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.
“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]
It is presently unclear whether UA supplementation in humans can reproduce the anti-atrophy or pro-hypertrophic data reported previously.
“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]
5 weeks of supplemented diet (0.27% UA) induced hypertrophy in mice.
“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]
UA supplementation in mice (200 mg/kg via i.p. injection twice daily for 7 days) reduced muscle atrophy following denervation.
“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]
Ursolic acid reduces fasting- and denervation-induced muscle atrophy by inhibiting the mRNA expression of MAFbx and MuRF1 and induces skeletal muscle hypertrophy in SD rats.
“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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InfluentialSacheck, J. M., Hyatt, J. K., Raffaello, A., Thomas Jagoe, R., Roy, R. R., Reggie Edgerton, V., Lecker, S. H., & Goldberg, A. L. (2007) · The FASEB Journal · doi:10.1096/fj.06-6604com · Cited by 585 · cited 2× · see citing works
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Self-citationAnti-glycative effects of oleanolic acid and ursolic acid in kidney of diabetic mice
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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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“However, ursolic acid did not alter levels of mRNAs encoding myostatin (which reduces muscle mass [Lee, 2004]), or twist or myogenin (which are induced by IGF-I during development [Dupont et al., 2001; Tureckova et al., 2001]).”
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“In addition, increased skeletal muscle IGF1 expression reduces denervation-induced muscle atrophy (Shavlakadze et al., 2005) and stimulatesmuscle hypertrophy (Barton-Davis et al.”
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Drug repurposing: progress, challenges and recommendations
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“[154] identified mRNA sequences regulated by fasting in human and mice muscles.”
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“In vivo models have been used to validate predictions resulting from this approach, including ursolic acid for muscle weight loss 16 and the anticonvulsant drug topiramate for inflammatory bowel disease.”
BackgroundMethodA review of connectivity map and computational approaches in pharmacogenomics
Musa, A., Ghoraie, L. S., Zhang, S., Galzko, G., Yli-Harja, O. P., Dehmer, M., Haibe‐Kains, B., & Emmert‐Streib, F. (2017) · Briefings in Bioinformatics · doi:10.1093/bib/bbw112 · Cited by 275 · see citing works
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BackgroundMethodThe role of E3 ubiquitin-ligases MuRF-1 and MAFbx in loss of skeletal muscle mass
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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).”
BackgroundMethodInfluentialSelf-citationTranscriptional data: a new gateway to drug repositioning?
Iorio, F., Rittman, T., Ge, H., Menden, M. P., & Sáez-Rodríguez, J. (2012) · Drug Discovery Today · doi:10.1016/j.drudis.2012.07.014 · Cited by 237 · see citing works
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Applications of Connectivity Map in drug discovery and development
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Ursolic acid in health and disease
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“[9] have reported that UA ameliorates skeletal muscle atrophy by inhibiting of muscle-atrophy-related pathways.”
BackgroundNew strategies in sport nutrition to increase exercise performance
Close, G. L., Hamilton, D. L., Philp, A., Burke, L. M., & Morton, J. P. (2016) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2016.01.016 · Cited by 221 · see citing works
“presently unclear whether UA supplementation in humans can reproduce the anti-atrophy or pro-hypertrophic data reported previously [187].”
BackgroundInfluentialKunkel, S. D., Elmore, C., Bongers, K. S., Ebert, S. M., Fox, D. K., Dyle, M. C., Bullard, S. A., & Adams, C. M. (2012) · PLoS ONE · doi:10.1371/journal.pone.0039332 · Cited by 220 · see citing works
“In our previous study of non-obese mice, we found that ursolic acid also increased the level of Igf1 mRNA in skeletal muscle [5].”
BackgroundMethodInfluentialTargeting obesity with plant-derived pancreatic lipase inhibitors: A comprehensive review
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“Even with this limited-scale dataset, query of CMAP has provided biological insight across diverse disease areas [6-9].”
