Melatonin prevents mitochondrial dysfunction and insulin resistance in rat skeletal muscle
Abstract
Melatonin has a number of beneficial metabolic actions and reduced levels of melatonin may contribute to type 2 diabetes. The present study investigated the metabolic pathways involved in the effects of melatonin on mitochondrial function and insulin resistance in rat skeletal muscle. The effect of melatonin was tested both in vitro in isolated rats skeletal muscle cells and in vivo using pinealectomized rats (PNX). Insulin resistance was induced in vitro by treating primary rat skeletal muscle cells with palmitic acid for 24 hr. Insulin‐stimulated glucose uptake was reduced by palmitic acid followed by decreased phosphorylation of AKT which was prevented my melatonin. Palmitic acid reduced mitochondrial respiration, genes involved in mitochondrial biogenesis and the levels of tricarboxylic acid cycle intermediates whereas melatonin counteracted all these parameters in insulin‐resistant cells. Melatonin treatment increases CAMK II and p‐CREB but had no effect on p‐AMPK. Silencing of CREB protein by si RNA reduced mitochondrial respiration mimicking the effect of palmitic acid and prevented melatonin‐induced increase in p‐AKT in palmitic acid‐treated cells. PNX rats exhibited mild glucose intolerance, decreased energy expenditure and decreased p‐AKT, mitochondrial respiration, and p‐CREB and PGC‐1 alpha levels in skeletal muscle which were restored by melatonin treatment in PNX rats. In summary, we showed that melatonin could prevent mitochondrial dysfunction and insulin resistance via activation of CREB‐PGC‐1 alpha pathway. Thus, the present work shows that melatonin play an important role in skeletal muscle mitochondrial function which could explain some of the beneficial effects of melatonin in insulin resistance states.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Melatonin provokes the IRS1-PI3K-PKC route to improve glucose absorption in skeletal muscle.
“It also provokes the IRS1-PI3K-PKC route to improve glucose absorption in skeletal muscle. 24”
From Melatonin supplementation improves glycemic hemostasis, lipid profile, and adipokine concentrations of obese women: A double-blind randomized clinical trial (2024) · cites this paper as [24]
Cites
Wu, Z., Puigserver, P., Andersson, U., Zhang, C., Adelmant, G., Mootha, V., Troy, A., Cinti, S., Lowell, B., Scarpulla, R. C., et al. (1999) · Cell · doi:10.1016/s0092-8674(00)80611-x · Cited by 4,139 · see citing works
PGC-1α, SIRT1 and AMPK, an energy sensing network that controls energy expenditure
Cantó, C., & Auwerx, J. (2009) · Current Opinion in Lipidology · doi:10.1097/mol.0b013e328328d0a4 · Cited by 1,624 · see citing works
Analysis of mitochondrial function in situ in permeabilized muscle fibers, tissues and cells
Kuznetsov, A. V., Veksler, V., Gellerich, F. N., Saks, V. A., Margreiter, R., & Kunz, W. S. (2008) · Nature Protocols · doi:10.1038/nprot.2008.61 · Cited by 805 · see citing works
Variants in MTNR1B influence fasting glucose levels
Prokopenko, I., Langenberg, C., Florez, J. C., Saxena, R., Soranzo, N., Þorleifsson, G., Loos, R. J. F., Manning, A. K., Jackson, A., Aulchenko, Y. S., et al. (2008) · Nature Genetics · doi:10.1038/ng.290 · Cited by 743 · see citing works
Melatonin, energy metabolism, and obesity: a review
Cipolla‐Neto, J., do Amaral, F. G., Afeche, S. C., Tan, D. X., & Reiter, R. J. (2014) · Journal of Pineal Research · doi:10.1111/jpi.12137 · Cited by 588 · see citing works
