Evidence of Metabolic Dysfunction in Amyotrophic Lateral Sclerosis (ALS) Patients and Animal Models

Abstract

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.

Exploring the Role of Metabolic Hormones in Amyotrophic Lateral Sclerosis

“…Increasing evidence indicates that decreased brain metabolism, impaired metabolic hormone signaling, and resistance are associated with the progression of neurodegenerative disorders, including ALS [16]. Disruptions in glucose metabolism and insulin signaling pathways are significant factors in ALS pathogenesis.…”

A Comprehensive Review on the Role of Obesity in Functional Cognition (Part II): Cognition Impairment and Underlying Mechanisms, and Development of Neurodegenerative Diseases

“…Although the specific mechanisms responsible for the development and advancement of ALS are not yet fully understood, there exists evidence indicating a potential involvement of metabolic changes linked to obesity in the beginning and course of the disease. Dysregulated lipid metabolism, mitochondrial dysfunction, and systemic inflammation, which are frequently identified in individuals with obesity, may potentially contribute to the degeneration of motor neurons in ALS (37). Moreover, certain genetic variants, like as the C9orf72 mutation, that are correlated with ALS have been found to be connected with changes in metabolism and obesity (38).…”

Predictors of Protein-Energy Malnutrition in Patients with Amyotrophic Lateral Sclerosis

“…Рядом исследователей показано, что при БАС преимущественно поражаются быстрые мышечные волокна, которые используют гликолиз в качестве основного источника энергии, тогда как устойчивые к БАС медленно сокращающиеся мышечные волокна генерируют всю необходимую им АТФ за счет окислительных митохондриальных процессов [9,10]. Вполне вероятно, что метаболическая дисфункция способствует нейродегенерации наряду с другими патологическими механизмами, такими как агрегация белков, эксайтотоксичность нейронов и нейровоспаление [11].…”