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J Biol Chem. 2014 May 23;289(21):14913-24. doi: 10.1074/jbc.M114.556241. Epub 2014 Apr 9.

Systems-based discovery of tomatidine as a natural small molecule inhibitor of skeletal muscle atrophy.

Author information

1
From the Departments of Internal Medicine and Molecular Physiology and Biophysics, and Fraternal Order of Eagles Diabetes Research Center, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242 and.
2
From the Departments of Internal Medicine and Molecular Physiology and Biophysics, and Fraternal Order of Eagles Diabetes Research Center, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242 and the Iowa City Veterans Affairs Medical Center, Iowa City, Iowa 52246.
3
From the Departments of Internal Medicine and Molecular Physiology and Biophysics, and Fraternal Order of Eagles Diabetes Research Center, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242 and the Iowa City Veterans Affairs Medical Center, Iowa City, Iowa 52246 christopher-adams@uiowa.edu.

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.

KEYWORDS:

Muscle Atrophy; Skeletal Muscle; Skeletal Muscle Metabolism; Systems Biology; Tomatidine; mTOR complex (mTORC)

PMID:
24719321
PMCID:
PMC4031541
DOI:
10.1074/jbc.M114.556241
[Indexed for MEDLINE]
Free PMC Article

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