ArticleThe Journal of biological chemistry2015
Identification and Small Molecule Inhibition of an Activating Transcription Factor 4 (ATF4)-dependent Pathway to Age-related Skeletal Muscle Weakness and Atrophy.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 76 papers.
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Who cites it
76 citing papers in PubMed, 106 citations in OpenAlex.
- Trial
- Metformin Partially Attenuates Simvastatin-Induced Myotoxic Responses in C2C12 Myotubes Through Metabolic Adaptation.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- Mitochondria-sarcoplasmic reticulum crosstalk as a modulator of skeletal muscle mass.Journal of physiology and biochemistry · 2026Review
- The Effect of Resistance Training and Ursolic Acid on the PI3K-AKT-mTOR Pathway in Aged Diabetic Rats: A Comparative Study.Aging medicine (Milton (N.S.W)) · 2026Article
- Dietary supplementation with ursolic acid preserves skeletal muscle mass and strength in mouse models of cancer cachexia.American journal of physiology. Cell physiology · 2026Article
- Unfolding Resilience: Molecular Integration of the Integrated Stress Response and Mitochondrial UPR in Skeletal Muscle Homeostasis.Muscles (Basel, Switzerland) · 2026Review
- Tomatidine is a senotherapeutic compound that improves cognitive function and reduces cellular senescence in aged mice.EMBO molecular medicine · 2026Article
- ATF4 Coordinates Transcriptomic and Structural Adaptations in Aging Muscle.bioRxiv : the preprint server for biology · 2026Article
- An RNA-sequencing analysis to determine potential upstream transcriptional regulators of essential amino acid deficiency responses in bovine mammary epithelial cells.BMC genomics · 2026Article
- Spatial-Bioenergetic-Immune Axis in Type 2 Diabetes Mellitus-Associated Sarcopenia: A Review from Pathogenesis to Targeted Reconstruction.Journal of inflammation research · 2026Review
- Emerging roles for integrated stress response signaling in homeostasis.The FEBS journal · 2025Review
- Transcriptional regulation of solute carrier family 6 member 9 gene.Molecular biology reports · 2025Article
- The commonly used antibiotic streptomycin reduces protein synthesis and differentiation in cultured C2C12 myotubes.Physiological reports · 2025Article
- Irisin: muscle's novel player in endoplasmic reticulum stress and disease.Molecular and cellular biochemistry · 2025Review
- Tomatidine Attenuates Inflammatory Responses to Exercise-Like Stimulation in Donor-derived Skeletal Muscle Myobundles.Medical research archives · 2025Article
- Combined Exercise and Ursolic Acid Improve Hippocampal Neuronal Markers and Exploratory-Locomotor Behavior in Aged Diabetic Rats.Journal of aging research · 2025Article
- Exerkines and myokines in aging sarcopenia.Frontiers in endocrinology · 2025Review
- Transcriptome sequencing analysis reveals the molecular mechanism of sepsis-induced muscle atrophy.Journal of thoracic disease · 2024Article
- Advancements in Drug Delivery Systems for the Treatment of Sarcopenia: An Updated Overview.International journal of molecular sciences · 2024Review
- Article
16 more citing papers are in PubMed but not listed here.
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Authors and funding
11 authors at 3 institutions in 1 country.
Funding
Abstract
Aging reduces skeletal muscle mass and strength, but the underlying molecular mechanisms remain elusive. Here, we used mouse models to investigate molecular mechanisms of age-related skeletal muscle weakness and atrophy as well as new potential interventions for these conditions. We identified two small molecules that significantly reduce age-related deficits in skeletal muscle strength, quality, and mass: ursolic acid (a pentacyclic triterpenoid found in apples) and tomatidine (a steroidal alkaloid derived from green tomatoes). Because small molecule inhibitors can sometimes provide mechanistic insight into disease processes, we used ursolic acid and tomatidine to investigate the pathogenesis of age-related muscle weakness and atrophy. We found that ursolic acid and tomatidine generate hundreds of small positive and negative changes in mRNA levels in aged skeletal muscle, and the mRNA expression signatures of the two compounds are remarkably similar. Interestingly, a subset of the mRNAs repressed by ursolic acid and tomatidine in aged muscle are positively regulated by activating transcription factor 4 (ATF4). Based on this finding, we investigated ATF4 as a potential mediator of age-related muscle weakness and atrophy. We found that a targeted reduction in skeletal muscle ATF4 expression reduces age-related deficits in skeletal muscle strength, quality, and mass, similar to ursolic acid and tomatidine. These results elucidate ATF4 as a critical mediator of age-related muscle weakness and atrophy. In addition, these results identify ursolic acid and tomatidine as potential agents and/or lead compounds for reducing ATF4 activity, weakness, and atrophy in aged skeletal muscle.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.