Self-citationTan, D. ‐., Manchester, L. C., Fuentes‐Broto, L., Paredes, S. D., & Reiter, R. J. (2010) · Obesity Reviews · doi:10.1111/j.1467-789x.2010.00756.x · Cited by 343 · see citing works
Role of PGC-1α Signaling in Skeletal Muscle Health and Disease
Kang, C., & Li Ji, L. (2012) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2012.06738.x · Cited by 291 · see citing works
Melatonin Reduces Body Weight Gain in Sprague Dawley Rats with Diet-Induced Obesity
Prunet‐Marcassus, B., Desbazeille, M., Bros, A., Louche, K., Delagrange, P., Renard, P., Casteilla, L., & Pénicaud, L. (2003) · Endocrinology · doi:10.1210/en.2003-0693 · Cited by 281 · see citing works
López, A., García, J. A., Escames, G., Venegas, C., Ortiz, F., López, L. C., & Acuña-Castroviejo, D. (2008) · Journal of Pineal Research · doi:10.1111/j.1600-079x.2008.00647.x · Cited by 277 · see citing works
Zechner, C., Lai, L., Zechner, J. F., Geng, T., Yan, Z., Rumsey, J. W., Collia, D., Chen, Z., Wozniak, D. F., Leone, T. C., et al. (2010) · Cell Metabolism · doi:10.1016/j.cmet.2010.11.008 · Cited by 274 · cited 1× · see citing works
“The recovery of PGC-1 alpha by melatonin in the presence of palmitic acid could also play a role in the recovery of mitochondrial respiration because PGC-1 alpha promotes both oxidative phosphorylation-linked and uncoupling-linked respiration in differentiated myotubes oxidative capacity in skeletal muscle cells [21,…”
BackgroundErren, T. C., & Reiter, R. J. (2009) · Journal of Pineal Research · doi:10.1111/j.1600-079x.2009.00665.x · Cited by 250 · see citing works
Melatonin-mitochondria Interplay in Health and Disease
Acuña-Castroviejo, D., López, L. C., Escames, G., López, A., García, J. A., & Reiter, R. J. (2011) · Current Topics in Medicinal Chemistry · doi:10.2174/156802611794863517 · Cited by 245 · see citing works
Pinealectomy causes glucose intolerance and decreases adipose cell responsiveness to insulin in rats
Lima, F. B., Machado, U. F., Bartol, I., Seraphim, P. M., Sumida, D. H., de Moraes, S. M. F., Hell, N. S., Okamoto, M. M., Saad, M. J. A., Carvalho, C. R. D. O., et al. (1998) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1998.275.6.e934 · Cited by 220 · see citing works
Self-citationPeschke, E., Frese, T., Chankiewitz, E., Peschke, D., Preiß, U., Schneyer, U., Spessert, R., & Mühlbauer, E. (2005) · Journal of Pineal Research · doi:10.1111/j.1600-079x.2005.00287.x · Cited by 197 · see citing works
Interacting epidemics? Sleep curtailment, insulin resistance, and obesity
Lucassen, E. A., Rother, K. I., & Cizza, G. (2012) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2012.06655.x · Cited by 191 · see citing works
Sartori, C. S., Dessen, P., Mathieu, C., Monney, A., Bloch, J., NICOD, P. H., Scherrer, U., & Duplain, H. (2009) · Endocrinology · doi:10.1210/en.2009-0425 · Cited by 164 · see citing works
Agil, A., Reiter, R. J., Jiménez‐Aranda, A., Arias, R. I., Navarro‐Alarcón, M., Marchal, J. A., Adem, A., & Fernández‐Vázquez, G. (2012) · Journal of Pineal Research · doi:10.1111/jpi.12012 · Cited by 159 · see citing works
Coll, T., Jové, M., Rodríguez‐Calvo, R., Eyre, E., Palomer, X., Sánchez, R. M., Merlos, M., Laguna, J. C., & Vázquez‐Carrera, M. (2006) · Diabetes · doi:10.2337/db05-1494 · Cited by 149 · see citing works
Zhang, L., Zhang, H., Liang, X., Zhang, H., Zhang, T., & Liu, F. (2013) · Behavioural Brain Research · doi:10.1016/j.bbr.2013.07.051 · Cited by 143 · see citing works
Ha, E., Yim, S., Chung, J., Yoon, K., Kang, I., Cho, Y. H., & Baik, H. H. (2006) · Journal of Pineal Research · doi:10.1111/j.1600-079x.2006.00334.x · Cited by 124 · see citing works
