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mRNA Expression Signatures of Human Skeletal Muscle Atrophy Identify a Natural Compound that Increases Muscle Mass
Open accessAbstract
Skeletal muscle atrophy is a common and debilitating condition that lacks a pharmacologic therapy. To develop a potential therapy, we identified 63 mRNAs that were regulated by fasting in both human and mouse muscle, and 29 mRNAs that were regulated by both fasting and spinal cord injury in human muscle. We used these two unbiased mRNA expression signatures of muscle atrophy to query the Connectivity Map, which singled out ursolic acid as a compound whose signature was opposite to those of atrophy-inducing stresses. A natural compound enriched in apples, ursolic acid reduced muscle atrophy and stimulated muscle hypertrophy in mice. It did so by enhancing skeletal muscle insulin/IGF-I signaling and inhibiting atrophy-associated skeletal muscle mRNA expression. Importantly, ursolic acid's effects on muscle were accompanied by reductions in adiposity, fasting blood glucose, and plasma cholesterol and triglycerides. These findings identify a potential therapy for muscle atrophy and perhaps other metabolic diseases.
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“UA appeared to mediate its effects through enhancement of insulin/IGF-I signaling and a reduction in the expression of the atrophy-associated genes MuRF1 and MAFbx [187]”
From New strategies in sport nutrition to increase exercise performance (2016) · cites this paper as [187]
In the citing paper
“Therefore, it is presently unclear whether UA supplementation in humans can reproduce the anti-atrophy or pro-hypertrophic data reported previously [187].”
From New strategies in sport nutrition to increase exercise performance (2016) · cites this paper as [187]
In the citing paper
“whilst 5 weeks of supplemented diet (0.27% UA) induced hypertrophy [187].”
From New strategies in sport nutrition to increase exercise performance (2016) · cites this paper as [187]
In the citing paper
“UA supplementation in mice (200 mg / kg via i.p. injection twice daily for 7 days) reduced muscle atrophy following denervation”
From New strategies in sport nutrition to increase exercise performance (2016) · cites this paper as [187]
In the citing paper
“Ursolic acid, a pentacyclic triterpenoid abundant in apples, reduces fasting- and denervation-induced muscle atrophy by inhibiting the mRNA expression of MAFbx and MuRF1 and induces skeletal muscle hypertrophy in SD rats [145].”
From Nutraceuticals in the Prevention and Treatment of the Muscle Atrophy (2021) · cites this paper as [145]
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“The connectivity score, represented on the y axis, is a measure of the strength of the correlation (Lamb et al., 2006). p < 0.004 for all compounds shown.”
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“Previous studies demonstrated that skeletal muscle atrophy is driven by conserved changes in skeletal muscle gene expression (Bodine et al., 2001a; Sandri et al., 2004).”
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“Previous studies demonstrated that skeletal muscle atrophy is driven by conserved changes in skeletal muscle gene expression (Bodine et al., 2001a; Sandri et al., 2004).”
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“Previous studies demonstrated that skeletal muscle atrophy is driven by conserved changes in skeletal muscle gene expression (Bodine et al., 2001a; Sandri et al., 2004).”
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“We next examined whether ursolic acid might increase Akt activation in C2C12 skeletal myotubes, awell-established in vitro model of skeletal muscle (Sandri et al., 2004; Stitt et al., 2004).”
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“Interestingly, because it exerts beneficial effects in animal models of diabetes and hyperlipidemia (Liu, 1995; Wang et al., 2009), ursolic acid is thought to be the active component in a variety of folkloric antidiabetic herbal medicines (Liu, 1995, 2005).”
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“We also measured the effect of ursolic acid on plasma IGF-I levels, which primarily reflect growth hormone-mediated hepatic IGF-I production (Yakar et al., 1999).”
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“However, neither global nor muscle-specific PTP1B knockout mice were found to possess increased muscle mass (Delibegovic et al., 2007; Klaman et al., 2000).”
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“, 2005) and stimulatesmuscle hypertrophy (Barton-Davis et al., 1998; Musaro et al., 2001).”
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“Of these, PGC-1a mRNA encodes a protein that inhibits atrophy-associated gene expression and skeletal muscle atrophy in mice (Sandri et al., 2006).”
