauma, inflammation, tumors, etc. The body’s adaptation to hypoxia is a highly important phenomenon in both health and disease. Most cellular responses to hypoxia are associated with a family of transcription factors called hypoxia-inducible factors (HIFs), which induce the expression of a wide range of genes that help cells adapt to a hypoxic environment. Basic mechanisms of adaptation to hypoxia, and particularly HIF functions, have being extensively studied over recent decades, leading to the 2019 Nobel Prize in Physiology or Medicine. Based on their pivotal physiological importance, HIFs are attracting increasing attention as a new potential target for treating a large number of hypoxia-associated diseases. Most of the experimental work related to HIFs has focused on roles in the liver and kidney. However, increasing evidence clearly demonstrates that HIF-based responses represent an universal adaptation mechanism in all tissue types, including the central nervous system (CNS). In the CNS, HIFs are critically involved in the regulation of neurogenesis, nerve cell differentiation, and neuronal apoptosis. In this mini-review, we provide an overview of the complex role of HIF-1 in the adaptation of neurons and glia cells to hypoxia, with a focus on its potential involvement into various neuronal pathologies and on its possible role as a novel therapeutic target.
