glycogen and Amyotrophic-Lateral-Sclerosis

Aging is a major risk factor for neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). As metabolic alterations are a hallmark of aging and have previously been observed in ALS, it is important to examine the effect of aging in the context of ALS metabolic function. Here, using a newly established phenotypic metabolic approach, we examined the effect of aging on the metabolic profile of fibroblasts derived from ALS cases compared to controls. We found that ALS fibroblasts have an altered metabolic profile, which is influenced by age. In control cases, we found significant increases with age in NADH metabolism in the presence of several metabolites including lactic acid, trehalose, uridine and fructose, which was not recapitulated in ALS cases. Conversely, we found a reduction of NADH metabolism with age of biopsy, age of onset and age of death in the presence of glycogen in the ALS cohort. Furthermore, we found that NADH production correlated with disease progression rates in relation to a number of metabolites including inosine and α-ketoglutaric acid. Inosine or α-ketoglutaric acid supplementation in ALS fibroblasts was bioenergetically favourable. Overall, we found aging related defects in energy substrates that feed carbon into glycolysis at various points as well as the tricarboxylic acid (TCA) cycle in ALS fibroblasts, which was validated in induced neuronal progenitor cell derived iAstrocytes. Our results suggest that supplementing those pathways may protect against age related metabolic dysfunction in ALS.

Topics: Adult; Aged; Aging; Amyotrophic Lateral Sclerosis; Citric Acid Cycle; Disease Progression; Energy Metabolism; Female; Fibroblasts; Glycogen; Glycolysis; Humans; Inosine; Ketoglutaric Acids; Male; Middle Aged; NAD

Metabolic dysfunction is an important modulator of disease course in amyotrophic lateral sclerosis (ALS). We report here that a familial mouse model (transgenic mice over-expressing the G93A mutation of the Cu/Zn superoxide dismutase 1 gene) of ALS enters a progressive state of acidosis that is associated with several metabolic (hormonal) alternations that favor lipolysis. Extensive investigation of the major determinants of H(+) concentration (i.e., the strong ion difference and the strong ion gap) suggests that acidosis is also due in part to the presence of an unknown anion. Consistent with a compensatory response to avert pathological acidosis, ALS mice harbor increased accumulation of glycogen in CNS and visceral tissues. The altered glycogen is associated with fluctuations in lysosomal and neutral α-glucosidase activities. Disease-related changes in glycogen, glucose, and α-glucosidase activity are also found in spinal cord tissue samples of autopsied patients with ALS. Collectively, these data provide insights into the pathogenesis of ALS as well as potential targets for drug development.

Topics: Acidosis; Amyotrophic Lateral Sclerosis; Animals; Disease Models, Animal; Disease Progression; Glycogen; Humans; Mice; Mice, Transgenic; Mutation; Superoxide Dismutase

Polyglucosan body disease (PBD) is a slowly progressive adult-onset glycogen storage disorder that typically affects upper and lower neurons. Myopathy, as a complication of PBD has been reported rarely and clinically manifests as chronic limb-girdle muscle weakness. We report an unusual case of PBD myopathy presenting as an asymmetric motor syndrome that clinically overlapped with amyotrophic lateral sclerosis, further expanding the phenotype of this disorder.

Topics: Amyotrophic Lateral Sclerosis; Diagnosis, Differential; Female; Glucans; Glycogen; Glycogen Storage Disease; Humans; Microscopy, Electron, Transmission; Middle Aged; Muscle Fibers, Skeletal; Muscle Weakness; Muscle, Skeletal; Muscular Diseases; Reflex, Abnormal

The present study was undertaken to identify the metabolic and contractile characteristics of fast- and slow-twitch skeletal muscles in a transgenic mouse model of amyotrophic lateral sclerosis (ALS). In addition, we investigated the effects of oral creatine supplementation on muscle functional capacity in this model. Transgenic mice expressing a mutant (G93A) or wild type human SOD1 gene (WT) were supplemented with 2% creatine monohydrate from 60 to 120 days of age. Body weight, rotorod performance and grip strength were evaluated. In vitro contractility was evaluated on isolated m. soleus and m. extensor digitorum longus (EDL), and muscle metabolites were determined. Body weight, rotorod performance and grip strength were markedly decreased in G93A compared to WT mice, but were unaffected by creatine supplementation. Muscle ATP content decreased and glycogen content increased in G93A versus WT in both muscle types, but were unaffected by creatine supplementation. Muscle creatine content increased following creatine intake in G93A soleus. Twitch and tetanic contractions showed markedly slower contraction and relaxation times in G93A versus WT in both muscle types, with no positive effect of creatine supplementation. EDL but not soleus of G93A mice showed significant atrophy, which was partly abolished by creatine supplementation. It is concluded that overexpression of a mutant SOD1 transgene has profound effects on metabolic and contractile properties of both fast- and slow-twitch skeletal muscles. Furthermore, creatine intake does not exert a beneficial effect on muscle function in a transgenic mouse model of ALS.

Topics: Adenosine Triphosphate; Amyotrophic Lateral Sclerosis; Animals; Body Weight; Creatine; Glycogen; Humans; Mice; Mice, Transgenic; Models, Animal; Motor Activity; Muscle Contraction; Muscle Fibers, Fast-Twitch; Muscle Fibers, Slow-Twitch; Muscle, Skeletal; Muscular Atrophy; Mutation; Superoxide Dismutase; Superoxide Dismutase-1

Topics: Adolescent; Amyotrophic Lateral Sclerosis; Animals; Biopsy; Cats; Dermatomyositis; Esterases; Female; Glucosyltransferases; Glycogen; Guinea Pigs; Histocytochemistry; Humans; Male; Muscular Atrophy; Muscular Diseases; Muscular Dystrophies; Myofibrils; Nervous System Diseases; Oxidoreductases; Paralysis; Rabbits; Schwann Cells; Staining and Labeling; Transferases; Tyrosine

Topics: Amyotrophic Lateral Sclerosis; Glycogen; Humans; Microscopy, Electron; Mitochondria, Muscle; Muscles; Myofibrils; Myotonic Dystrophy; Nerve Degeneration; Spinal Cord Diseases