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“Previous studies demonstrated important roles for reduced PGC-1 expression (18), reduced Akt signaling (40), increased ATF4 expression (21), increased GSK-3 signaling (48), increased caspase-3 activity (17), and increased autophagy (15, 16).”
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“[9] have reported that UA ameliorates skeletal muscle atrophy by inhibiting of muscle-atrophy-related pathways.”
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“presently unclear whether UA supplementation in humans can reproduce the anti-atrophy or pro-hypertrophic data reported previously [187].”
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“In our previous study of non-obese mice, we found that ursolic acid also increased the level of Igf1 mRNA in skeletal muscle [5].”
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“…et al. 2009) and the discovery of a number of potential novel targeted pharmaconutrients [ursolic acid (UA), HMB, PA, etc. (Vukovich et al. 2001, Kunkel et al. 2011, Hoffman et al. 2012)], RE with appropriate supportive nutrition remains the current most effective and safe means by which to ©…”
BackgroundRecent developments on the extraction and application of ursolic acid. A review
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“Isometric contractile properties of the EDL muscle were evaluated according to methods previously described (7).”
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Chen, J., Wong, H. S., Leong, P. K., Leung, H. Y., Chan, W. M., & Ko, K. M. (2017) · Food & Function · doi:10.1039/c7fo00127d · Cited by 67
Mathes, S., Fahrner, A., Ghoshdastider, U., Rüdiger, H. A., Leunig, M., Wolfrum, C., & Krützfeldt, J. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2021013118 · Cited by 69
Hunt, L. C., Graça, F. A., Pagala, V., Wang, Y., Li, Y., Yuan, Z., Fan, Y., Labelle, M., Peng, J., & Demontis, F. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109971 · Cited by 74
“In recent years, application of RNA-seq to the analysis of muscle atrophy has indeed provided novel insight into the transcriptional changes associated with atrophy and muscle homeostasis (Chapman et al., 2020; Kunkel et al., 2011; Llano-Diez et al., 2019; Mahmassani et al., 2019; Terry et al., 2018).”
BackgroundDamanti, S., Azzolino, D., Roncaglione, C., Arosio, B., Rossi, P. D., & Cesari, M. (2019) · Nutrients · doi:10.3390/nu11091991 · Cited by 72
“Furthermore, it was able to stimulate the insulin/IGF-1 axis producing muscular hypertrophy [167].”
BackgroundRe Cecconi, A. D., Forti, M., Chiappa, M., Zhu, Z., Zingman, L. V., Cervo, L., Beltrame, L., Marchini, S., & Piccirillo, R. (2019) · Cancers · doi:10.3390/cancers11101541 · Cited by 66
“Each mouse was subjected to 5 consecutive tests to obtain the average peak value, which was normalized to body weight, as done in [77].”
MethodWijngaarden, M. A., van der Zon, G. C., van Dijk, K. W., Pijl, H., & Guigas, B. (2013) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00008.2013 · Cited by 65
“Among the fasting-induced changes in skeletal muscle metabolic gene expression observed in our study, some were previously reported, such as upregulations of PDK4 and UCP3, and are likely contributing to the whole body shift from glucose to lipid oxidation in humans (25, 27, 28, 32, 37, 39, 40).”
BackgroundResultNetwork based elucidation of drug response: from modulators to targets
Iorio, F., Sáez-Rodríguez, J., & di Bernardo, D. (2013) · BMC Systems Biology · doi:10.1186/1752-0509-7-139 · Cited by 67
“identified by querying drug-disease networks [41-44] or drug-drug networks [45,46].”
BackgroundUrsolic acid and mechanisms of actions on adipose and muscle tissue: a systematic review
Katashima, C. K., Silva, V. R. R., Gomes, T. L. N., Pichard, C., & Pimentel, G. D. (2017) · Obesity Reviews · doi:10.1111/obr.12523 · Cited by 65
“Kunkel and colleagues observed that UA attenuates muscle atrophy under fasting conditions and muscle denervation and may increase hypertrophy (8).”
