Abstract
Sarcopenia is the age-related loss of muscle mass and function and no pharmacological medication has been approved for its treatment. We established an atrogin-1/MAFbx promoter assay to find drug candidates that inhibit myotube atrophy. Alverine citrate (AC) was identified using high-throughput screening of an existing drug library. AC is an established medicine for stomach and intestinal spasms. AC treatment increased myotube diameter and inhibited atrophy signals induced by either C26-conditioned medium or dexamethasone in cultured C2C12 myoblasts. AC also enhanced myoblast fusion through the upregulation of fusion-related genes during C2C12 myoblast differentiation. Oral administration of AC improves muscle mass and physical performance in aged mice, as well as hindlimb-disused mice. Taken together, our data suggest that AC may be a novel therapeutic candidate for improving muscle weakness, including sarcopenia.
Keywords:
Aging; Alverine citrate; Sarcopenia; Skeletal muscle atrophy.
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aging / genetics*
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Aging / metabolism
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Animals
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Biomarkers / metabolism
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Cadherins / genetics
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Cadherins / metabolism
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Caveolin 3 / genetics
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Caveolin 3 / metabolism
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Cell Differentiation / drug effects*
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Cell Line
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Dexamethasone / pharmacology
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Disease Models, Animal
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Gene Expression
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High-Throughput Screening Assays
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Immobilization
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Integrin beta1 / genetics
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Integrin beta1 / metabolism
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Mice
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Mice, Inbred C57BL
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Muscle Development / genetics
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Muscle Fibers, Skeletal / drug effects
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Muscle Fibers, Skeletal / metabolism
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Muscle Fibers, Skeletal / pathology
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Muscle Strength / drug effects
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Muscle, Skeletal / drug effects
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Muscle, Skeletal / metabolism
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Muscle, Skeletal / pathology
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Muscular Atrophy / genetics
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Muscular Atrophy / metabolism
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Muscular Atrophy / pathology
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Muscular Atrophy / prevention & control*
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Myoblasts / drug effects
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Myoblasts / metabolism
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Myoblasts / pathology
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Parasympatholytics / pharmacology*
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Propylamines / pharmacology*
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Sarcopenia / genetics
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Sarcopenia / metabolism
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Sarcopenia / pathology
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Sarcopenia / prevention & control*
Substances
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Biomarkers
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Cadherins
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Cav3 protein, mouse
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Caveolin 3
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Cdh2 protein, mouse
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Integrin beta1
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Itgb1 protein, mouse
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Parasympatholytics
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Propylamines
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alverine
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Dexamethasone