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Discovery of myostatin and its relationship to muscle mass in "Mighty Mice"
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Investigated the myostatin signaling pathway and its regulation
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Found that systematic over expression of myostatin in adult mice induced muscle and fat loss (like in human cachexia syndromes). Concluded that myostatin acts systematically in adult animals and may be useful when looking at cachexia.
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Further development of the ActRIIB pathway through experimentation
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Soluble ActIIB/Fc may inhibit the activities of ligands like myostatin. This can be useful in treatment of neuromuscular disease, endocrine disorders, and cancer.
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Hypothesized that BMP-11, activins A, B, and AB all work together with myostatin to limit muscle growth in vivo. Treatments may need to neutralize these ligands with ActRIIB-Fc to increase muscle mass.
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Link between ActRIIB activation and cancer cachexia. Pharmacological blockade of ActRIIB pathway prevents further muscle wasting and completely reverses muscle atrophy -> Prolongs survival. Stops ubiquitin action, stimulates muscle stem cell growth.
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Activin A reduces muscle mass and function by stimulating the ActRIIB pathway, which increases transcription of atrophy-related ubiquitin ligases. Muscle wasting from high activin levels are fully reversible. Treatment for cachexia may target activin.