BackgroundInfluentialNutraceuticals in the Prevention and Treatment of the Muscle Atrophy
Wang, Y., Liu, Q., Quan, H., Kang, S.-G., Huang, K., & Tong, T. (2021) · Nutrients · doi:10.3390/nu13061914 · Cited by 61
Bongers, K. S., Fox, D. K., Kunkel, S. D., Stebounova, L. V., Murry, D. J., Pufall, M. A., Ebert, S. M., Dyle, M. C., Bullard, S. A., Dierdorff, J. M., et al. (2014) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00472.2014 · Cited by 64
Wagner, A., Cohen, N., Kelder, T., Amit, U., Liebman, E., Steinberg, D. M., Radonjić, M., & Ruppin, E. (2015) · Molecular Systems Biology · doi:10.15252/msb.20145486 · Cited by 65
Apigenin Enhances Skeletal Muscle Hypertrophy and Myoblast Differentiation by Regulating Prmt7
Jang, Y. J., Son, H. J., Choi, Y. M., Ahn, J., Jung, C. H., & Ha, T. Y. (2017) · Oncotarget · doi:10.18632/oncotarget.20962 · Cited by 59
“Ursolic acid is found in apples and induces skeletal muscle hypertrophy and growth by enhancing IGF-1 signaling [28].”
BackgroundResultRecent advances in pharmacological, hormonal, and nutritional intervention for sarcopenia
Sakuma, K., & Yamaguchi, A. (2017) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-017-2077-9 · Cited by 60
“[58] studied serum-starved skeletal myotubes and found that ursolic acid rapidly stimulated IGF-I receptor and insulin re-”
BackgroundInfluentialBiology of Activating Transcription Factor 4 (ATF4) and Its Role in Skeletal Muscle Atrophy
Ebert, S. M., Rasmussen, B. B., Judge, A. R., Judge, S. M., Larsson, L., Wek, R. C., Anthony, T. G., Marcotte, G. R., Miller, M. J., Yorek, M. A., et al. (2021) · Journal of Nutrition · doi:10.1093/jn/nxab440 · Cited by 64
Web-based drug repurposing tools: a survey
Sam, E., & Athri, P. (2017) · Briefings in Bioinformatics · doi:10.1093/bib/bbx125 · Cited by 62
Hill, M. A., & Gammie, S. C. (2022) · Scientific Reports · doi:10.1038/s41598-022-22179-z · Cited by 56
Novel Intriguing Strategies Attenuating to Sarcopenia
Sakuma, K., & Yamaguchi, A. (2012) · Journal of Aging Research · doi:10.1155/2012/251217 · Cited by 59
“[29] found that ursolic acid reduced skeletal muscle atrophy in the setting of two-distinct atrophyinducing stresses (fasting and muscle denervation).”
BackgroundInfluentialGorski, T., Mathes, S., & Krützfeldt, J. (2018) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1002/jcsm.12277 · Cited by 56
Mechanisms of protein balance in skeletal muscle
Anthony, T. G. (2016) · Domestic Animal Endocrinology · doi:10.1016/j.domaniend.2016.02.012 · Cited by 59
Ursolic acid ameliorates aging-metabolic phenotype through promoting of skeletal muscle rejuvenation
Bakhtiari, N., Hosseinkhani, S., Tashakor, A., & Hemmati, R. (2015) · Medical Hypotheses · doi:10.1016/j.mehy.2015.02.014 · Cited by 51
“Injections were done twice a day for 7 days [31].”
MethodEVALUATION OF ANALYTICAL METHODS FOR CONNECTIVITY MAP DATA
Cheng, J., Xie, Q. S., Kumar, V. D., Hurle, M. R., Freudenberg, J., Yang, L., & Agarwal, P. (2012) · Pacific Symposium on Biocomputing (PSB) · doi:10.1142/9789814447973_0002 · Cited by 51
External physical and biochemical stimulation to enhance skeletal muscle bioengineering
Handschin, C., Mortezavi, A., Plock, J. A., & Eberli, D. (2014) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2014.10.021 · Cited by 49
“acid as a compound that, in subsequent experiments, reduced denervation-induced muscle atrophy in mice [50].”
