Abstract
Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease leading to motor neuron cell death, but recent studies suggest that non-neuronal cells may contribute to the pathological mechanisms involved. Myostatin is a negative regulator of muscle growth whose function can be inhibited using neutralizing antibodies. In this study, we used transgenic mouse and rat models of ALS to test whether treatment with anti-myostatin antibody slows muscle atrophy, motor neuron loss, or disease onset and progression. Significant increases in muscle mass and strength were observed in myostatin-antibody-treated SOD1(G93A) mice and rats prior to disease onset and during early-stage disease. By late stage disease, only diaphragm muscle remained significantly different in treated animals in comparison to untreated controls. Myostatin inhibition did not delay disease onset nor extend survival in either the SOD1(G93A) mouse or rat. Together, these results indicate that inhibition of myostatin does not protect against the onset and progression of motor neuron degenerative disease. However, the preservation of skeletal muscle during early-stage disease and improved diaphragm morphology and function maintained through late stage disease suggest that anti-myostatin therapy may promote some improved muscle function in ALS.
MeSH terms
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Age of Onset
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Amyotrophic Lateral Sclerosis / immunology
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Amyotrophic Lateral Sclerosis / physiopathology
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Amyotrophic Lateral Sclerosis / therapy*
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Animals
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Animals, Genetically Modified
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Antibodies / immunology
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Antibodies / pharmacology*
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Antibodies / therapeutic use
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Cell Death / drug effects
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Cell Death / physiology
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Diaphragm / immunology
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Diaphragm / innervation
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Diaphragm / physiopathology
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Disease Models, Animal
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Female
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Growth Inhibitors / antagonists & inhibitors*
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Growth Inhibitors / immunology
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Growth Inhibitors / metabolism
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Humans
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Male
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Mice
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Mice, Knockout
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Motor Neurons / immunology
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Motor Neurons / pathology
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Muscle Weakness / immunology
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Muscle Weakness / physiopathology
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Muscle Weakness / therapy
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Muscle, Skeletal / immunology
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Muscle, Skeletal / innervation
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Muscle, Skeletal / physiopathology*
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Muscular Atrophy / immunology
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Muscular Atrophy / physiopathology
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Muscular Atrophy / therapy*
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Myostatin
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Organ Size / drug effects
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Organ Size / immunology
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Rats
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Recovery of Function / drug effects
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Recovery of Function / immunology
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Superoxide Dismutase / genetics
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Superoxide Dismutase / metabolism
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Superoxide Dismutase-1
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Survival Rate
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Transforming Growth Factor beta / antagonists & inhibitors*
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Transforming Growth Factor beta / immunology
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Transforming Growth Factor beta / metabolism
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Treatment Outcome
Substances
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Antibodies
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Growth Inhibitors
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MSTN protein, human
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Mstn protein, mouse
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Mstn protein, rat
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Myostatin
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SOD1 protein, human
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Transforming Growth Factor beta
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Sod1 protein, mouse
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Sod1 protein, rat
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Superoxide Dismutase
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Superoxide Dismutase-1