Metabolic Profile and Pathological Alterations in the Muscle of Patients with Early-Stage Amyotrophic Lateral Sclerosis

Lanznaster, Débora; Bruno, Clément; Bourgeais, Jérôme; Emond, Patrick; Zemmoura, Ilyess; Lefèvre, Antoine; Reynier, Pascal; Eymieux, Sébastien; Blanchard, Emmanuelle; Vourc’h, Patrick; Andrés, Christian; Bakkouche, Salah Eddine; Hérault, Olivier; Favard, Luc; Corcia, Philippe; Blasco, Hélène

doi:10.3390/biomedicines10061307

Cited by 10 publications

(6 citation statements)

References 124 publications

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“…Specifically, dysregulated metabolites were linked to carbohydrate metabolism and amino acid pathways, previously associated with ALS [52]. Interestingly, mitochondrial dysfunctions are associated with metabolism deregulation in the muscles of ALS patients [51 ▪ ]. Because of the small cohort size, this study reinforces the need for more investigations into muscles of ALS patients at early stages.…”

Section: Early Involvement Of Metabolic Abnormalities In Amyotrophic ...supporting

confidence: 52%

“…Mutant SOD1 mouse models demonstrated early metabolic reprogramming in glycolytic muscles associated with mitochondrial dysfunctions [49,50]. In ALS patients, only one recent study explored muscle-specific metabolic defects [51 ▪ ]. At the time of diagnosis, Lanznaster and collaborators observed alterations in the metabolome of skeletal muscles of ALS patients.…”

Section: Early Involvement Of Metabolic Abnormalities In Amyotrophic ...mentioning

confidence: 99%

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Abnormal energy metabolism in ALS: a key player?

Burg

Bosch

2023

Current Opinion in Neurology

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Purpose of the review Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease of the motor system due to the selective and progressive degeneration of both upper and lower motor neurons. Disturbances in energy homeostasis were repeatedly associated with the ALS pathogenesis and appear early during the disease process. In this review, we highlight recent work demonstrating the crucial role of energy metabolism in ALS and discuss its potential clinical relevance. Recent findings The alteration of various metabolic pathways contributes to the heterogeneity of the clinical phenotype of ALS. Recent work showed that different ALS mutations selectively impact these pathways and translate to the disease phenotypes in patients and disease models. Strikingly, a growing number of studies point towards an early, even presymptomatic, contribution of abnormal energy homeostasis to the ALS pathogenesis. Advances in metabolomics generated valuable tools to study altered metabolic pathways, to test their therapeutic potential, and to develop personalized medicine. Importantly, recent preclinical studies and clinical trials demonstrated that targeting energy metabolism is a promising therapeutic approach. Summary Abnormal energy metabolism is a key player in ALS pathogenesis, emerging as a source of potential disease biomarkers and therapeutic targets.

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Section: Early Involvement Of Metabolic Abnormalities In Amyotrophic ...supporting

confidence: 52%

Section: Early Involvement Of Metabolic Abnormalities In Amyotrophic ...mentioning

confidence: 99%

Abnormal energy metabolism in ALS: a key player?

Burg

Bosch

2023

Current Opinion in Neurology

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“…Patients with SOD1and C90RF72-induced ALS show abnormal glucose metabolism and hypometabolism or hypermetabolism in different brain regions depending on pathological involvement [50]. Some researchers have reported alterations in the muscle metabolome, particularly abnormal metabolites related to carbohydrate metabolism and the amino acid pathway in patients with ALS [51,52]. This study demonstrated that mitochondria impairment is involved in muscle glycolysis, leading to ATP reduction.…”

Section: Discussionmentioning

confidence: 56%

Protective Effects of a Combined Herbal Medicine against Amyotrophic Lateral Sclerosis-Associated Inflammation and Oxidative Stress

Yang

2024

Applied Sciences

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Despite extensive studies to identify effective curative drugs for amyotrophic lateral sclerosis (ALS), only riluzole and edaravone have been approved by the Food and Drug Administration. However, these drugs only delay disease progression and exhibit adverse effects, necessitating the development of more effective drugs. Herbal medicines are effective against incurable diseases with various pathogenic factors owing to their low toxicity and presence of multiple components, which target multiple organs. Therefore, we aimed to investigate whether a combined herbal medicine (CHM), comprising Gastrodia elata, Cnidium officinale Makino, and Ostericum koreanum, affects muscle function and motor neuron death in an animal model of ALS. We treated 8-week-old hSOD1G93A mice with 1 mg/g CHM, administered orally once daily for 6 weeks. Muscle function was measured via a footprint test. Biochemical analyses, including immunoblotting, western blotting, and immunohistochemistry, of the muscles (tibialis anterior and gastrocnemius) and spinal cord of hSOD1G93A mice were performed. The CHM treatment improved movement and reduced motor neuron loss in the mouse spinal cord. It also enhanced anti-inflammatory and anti-oxidant activities and regulated autophagy in the mouse muscles and spinal cord. These findings suggest that CHM has multi-active components that effectively target muscles and the spinal cord, delaying disease progression.

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“…RD2RD2 seems to bring a benefit in instantaneous muscle strength rather than in unremitting muscle endurance pointing to a hindered effect of RD2RD2 under anaerobic muscle conditions. This might also exclude an effect of RD2RD2 on the mitochondria and their oxidative metabolism which are known to be implicated in ALS [ 30 ].…”

Section: Discussionmentioning

confidence: 99%

Oral Treatment with d-RD2RD2 Impedes Early Disease Mechanisms in SOD1*G93A Transgenic Mice but Does Not Prolong Survival

et al. 2023

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting upper and lower motor neurons, thus, progressing to complete muscle loss until the patient dies from respiratory arrest. The disease is not curable, and patients die approximately 2–5 years after diagnosis. Studying the underlying disease mechanisms to get access to new treatment options is, therefore, essential for patients’ benefit. However, so far, only three drugs that alleviate the symptoms have been approved by the U.S. Food and Drug Administration (FDA). A new drug candidate for the treatment of ALS is the all-d-enantiomeric peptide RD2RD2. In this study, we investigated the therapeutic effect of RD2RD2 in two setups. First, we analyzed disease progression and survival in 7 week-old B6.Cg-Tg(SOD1*G93A)1Gur/J mice. Second, we confirmed the result of the survival analysis in the B6SJL-Tg(SOD1*G93A)1Gur/J mouse line. Shortly before disease onset, the mice were treated daily with an oral dose of 50 mg/kg body weight. Treatment with RD2RD2 led to a delayed disease onset and reduced motor phenotype as shown using the SHIRPA test, the splay reflex test, and the pole test, but did not affect survival. In conclusion, RD2RD2 has the ability to delay the onset of symptoms.

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Metabolic Profile and Pathological Alterations in the Muscle of Patients with Early-Stage Amyotrophic Lateral Sclerosis

Cited by 10 publications

References 124 publications

Abnormal energy metabolism in ALS: a key player?

Abnormal energy metabolism in ALS: a key player?

Protective Effects of a Combined Herbal Medicine against Amyotrophic Lateral Sclerosis-Associated Inflammation and Oxidative Stress

Oral Treatment with d-RD2RD2 Impedes Early Disease Mechanisms in SOD1*G93A Transgenic Mice but Does Not Prolong Survival

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