BackgroundNatural products: Potential therapeutic agents to prevent skeletal muscle atrophy
Yadav, A., Yadav, S. S., Singh, S., & Dabur, R. (2022) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2022.174995 · Cited by 54
Fortney, K., Griesman, J., Kotlyar, M., Pastrello, C., Angeli, M., Tsao, M., & Jurišica, I. (2015) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1004068 · Cited by 48
“While a few studies have used multiple disease signatures in CMap analysis, e.g., [7,8] (though with one exception [12], they used only two or three signatures), they have all relied on essentially the same strategy of collapsing all disease signatures into a single meta-signature (by e.g.,…”
MethodDuarte, R. R. R., Copertino, D. C., Iñiguez, L., Marston, J. L., Bram, Y., Han, Y., Schwartz, R. E., Chen, S., Nixon, D. F., & Powell, T. R. (2021) · Molecular Medicine · doi:10.1186/s10020-021-00356-6 · Cited by 49
Iorio, F., Shrestha, R. L., Levin, N., Boilot, V., Garnett, M. J., Sáez-Rodríguez, J., & Draviam, V. M. (2015) · PLoS ONE · doi:10.1371/journal.pone.0139446 · Cited by 44
“This idea has been successfully applied in various contexts, including Crohn’s disease [7], skeletal muscle atrophy [8], cancer [9–11], and Alzheimer’s disease [12].”
BackgroundEMUDRA: Ensemble of Multiple Drug Repositioning Approaches to improve prediction accuracy
Zhou, X., Wang, M., Katsyv, I., Irie, H., & Zhang, B. (2018) · Bioinformatics · doi:10.1093/bioinformatics/bty325 · Cited by 43
Ursolic acid improves domoic acid-induced cognitive deficits in mice
Wu, D., Lu, J. L., Zhang, Y., Zheng, Y., Hu, B., Cheng, W. P., Zhang, Z.-F., & Li, M. (2013) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2013.04.038 · Cited by 44
“, 2012) and promoting FoxO1 nuclear exclusion (Kunkel et al., 2011).”
BackgroundMethodInfluentialSaul, M. C., Majdak, P., Perez, S., Reilly, M., Garland, T., & Rhodes, J. S. (2016) · Genes Brain & Behavior · doi:10.1111/gbb.12347 · Cited by 45
“The LINCS database has been used successfully as a pattern-matching tool in drug discovery (Kunkel et al. 2011; Lamb et al. 2006; Liu et al. 2015; Qu & Rajpal 2012; Wei et al. 2006).”
MethodCARM1 drives mitophagy and autophagy flux during fasting-induced skeletal muscle atrophy
Stouth, D. W., vanLieshout, T. L., Mikhail, A. I., Ng, S. Y., Raziee, R., Edgett, B. A., Vasam, G., Webb, E. K., Gilotra, K., Markou, M., et al. (2023) · Autophagy · doi:10.1080/15548627.2023.2288528 · Cited by 42
“Previous work demonstrated the effect of a 40 h fast on global mRNA expression in human QUAD muscle [37].”
BackgroundMuscle Dysfunction in Patients with Lung Diseases. A Growing Epidemic
Barreiro, E., Sznajder, J. I., Nader, G. A., & Budinger, G. R. S. (2015) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201412-2189oe · Cited by 42
Ursolic Acid Increases Glucose Uptake through the PI3K Signaling Pathway in Adipocytes
He, Y., Li, W., Li, Y., Zhang, S., Wang, Y., & Sun, C. (2014) · PLoS ONE · doi:10.1371/journal.pone.0110711 · Cited by 42
“However, UA has been reported to increase insulin receptor phosphorylation in the presence of insulin [18].”
