Abstract
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.
Highlights
Skeletal muscle atrophy is a common and serious condition that lacks a pharmacologic therapy
MRNA Expression Signatures of Tomatidine Negatively Correlate to mRNA Expression Signatures of Skeletal Muscle Atrophy—mRNA signatures are patterns of positive and negative changes in mRNA levels that occur in response to perturbations such as a disease or small molecule
Muscle atrophy signature 1 consists of mRNAs that are altered by fasting in both human and mouse skeletal muscle [7]
Summary
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. 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. 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. We used this method to identify a previously unrecognized small molecule inhibitor of skeletal muscle atrophy
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