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

Michael C Dyle; Scott M Ebert; Daniel P Cook; Steven D Kunkel; Daniel K Fox; Kale S Bongers; Steven A Bullard; Jason M Dierdorff; Christopher M Adams

doi:10.1074/jbc.M114.556241

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

Journal article

Open access

Peer reviewed

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

Michael C Dyle, Scott M Ebert, Daniel P Cook, Steven D Kunkel, Daniel K Fox, Kale S Bongers, Steven A Bullard, Jason M Dierdorff and Christopher M Adams

The Journal of biological chemistry, Vol.289(21), pp.14913-14924

05/23/2014

DOI: 10.1074/jbc.M114.556241

PMCID: PMC4031541

PMID: 24719321

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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.

Gene Expression - drug effects

TOR Serine-Threonine Kinases - metabolism

Humans

Mitochondria, Muscle - metabolism

Drug Discovery - methods

Immunoblotting

Male

Multiprotein Complexes - genetics

Muscle, Skeletal - metabolism

Muscle Fibers, Skeletal - drug effects

Muscle Fibers, Skeletal - metabolism

Tomatine - pharmacology

Mechanistic Target of Rapamycin Complex 1

Multiprotein Complexes - metabolism

Myoblasts, Skeletal - cytology

TOR Serine-Threonine Kinases - genetics

MCF-7 Cells

Muscle, Skeletal - drug effects

Muscle Proteins - metabolism

Muscular Atrophy - prevention & control

Mitochondria, Muscle - genetics

Myoblasts, Skeletal - metabolism

Cell Line

Muscular Atrophy - metabolism

Mice, Inbred C57BL

Cells, Cultured

Muscular Atrophy - genetics

Tomatine - analogs & derivatives

Reverse Transcriptase Polymerase Chain Reaction

Muscle Proteins - genetics

Animals

Signal Transduction - drug effects

Cell Line, Tumor

HL-60 Cells

Muscle Fibers, Skeletal - cytology

Mice

Mitochondria, Muscle - drug effects

Muscle, Skeletal - pathology

Myoblasts, Skeletal - drug effects

Details

Title: Subtitle: Systems-based discovery of tomatidine as a natural small molecule inhibitor of skeletal muscle atrophy
Creators: Michael C Dyle - 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
Scott M Ebert - 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
Daniel P Cook - 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
Steven D Kunkel - 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
Daniel K Fox - 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
Kale S Bongers - 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
Steven A Bullard - 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
Jason M Dierdorff - 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
Christopher M Adams - 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
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.289(21), pp.14913-14924
DOI: 10.1074/jbc.M114.556241
PMID: 24719321
PMCID: PMC4031541
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Publisher: United States
Grant note: I01 BX000976 / BLRD VA F31 AG046038 / NIA NIH HHS HL07638-27 / NHLBI NIH HHS AR059115-04, / NIAMS NIH HHS F30AG04496401 / NIA NIH HHS T32 HL007638 / NHLBI NIH HHS F30AG04330401 / NIA NIH HHS T32 GM007337 / NIGMS NIH HHS 1F31AG04603801 / NIA NIH HHS I01 RX001477 / RRD VA F30 AG044964 / NIA NIH HHS R01 AR059115 / NIAMS NIH HHS
Language: English
Date published: 05/23/2014
Academic Unit: Molecular Physiology and Biophysics; Internal Medicine
Record Identifier: 9984025670702771

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