BackgroundInsulin/IGF signaling and discoidin domain receptors: An emerging functional connection
Vella, V., Malaguarnera, R., Nicolosi, M. L., Morrione, A., & Belfiore, A. (2019) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2019.118522 · Cited by 41
Kim, M., Sung, B., Kang, Y. J., Kim, D. H., Lee, Y., Hwang, S. Y., Yoon, J.-H., Yoo, M., Kim, C. M., Chung, H. Y., et al. (2014) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2014.2046 · Cited by 40
Bakhtiari, N., Hosseinkhani, S., Soleimani, M., Hemmati, R., Noori-Zadeh, A., Javan, M., & Tashakor, A. (2016) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2016.01.010 · Cited by 40
Vilar, S., & Hripcsak, G. M. (2016) · Briefings in Bioinformatics · doi:10.1093/bib/bbw048 · Cited by 40
Pharmacologic approaches to prevent skeletal muscle atrophy after spinal cord injury
Otzel, D. M., Kok, H. J., Graham, Z., Barton, E. R., & Yarrow, J. F. (2021) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2021.07.023 · Cited by 41
Using the Connectivity Map to discover compounds influencing human osteoblast differentiation
Brum, A. M., van de Peppel, J., Nguyen, L., Aliev, A., Schreuders‐Koedam, M., Gajadien, T., van der Leije, C. S., van Kerkwijk, A., Eijken, M., van Leeuwen, J. P. T. M., et al. (2017) · Journal of Cellular Physiology · doi:10.1002/jcp.26298 · Cited by 39
“…osteoarthritic pain (Chang, Smith, Thorpe, Barratt, & Karim, 2010), adenocarcinoma (Wang et al., 2011), skeletal muscle atrophy (Dyle et al., 2014; Kunkel et al., 2011), emphysema-related lung disease (Campbell et al., 2012), kidney disease (Zhong et al., 2013), gliomas (Koh et al., 2013), NK…”
BackgroundWijngaarden, M. A., Bakker, L. E. H., van der Zon, G. C., Hoen, P. A. C. ’., van Dijk, K. W., Jazet, I. M., Pijl, H., & Guigas, B. (2014) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00215.2014 · Cited by 41
Zanforlin, E., Zagotto, G., & Ribaudo, G. (2017) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.7b00283 · Cited by 38
Coffee consumption promotes skeletal muscle hypertrophy and myoblast differentiation
Jang, Y. J., Son, H. J., Kim, J., Jung, C. H., Ahn, J., Hur, J., & Ha, T. Y. (2018) · Food & Function · doi:10.1039/c7fo01683b · Cited by 39
Kim, J. C., Kang, Y. S., Noh, E. B., Seo, B. W., Seo, D. Y., Park, G. D., & Kim, S. H. (2018) · The Korean Journal of Physiology & Pharmacology · doi:10.4196/kjpp.2018.22.4.427 · Cited by 36
“Furthermore, MuRF1 and Atrogin-1 expression, which are atrophy-related genes, which are atrophy-related genes, are controlled by UA [24,26].”
BackgroundInfluential
Metadata
- Authors
- Kunkel, S. D., Suneja, M., Ebert, S. M., Bongers, K. S., Fox, D. K., Malmberg, S. E., Alipour, F., Shields, R. K., & Adams, C. M.
- Affiliations
- University of Iowa (US)
- Corresponding author
- Adams, Christopher M.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2011-06
- Volume
- 13
- Issue
- 6
- Pages
- 627-638
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC3120768
- OpenAlex
- W2099582158
- Cited by
- 345
- References
- 35
- Citations by year
- 2026: 15 · 2025: 17 · 2024: 18 · 2023: 22 · 2022: 23 · 2021: 36 · 2020: 24 · 2019: 35 · 2018: 26 · 2017: 24 · 2016: 25 · 2015: 27 · 2014: 16 · 2013: 19 · 2012: 16
- FWCI
- 6.71
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 777 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Diabetes Association (1R01AR059115-01)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases
- U.S. Department of Veterans Affairs
- Doris Duke Charitable Foundation
- Institute of Clinical and Translational Sciences
- National Institutes of Health (HL007121, T32 GM073610)
- University of Georgia Research Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Physiology (medical) › Nutrition and Health in Aging
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Keywords
- skeletal muscle atrophy, ursolic acid, muscle hypertrophy, fasting, spinal cord injury, mRNA expression signature, adiposity, metabolic disorders, natural compounds, apple
- MeSH terms
- Ursolic Acid, Animals, Cell Line, Fasting, Gene Expression Regulation, Hindlimb, Humans, Insulin, Insulin-Like Growth Factor I, Mice, Inbred C57BL, Muscle Denervation, Muscular Atrophy, Triterpenes, Signal Transduction, Gene Expression, Muscle, Skeletal, Muscle Fibers, Skeletal, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, Mice, Muscle Strength
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