Nogueira, T. C. A., Lellis‐Santos, C., de Jesus, D. S., Taneda, M., Rodrigues, S. C., do Amaral, F. G., Lopes, A. M. S., Cipolla‐Neto, J., Bordin, S. A., & Anhê, G. F. (2011) · Endocrinology · doi:10.1210/en.2010-1088 · Cited by 122 · see citing works
Self-citationMelatonin improves metabolic syndrome induced by high fructose intake in rats
Kitagawa, A., Ohta, Y., & Ohashi, K. (2012) · Journal of Pineal Research · doi:10.1111/j.1600-079x.2011.00955.x · Cited by 116 · see citing works
de Araújo, M. C. P. M., Haber, E. P., Carpinelli, Â. R., & Cipolla‐Neto, J. (2002) · Journal of Pineal Research · doi:10.1034/j.1600-079x.2002.02925.x · Cited by 116 · see citing works
Self-citationNishida, S., Segawa, T., Murai, I., & Nakagawa, S. (2002) · Journal of Pineal Research · doi:10.1034/j.1600-079x.2002.10797.x · Cited by 115 · see citing works
Melatonin and the Metabolic Syndrome: Physiopathologic and Therapeutical Implications
Cardinali, D. P., Cano, P., Jiménez‐Ortega, V., & Esquifino, A. I. (2011) · Neuroendocrinology · doi:10.1159/000324699 · Cited by 110 · see citing works
Mäntele, S., Otway, D. T., Middleton, B., Bretschneider, S., Wright, J., Robertson, M. D., Skene, D. J., & Johnston, J. D. (2012) · PLoS ONE · doi:10.1371/journal.pone.0037123 · Cited by 99 · see citing works
Melatonin improves insulin sensitivity independently of weight loss in old obese rats
Zanuto, R., de Siqueira-Filho, M. A., Caperuto, L. C., Bacurau, R. F. P., Hirata, E., Garcia, R. A. P., do Amaral, F. G., Marçal, A. C., Ribeiro, L. M., Camporez, J. P., et al. (2013) · Journal of Pineal Research · doi:10.1111/jpi.12056 · Cited by 98 · see citing works
Self-citationMelatonin synthesis impairment as a new deleterious outcome of diabetes‐derived hyperglycemia
do Amaral, F. G., Turati, A. D. O., Barone, M. T. U., Scialfa, J. H., Buonfiglio, D. D. C., Peres, R., Garcia, R. A. P., Afeche, S. C., Lima, L. D. S., Scavone, C., et al. (2014) · Journal of Pineal Research · doi:10.1111/jpi.12144 · Cited by 83 · see citing works
Self-citationDifferent Sensitivity of Glucose and Amino Acid Metabolism to Insulin in NIDDM
Luzi, L., Petrides, A. S., & Fronzo, R. A. D. (1993) · Diabetes · doi:10.2337/diab.42.12.1868 · Cited by 78 · see citing works
Melatonin reduces body weight gain and increases nocturnal activity in male Wistar rats.
Terrón, M., Delgado-Adámez, J., Pariente, J., Barriga, C., Paredes, S., & Rodríguez, A. B. (2013) · Physiology and Behavior · doi:10.1016/j.physbeh.2013.04.006 · Cited by 77 · see citing works
Melatonin–insulin interactions in patients with metabolic syndrome
Robeva, R. N., Кirilov, G., Tomova, A., & Kumanov, P. (2007) · Journal of Pineal Research · doi:10.1111/j.1600-079x.2007.00527.x · Cited by 76 · see citing works
Fukunaga, K., Horikawa, K., Shibata, S., Takeuchi, Y., & Miyamoto, E. (2002) · Journal of Neuroscience Research · doi:10.1002/jnr.10400 · Cited by 72 · see citing works
Melatonin restores muscle regeneration and enhances muscle function after crush injury in rats
Stratos, I., Richter, N., Rotter, R., Li, Z., Zechner, D., Mittlmeier, T., & Vollmar, B. (2011) · Journal of Pineal Research · doi:10.1111/j.1600-079x.2011.00919.x · Cited by 70 · see citing works
Rodríguez, M. I., Escames, G., López, L. C., García, J. A. G., Ortiz, F., López, A., & Acuña-Castroviejo, D. (2007) · Journal of Endocrinology · doi:10.1677/joe-07-0260 · Cited by 70 · see citing works
Melatonin restores the mitochondrial production of ATP in septic mice.