Skeletal muscle homeostasis and plasticity in youth and ageing: impact of nutrition and exercise
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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
López‐Hortas, L., Pérez-Larrán, P., González‐Muñoz, M. J., Falqué, E., & Domı́nguez, H. (2017) · Food Research International · doi:10.1016/j.foodres.2017.10.028 · Cited by 183 · see citing works
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CURRENT NUTRITIONAL RECOMMENDATIONS AND NOVEL DIETARY STRATEGIES TO MANAGE SARCOPENIA
Calvani, R., Miccheli, A., Landi, F., Bossola, M., Cesari, M., Leeuwenburgh, C., Sieber, C. C., Bernabei, R., & Marzetti, E. (2013) · The Journal of Frailty & Aging · doi:10.14283/jfa.2013.7 · Cited by 163 · see citing works
Bongers, K. S., Fox, D. K., Ebert, S. M., Kunkel, S. D., Dyle, M. C., Bullard, S. A., Dierdorff, J. M., & Adams, C. M. (2013) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00380.2013 · Cited by 145 · see citing works
“Unilateral hindlimb denervation was performed as described previously (18); mice were anesthetized with an intraperitoneal injection of 91 mg/kg ketamine and 9.”
Terpenoids as Potential Geroprotectors
Николаевна, П. Е., Plyusnin, S., Babak, T. V., Lashmanova, E., Maganova, F., Koval, L. A., Platonova, E. Y., Shaposhnikov, M. V., & Moskalev, A. (2020) · Antioxidants · doi:10.3390/antiox9060529 · Cited by 142 · see citing works
Dyle, M. C., Ebert, S. M., Cook, D. P., Kunkel, S. D., Fox, D. K., Bongers, K. S., Bullard, S. A., Dierdorff, J. M., & Adams, C. M. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.556241 · Cited by 138 · see citing works
“Isometric contractile properties of the EDL muscle were evaluated according to methods previously described (7).”
BackgroundMethodInfluentialSystematic evaluation of connectivity map for disease indications
Cheng, J., Yang, L., Kumar, V. D., & Agarwal, P. (2014) · Genome Medicine · doi:10.1186/s13073-014-0095-1 · Cited by 131 · see citing works
Ursocholanic acid rescues mitochondrial function in common forms of familial Parkinson’s disease
Mortiboys, H., Aasly, J. O., & Bandmann, O. (2013) · Brain · doi:10.1093/brain/awt224 · Cited by 124 · see citing works
“All data are presented as a ratio of pAkt (Ser473): total Akt.”
BackgroundInfluentialBond, P. (2016) · Journal of the International Society of Sports Nutrition · doi:10.1186/s12970-016-0118-y · Cited by 121 · see citing works
Ebert, S. M., Dyle, M. C., Bullard, S. A., Dierdorff, J. M., Murry, D. J., Fox, D. K., Bongers, K. S., Lira, V. A., Meyerholz, D. K., Talley, J. J., et al. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.681445 · Cited by 120 · see citing works
“Quantification of Ursolic Acid and Tomatidine in Mouse Plasma—Mouse plasma was collected as described previously (10), and plasma levels of ursolic acid and tomatidine were determined with validated liquid chromatography/mass spectrometry (LC/MS) assays.”
BackgroundMethodInfluentialThe road ahead for health and lifespan interventions
Gonzalez-Freire, M., Diaz-Ruiz, A., Hauser, D., Martinez-Romero, J., Ferrucci, L., Bernier, M., & de Cabo, R. (2020) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101037 · Cited by 118 · see citing works
Fox, D. K., Ebert, S. M., Bongers, K. S., Dyle, M. C., Bullard, S. A., Dierdorff, J. M., Kunkel, S. D., & Adams, C. M. (2014) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00010.2014 · Cited by 119 · see citing works
“Forelimb grip strength was determined using a grip strength meter equipped with a triangular pull bar (Columbus Instruments), as described previously (34).”
MethodMisra, R. C., Maiti, P., Chanotiya, C. S., Shanker, K., & Ghosh, S. (2013) · PLANT PHYSIOLOGY · doi:10.1104/pp.113.232884 · Cited by 116 · see citing works
“…compounds) are known for a variety of pharmaceutical properties, including anti-inflammatory, hepatoprotective, antitumor, antihyperlipidemic, antiulcer, and antimicrobial benefits (Kunkel et al., 2011; Wilkinson et al., 2011; Kurek et al., 2012; da Silva Ferreira et al., 2013; Kong et al., 2013).”
