Systems-based Discovery of Tomatidine as a Natural Small Molecule Inhibitor of Skeletal Muscle Atrophy*
| Autor: | Scott M. Ebert, Steven D. Kunkel, Christopher M. Adams, Steven A. Bullard, Michael C. Dyle, Daniel K. Fox, Jason M. Dierdorff, Daniel P. Cook, Kale S. Bongers |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Muscle Atrophy
Male Anabolism Muscle Fibers Skeletal Gene Expression Muscle Proteins Mitochondrion Biochemistry chemistry.chemical_compound Mice Drug Discovery Cells Cultured Tomatine Myogenesis Reverse Transcriptase Polymerase Chain Reaction Systems Biology TOR Serine-Threonine Kinases Muscle atrophy 3. Good health Tomatidine Muscular Atrophy medicine.anatomical_structure MCF-7 Cells Signal transduction medicine.symptom Skeletal Muscle Metabolism Signal Transduction medicine.medical_specialty Skeletal Muscle Myoblasts Skeletal Immunoblotting HL-60 Cells Biology Mechanistic Target of Rapamycin Complex 1 Cell Line Internal medicine Cell Line Tumor medicine Animals Humans Muscle Skeletal Molecular Biology Cell growth Skeletal muscle Cell Biology Mitochondria Muscle Mice Inbred C57BL Endocrinology Metabolism mTOR complex (mTORC) chemistry Multiprotein Complexes |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 1083-351X 0021-9258 |
| Popis: | Background: Skeletal muscle atrophy is a common and serious condition that lacks a pharmacologic therapy. Results: We used a systems-based strategy to identify tomatidine, a natural compound from tomato plants, as a novel small molecule inhibitor of muscle atrophy. Conclusion: Tomatidine may have utility as a therapeutic agent or lead compound for muscle atrophy. Significance: These results suggest new therapeutic strategies for muscle atrophy. Skeletal muscle atrophy is a common and debilitating condition that lacks an effective therapy. To address this problem, we used a systems-based discovery strategy to search for a small molecule whose mRNA expression signature negatively correlates to mRNA expression signatures of human skeletal muscle atrophy. This strategy identified a natural small molecule from tomato plants, tomatidine. Using cultured skeletal myotubes from both humans and mice, we found that tomatidine stimulated mTORC1 signaling and anabolism, leading to accumulation of protein and mitochondria, and ultimately, cell growth. Furthermore, in mice, tomatidine increased skeletal muscle mTORC1 signaling, reduced skeletal muscle atrophy, enhanced recovery from skeletal muscle atrophy, stimulated skeletal muscle hypertrophy, and increased strength and exercise capacity. Collectively, these results identify tomatidine as a novel small molecule inhibitor of muscle atrophy. Tomatidine may have utility as a therapeutic agent or lead compound for skeletal muscle atrophy. |
| Databáze: | OpenAIRE |
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