López, L. C., Escames, G., Ortiz, F., Ros, E., & Acuña-Castroviejo, D. (2006) · PubMed · Cited by 69 · see citing works
Light/Dark Cycle-dependent Metabolic Changes in Adipose Tissue of Pinealectomized Rats
Alonso‐Vale, M. I. C., Borges‐Silva, C. N., Anhê, G. F., Andreotti, S., Machado, M. A., Cipolla‐Neto, J., & Lima, F. B. (2004) · Hormone and Metabolic Research · doi:10.1055/s-2004-825723 · Cited by 64 · see citing works
Self-citationKong, P., Byun, J.-S., Lim, S.-Y., Lee, J.-J., Hong, S. J., Kwon, K.-J., & Kim, S. (2008) · Korean Journal of Physiology and Pharmacology · doi:10.4196/kjpp.2008.12.2.37 · Cited by 63 · see citing works
Yang, C., Aye, C. C., Li, X., Díaz‐Ramos, A., Antonio Zorzano, A., & Mora, S. (2012) · Bioscience Reports · doi:10.1042/bsr20120034 · Cited by 58 · see citing works
de Oliveira, A. C., Andreotti, S., de Farias, T. D. S. M., Torres‐Leal, F. L., de Proença, A. R. G., Campaña, A. B., de Souza, A. H., Sertié, R. A. L., Carpinelli, Â. R., Cipolla‐Neto, J., et al. (2012) · Endocrinology · doi:10.1210/en.2011-1675 · Cited by 55 · see citing works
Self-citationBorges‐Silva, C. N., Fonseca‐Alaniz, M. H., Alonso‐Vale, M. I. C., Takada, J., Andreotti, S., Peres, S. B., Cipolla‐Neto, J., Pithon‐Curi, T. C., & Lima, F. B. (2005) · Journal of Pineal Research · doi:10.1111/j.1600-079x.2005.00241.x · Cited by 53 · see citing works
Self-citationBarbosa, M. R., Sampaio, I. H., Teodoro, B. G., Sousa, T. A. E., Zoppi, C. C., Queiroz, A. L., Passos, M. A., Alberici, L. C., Teixeira, F. R., Manfiolli, A. O., et al. (2013) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2013.04.029 · Cited by 52 · see citing works
Self-citationMartins, E. R., Fernandes, L. C., Bartol, I., et al. (1998) · Journal of Neuroimmunology · doi:10.1016/s0165-5728(97)00191-4 · Cited by 49 · see citing works
Tongjaroenbuangam, W., Ruksee, N., Mahanam, T., & Govitrapong, P. (2013) · Neurochemistry International · doi:10.1016/j.neuint.2013.08.011 · Cited by 46 · see citing works
Qiu, Y., Wu, L., Wang, B., et al. (2007) · Spine · doi:10.1097/01.brs.0000257536.34431.96 · Cited by 31 · see citing works
Qiu, Y., Wu, L., Wang, B., et al. (2006) · PubMed · Cited by 2 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Zhou, H., Zhang, Y., Hu, S., Shi, C., Zhu, P., Ma, Q., Jin, Q., Cao, F., Tian, F., & Chen, Y. (2017) · Journal of Pineal Research · doi:10.1111/jpi.12413 · Cited by 378 · see citing works
Skeletal muscle insulin resistance: role of mitochondria and other ROS sources
Di Meo, S., Iossa, S., & Venditti, P. (2017) · Journal of Endocrinology · doi:10.1530/joe-16-0598 · Cited by 282 · see citing works
Melatonin prevents obesity through modulation of gut microbiota in mice
Xu, P., Wang, J., Hong, F., Wang, S., Jin, X., Xue, T., Jia, L., & Zhai, Y. (2017) · Journal of Pineal Research · doi:10.1111/jpi.12399 · Cited by 281 · see citing works
Increased melatonin signaling is a risk factor for type 2 diabetes
Tuomi, T., Nagorny, C. L. F., Singh, P., Bennet, H., Yu, Q., Alenkvist, I., Isomaa, B., Östman, B., Söderström, J., Pesonen, A.-K., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.04.009 · Cited by 262 · see citing works