Backgroundgene2drug: a computational tool for pathway-based rational drug repositioning
Napolitano, F., Carrella, D., Mandriani, B., Pisonero‐Vaquero, S., Sirci, F., Medina, D. L., Brunetti‐Pierri, N., & di Bernardo, D. (2017) · Bioinformatics · doi:10.1093/bioinformatics/btx800 · Cited by 110 · see citing works
“Computational analysis of transcriptional responses of cells to chemical and genetic perturbations or in disease has been successfully applied for preclinical investigations of new drug indications [8, 4, 22, 11, 23, 16].”
BackgroundAmino acid sensing in skeletal muscle
Moro, T., Ebert, S. M., Adams, C. M., & Rasmussen, B. B. (2016) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2016.06.010 · Cited by 104 · see citing works
“Furthermore, when administered to young adult mice without muscle atrophy, [9_TD$DIFF]ursolic [10_TD$DIFF]acid and tomatidine stimulate skeletal muscle hypertrophy and increase strength, muscle quality, and endurance exercise capacity [63,64,66].”
BackgroundSelf-citationThe exercise-inducible bile acid receptor Tgr5 improves skeletal muscle function in mice
Sasaki, T., Kuboyama, A., Mita, M., Murata, S., Shimizu, M., Inoue, J., Mori, K., & Sato, R. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.002733 · Cited by 105 · see citing works
“Additionally, obacunone and ursolic acid, both of which are known to activate TGR5, have been shown to increase muscle mass in mice (42, 43).”
BackgroundSarcopenia, a condition shared by various diseases: can we alleviate or delay the progression?
Tarantino, G., Sinatti, G., Citro, V., Santini, S. J., & Balsano, C. (2023) · Internal and Emergency Medicine · doi:10.1007/s11739-023-03339-z · Cited by 104 · see citing works
“Recently, independently of polyphenols, some other natural compounds, such as ursolic acid, enhance insulin/ IGF-I signaling in skeletal muscle and inhibit skeletal muscle atrophy-associated mRNA expression [66], tanshinone IIA, which stimulates C2C12 myotube hypertrophy through an estrogen receptor-mediated mechanism…”
Backgroundvan Noort, V., Schölch, S., Iskar, M., Zeller, G., Ostertag, K., Schweitzer, C., Werner, K., Weitz, J., Koch, M., & Peer Bork, B. (2014) · Cancer Research · doi:10.1158/0008-5472.can-13-3540 · Cited by 105 · see citing works
Wang, Y., Ma, J., Qiu, W., Zhang, J., Feng, S., Zhou, X., Wang, X., Jin, L. G., Long, K., Liu, L., et al. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19092837 · Cited by 102 · see citing works
Shen, Y., Zhang, R., Xu, L., Wan, Q., Zhu, J., Gu, J., Huang, Z., Ma, W., Shen, M., Ding, F., et al. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.01298 · Cited by 97 · see citing works
Ursolic Acid and Related Analogues: Triterpenoids with Broad Health Benefits
Nguyen, H. N., Ullevig, S. L., Short, J. D., Wang, L., Ahn, Y. J., & Asmis, R. (2021) · Antioxidants · doi:10.3390/antiox10081161 · Cited by 89 · see citing works
The Role of IGF-1 Signaling in Skeletal Muscle Atrophy
Timmer, L. T., Hoogaars, W. M. H., & Jaspers, R. T. (2018) · Advances in experimental medicine and biology · doi:10.1007/978-981-13-1435-3_6 · Cited by 88 · see citing works
Use of big data in drug development for precision medicine: an update
Qian, T., Zhu, S., & Hoshida, Y. (2019) · Expert Review of Precision Medicine and Drug Development · doi:10.1080/23808993.2019.1617632 · Cited by 85 · see citing works
Lin, J., Chen, S., Lu, C., Lin, J., & Yen, G. (2020) · Phytotherapy Research · doi:10.1002/ptr.6669 · Cited by 79 · see citing works
Skeletal Muscle Atrophy: Discovery of Mechanisms and Potential Therapies
