Statins accelerate disease progression and shorten survival in SOD1(G93A) mice

HMG-CoA reductase inhibitors (statins) and H63D HFE polymorphism may modify amyotrophic lateral sclerosis (ALS). We hypothesized that statins worsen phenotype in ALS mice, dependent on HFE genotype. Mice harboring SOD1(G93A) heterozygous for H67D Hfe (homologous to human H63D HFE) were administered...

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Bibliographic Details
Published in:Muscle & nerve 2016-08, Vol.54 (2), p.284-291
Main Authors: Su, Xiaowei W, Nandar, Wint, Neely, Elizabeth B, Simmons, Zachary, Connor, James R
Format: Article
Language:English
Subjects:
Amyotrophic Lateral Sclerosis - chemically induced
Amyotrophic Lateral Sclerosis - genetics
Amyotrophic Lateral Sclerosis - mortality
Animals
Disease Models, Animal
Disease Progression
Extremities - physiopathology
Ferritins - metabolism
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors - adverse effects
Male
Mice
Mice, Transgenic
Mitochondria - metabolism
Motor Activity - drug effects
Motor Activity - genetics
Muscle Strength - drug effects
Muscle Strength - genetics
Muscle, Skeletal - pathology
Muscle, Skeletal - ultrastructure
ROC Curve
Spinal Cord - ultrastructure
Superoxide Dismutase - genetics
Ubiquinone - analogs & derivatives
Ubiquinone - pharmacology
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Summary:HMG-CoA reductase inhibitors (statins) and H63D HFE polymorphism may modify amyotrophic lateral sclerosis (ALS). We hypothesized that statins worsen phenotype in ALS mice, dependent on HFE genotype. Mice harboring SOD1(G93A) heterozygous for H67D Hfe (homologous to human H63D HFE) were administered simvastatin and/or coenzyme Q10, and were allowed to reach end stage. Disease progression was measured by grip strength. A separate group of animals was administered simvastatin and euthanized at the symptomatic 120-day time-point. Mitochondria from gastrocnemius muscle and lumbar spine were analyzed. Simvastatin and H67D Hfe accelerated disease progression. Simvastatin decreased survival. Coenzyme Q10 did not rescue statin-induced effects. Statins did not alter mitochondrial protein levels. Statins and Hfe genotype alter disease course in the ALS mouse model. Because the H63D HFE polymorphism is present in 30% of patients with ALS, studying disease progression in patients who receive statins, stratified for HFE genotype, may guide therapy. Muscle Nerve, 2016 Muscle Nerve 54: 284-291, 2016.
ISSN:1097-4598
DOI:10.1002/mus.25048