Systems-based discovery of tomatidine as a natural small molecule inhibitor of skeletal 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.
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.
Michael C
MC
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
SM
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
DP
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
SD
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
DK
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
KS
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 the Iowa City Veterans Affairs Medical Center, Iowa City, Iowa 52246.
Steven A
SA
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.
Jason M
JM
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 the Iowa City Veterans Affairs Medical Center, Iowa City, Iowa 52246 christopher-adams@uiowa.edu.
Christopher M
CM
Adams
D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D055808:Drug Discovery / Q000379:methods; D015870:Gene Expression / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D015151:Immunoblotting; D061986:MCF-7 Cells; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009133:Muscular Atrophy / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D032448:Myoblasts, Skeletal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D014053:Tomatine / Q000031:analogs & derivatives* / Q000494:pharmacology
D046912:Multiprotein Complexes; D009124:Muscle Proteins; C003677:tomatidine; D014053:Tomatine; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
Muscle Atrophy; Skeletal Muscle; Skeletal Muscle Metabolism; Systems Biology; Tomatidine; mTOR complex (mTORC)