Ebert, S. M., Al-Zougbi, A., Bodine, S. C., & Adams, C. M. (2019) · Physiology · doi:10.1152/physiol.00003.2019 · Cited by 80 · see citing works
Supplements with purported effects on muscle mass and strength
Valenzuela, P. L., Morales, J. S., Emanuele, E., Pareja-Galeano, H., & Lucia, A. (2019) · European Journal of Nutrition · doi:10.1007/s00394-018-1882-z · Cited by 78 · see citing works
Severe SMA mice show organ impairment that cannot be rescued by therapy with the HDACi JNJ-26481585
Schreml, J., Rießland, M., Paterno, M., Garbes, L., Roßbach, K., Ackermann, B., Kramer, J. S., Somers, E., Parson, S. H., Heller, R., et al. (2012) · European Journal of Human Genetics · doi:10.1038/ejhg.2012.222 · Cited by 78 · see citing works
Misra, R. C., Sharma, S. R., Sandeep, S., Garg, A., Chanotiya, C. S., & Ghosh, S. (2017) · New Phytologist · doi:10.1111/nph.14412 · Cited by 76 · see citing works
“…and anti-microbial properties, and products based on these PCTs are available in global markets as dietary supplements, over-the-counter drugs and cosmetics (Kunkel et al., 2011; Pollier & Goossens, 2012; Wo zniak et al., 2015; Yamamoto et al., 2015; Kashyap et al., 2016; Silva et al., 2016).”
BackgroundSarcopenia: Pharmacology of Today and Tomorrow
Brotto, M., & de Abreu, E. L. (2012) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.112.191759 · Cited by 75 · see citing works
“2D) has also been found to be effective in treating mice with atrophy (Kunkel et al., 2011).”
BackgroundMethodDorantes-Iturbide, G., Orzuna‐Orzuna, J. F., Lara-Bueno, A., Martínez, G. D. M., Miranda‐Romero, L. A., & Lee-Rangel, H. A. (2022) · Veterinary Sciences · doi:10.3390/vetsci9090475 · Cited by 81 · see citing works
“Although there is little information on the mechanisms of action of EOs and their bioactive metabolites on muscle development in ruminants, there is evidence that terpenoids reduce proteolytic degradation in muscle tissue in rats [64] and increase hypertrophy in skeletal muscle cells [65].”
Background“Nutraceuticals” in relation to human skeletal muscle and exercise
Deane, C. S., Wilkinson, D. J., Phillips, B. E., Smith, K., Etheridge, T., & Atherton, P. J. (2017) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00230.2016 · Cited by 73 · see citing works
Yu, R., Chen, J., Xu, J., Cao, J., Wang, Y., Thomas, S. S., & Hu, Z. (2016) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1002/jcsm.12162 · Cited by 73 · see citing works
Caloric restriction and exercise “mimetics”: ready for prime time
Handschin, C. (2016) · Pharmacological Research · doi:10.1016/j.phrs.2015.11.009 · Cited by 72 · see citing works
“Ursolic acid was identified in a screen comparing the gene expression pattern of different human settings of muscle atrophy with those of the Connectivity map, a collection of global gene expression data of various compounds in different cell types [74].”
BackgroundDuarte, Y., Márquez‐Miranda, V., Miossec, M. J., & González-Nilo, F. D. (2019) · Wiley Interdisciplinary Reviews Nanomedicine and Nanobiotechnology · doi:10.1002/wnan.1554 · Cited by 75 · see citing works
Ursolic acid stimulates mTORC1 signaling after resistance exercise in rat skeletal muscle
Ogasawara, R., Sato, K., Higashida, K., Nakazato, K., & Fujita, S. (2013) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00302.2013 · Cited by 70 · see citing works
“A recent study based on microarray analysis identified UA as an inhibitor of skeletal muscle atrophy and also, interestingly, revealed that skeletal muscle hypertrophy occurs by daily UA consumption (13).”