Ahuja, P., Ng, C. F., Pang, B. P. S., Chan, W. S., Tse, M. C. L., Bi, X., Kwan, H.-L. R., Brobst, D., Herlea-Pana, O., Yang, X., et al. (2022) · Autophagy · doi:10.1080/15548627.2021.1985257 · Cited by 116 · see citing works
Farias, T. D. S. M. D., Cruz, M. M., Sa, R. C. D. C. D., Severi, I., Perugini, J., Senzacqua, M., Cerutti, S. M., Giordano, A., Cinti, S., & Alonso-Vale, M. I. C. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00750 · Cited by 74 · see citing works
Sayed, R. K. A., Fernández-Ortiz, M., Diaz-Casado, M. E., Rusanova, I., Rahim, I., Escames, G., López, L. C., Mokhtar, D. M., & Acuña-Castroviejo, D. (2018) · The Journals of Gerontology Series A · doi:10.1093/gerona/gly059 · Cited by 45 · see citing works
Mesri Alamdari, N., Namazi Shabestari, A., Najafipour, F., & Mirmazhari, A. (2024) · Biomedicine Advances · doi:10.34172/bma.05 · Cited by 4 · see citing works
“Our results showed a remarkable decrement in insulin concentrations and HOMA-IR, but no notable following adjustments were done for confounders which are consistent with former animal 9,11,24 and clinical research.”
- Authors
- Teodoro, B. G., Baraldi, F. G., Sampaio, I. H., Bomfim, L. H. M., Queiroz, A. L., Passos, M. A., Carneiro, E. M., Alberici, L. C., Gomis, R., Amaral, F. G., Cipolla‐Neto, J., Araújo, M. B., Lima, T., Akira Uyemura, S., Silveira, L. R., & Vieira, E.
- Affiliations
- Federal Institute of São Paulo (BR)
- Department of Biochemistry and Immunology Faculty of Medicine of Ribeirão Preto University of Sao Paulo (USP) Ribeirão Preto Brazil
- Universidade de São Paulo (BR)
- Universidade Estadual de Campinas (UNICAMP) (BR)
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) Barcelona Spain
- Núcleo Pesquisas em Produtos Naturais e Sintéticos (NPPNS) Department of Physics and Chemistry Faculty of Pharmaceutical Sciences of Ribeirão Preto University of São Paulo Ribeirão Preto Brazil
- Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas (ES)
- Corresponding author
- Silveira, Leonardo R.
- Vieira, Elaine
- ORCID
- Venue
- Journal of Pineal Research
- Publisher
- Wiley
- Published
- 2014-07-22
- Volume
- 57
- Issue
- 2
- Pages
- 155-167
- ISSN
- 0742-3098 (ISSN-L)
- 1600-079X
- OpenAlex
- W1987975373
- Cited by
- 106
- References
- 45
- Citations by year
- 2026: 2 · 2025: 8 · 2024: 6 · 2023: 10 · 2022: 12 · 2021: 10 · 2020: 7 · 2019: 2 · 2018: 7 · 2017: 14 · 2016: 15 · 2015: 11 · 2014: 1
- FWCI
- 6.66
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Pineal Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Fundação de Amparo à Pesquisa do estado de São Paulo - FAPESP
- Conselho Nacional de Desenvolvimento Científico e Tecnológico - CNPq
- Spanish Ministry of Science and Innovation (2010-19527)
- Government of Catalonia (1426)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- melatonin, insulin resistance, skeletal muscle, mitochondrial dysfunction, type 2 diabetes, CREB, PGC-1α, Akt phosphorylation, palmitic acid, mitochondrial respiration, mitochondrial biogenesis, TCA cycle, pinealectomy, glucose uptake
- MeSH terms
- Animals, Cells, Cultured, Citric Acid Cycle, Glucose Tolerance Test, Insulin Resistance, Male, Melatonin, Oxygen Consumption, Signal Transduction, Rats, Wistar, Muscle, Skeletal, Rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