BackgroundResultInfluentialBang, H. S., Seo, D. Y., Chung, Y. M., Oh, K.-M., Park, J. J., Arturo, F., Jeong, S.-H., Kim, N., & Han, J. (2014) · The Korean Journal of Physiology & Pharmacology · doi:10.4196/kjpp.2014.18.5.441 · Cited by 69 · see citing works
“Above all, the underlying mechanism of UA is the enhancement or maintenance of skeletal muscle mass and function in vivo and vitro [22,25-27].”
BackgroundUrolithin B, a Newly Identified Regulator of Skeletal Muscle Mass
Rodriguez, J., Pierre, N., Naslain, D., Bontemps, F., Ferreira, D., Priem, F., Deldicque, L., & Francaux, M. (2017) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1002/jcsm.12190 · Cited by 70 · see citing works
HSP90 inhibitor geldanamycin reverts IL-13– and IL-17–induced airway goblet cell metaplasia
Pezzulo, A. A., Tudas, R. A., Stewart, C. G., Buonfiglio, L. G. V., Lindsay, B. D., Taft, P. J., Gansemer, N. D., & Zabner, J. (2019) · Journal of Clinical Investigation · doi:10.1172/jci123524 · Cited by 69 · see citing works
Williams, G. H., Gatt, A. P., Clarke, E. E., Corcoran, J. P. T., Doherty, P., Chambers, D. J., & Ballard, C. G. (2019) · Translational Psychiatry · doi:10.1038/s41398-019-0555-x · Cited by 69 · see citing works
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 · see citing works
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 67 · see citing works
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 69 · see citing works
“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., & Cesari, M. (2019) · Nutrients · doi:10.3390/nu11091991 · Cited by 62 · see citing works
“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 · see citing works
“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 63 · see citing works
“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 64 · see citing works
“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 · see citing works
“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 · see citing works
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 61 · see citing works
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 60 · see citing works
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 · see citing works
“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 34 · see citing works
“[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 61 · see citing works
Web-based drug repurposing tools: a survey
Sam, E., & Athri, P. (2017) · Briefings in Bioinformatics · doi:10.1093/bib/bbx125 · Cited by 58 · see citing works
Hill, M. A., & Gammie, S. C. (2022) · Scientific Reports · doi:10.1038/s41598-022-22179-z · Cited by 56 · see citing works
Novel Intriguing Strategies Attenuating to Sarcopenia
Sakuma, K., & Yamaguchi, A. (2012) · Journal of Aging Research · doi:10.1155/2012/251217 · Cited by 57 · see citing works
“[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 53 · see citing works
Mechanisms of protein balance in skeletal muscle
Anthony, T. G. (2016) · Domestic Animal Endocrinology · doi:10.1016/j.domaniend.2016.02.012 · Cited by 57 · see citing works
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 · see citing works
“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 · see citing works
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 48 · see citing works
“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., Singh, S., & Dabur, R. (2022) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2022.174995 · Cited by 45 · see citing works
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 · see citing works
“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 · see citing works
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 45 · see citing works
“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 · see citing works
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 · see citing works
“, 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 44 · see citing works
“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 · see citing works
“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 41 · see citing works
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 41 · see citing works
“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 · see citing works
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 · see citing works
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 · see citing works
Vilar, S., & Hripcsak, G. M. (2016) · Briefings in Bioinformatics · doi:10.1093/bib/bbw048 · Cited by 40 · see citing works
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 39 · see citing works
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 · see citing works
“…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 38 · see citing works
Zanforlin, E., Zagotto, G., & Ribaudo, G. (2017) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.7b00283 · Cited by 38 · see citing works
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 · see citing works
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 · see citing works
“Furthermore, MuRF1 and Atrogin-1 expression, which are atrophy-related genes, which are atrophy-related genes, are controlled by UA [24,26].”
BackgroundInfluential
- 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 › Nutrition and Health in Aging
- Health Sciences › Medicine › Physiology › 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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