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Muscle insulin sensitivity and glucose metabolism are controlled by the intrinsic muscle clock
Open accessAbstract
Circadian rhythms control metabolism and energy homeostasis, but the role of the skeletal muscle clock has never been explored. We generated conditional and inducible mouse lines with muscle-specific ablation of the core clock gene Bmal1. Skeletal muscles from these mice showed impaired insulin-stimulated glucose uptake with reduced protein levels of GLUT4, the insulin-dependent glucose transporter, and TBC1D1, a Rab-GTPase involved in GLUT4 translocation. Pyruvate dehydrogenase (PDH) activity was also reduced due to altered expression of circadian genes Pdk4 and Pdp1, coding for PDH kinase and phosphatase, respectively. PDH inhibition leads to reduced glucose oxidation and diversion of glycolytic intermediates to alternative metabolic pathways, as revealed by metabolome analysis. The impaired glucose metabolism induced by muscle-specific Bmal1 knockout suggests that a major physiological role of the muscle clock is to prepare for the transition from the rest/fasting phase to the active/feeding phase, when glucose becomes the predominant fuel for skeletal muscle.
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“Disruption of the muscle clock has also been shown to have significant impact on glucose intolerance and insulin resistance with very small changes in fiber types (Dyar et al., 2014; Schroder et al., 2015; Harfmann et al., 2016).”
From Myosteatosis in the Context of Skeletal Muscle Function Deficit: An Interdisciplinary Workshop at the National Institute on Aging (2020) · cites this paper as Dyar et al., 2014
In the citing paper
“In addition, prolonged loss of Bmal1 function was also associated with increased fibrosis within the muscle.”
From Myosteatosis in the Context of Skeletal Muscle Function Deficit: An Interdisciplinary Workshop at the National Institute on Aging (2020) · cites this paper as Dyar et al., 2014
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“These animals showed reduced protein levels of GLUT4 and an impaired insulin-stimulated glucose uptake in their muscles.”
From Circadian control of glucose metabolism (2014) · cites this paper as [153]
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“For example, the hepatic clock regulates fasting glycemic control and glucose clearance (8), the pancreatic clock regulates insulin secretion and its response to glucose (9-11), the adipose clock regulates lipid storage and mobilization (12,13), and the skeletal muscle clock regulates glucose uptake and metabolism (14).”
From Circadian rhythms, metabolism, and chrononutrition in rodents and humans (2016) · cites this paper as [14]
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Mop3 is an essential component of the master circadian pacemaker in mammals.
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BackgroundDisruption of the clock components CLOCK and BMAL1 leads to hypoinsulinaemia and diabetes
Marcheva, B., Ramsey, K. M., Buhr, E. D., Kobayashi, Y., Su, H., Ko, C. H., Ivanova, G., Omura, C., Mo, S., Vitaterna, M. H., et al. (2010) · Nature · doi:10.1038/nature09253 · Cited by 1,525 · cited 1×
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“What is the cause of the altered response to insulin in muscles from Bmal1 mKO mice? The canonical insulin signaling pathway is apparently not responsible for this change, since AKT phosphorylation, which is reduced in obesity and diabetes [60], was unchanged, and was similarly increased by insulin in muscles from con…”
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Items 101–200 of 458
Physiological links between circadian rhythms, metabolism and nutrition
Johnston, J. D. (2014) · Experimental Physiology · doi:10.1113/expphysiol.2014.078295 · Cited by 59
“Skeletal muscle-specific clock disruption leads to decreased insulin-dependent glucose uptake in skeletal muscles and also altered muscle glucose metabolism (Dyar et al. 2014).”
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Emerging Insight Into the Role of Circadian Clock Gene BMAL1 in Cellular Senescence
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Liver and muscle circadian clocks cooperate to support glucose tolerance in mice
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“Genes involved in glycolysis, gluconeogenesis, glucose oxidation, and related pathways, are driven daily by clock transcription factors, including Bmal1.(15,27,31,32) This basal transcriptional state, which results in a partial ability to metabolize glucose, is further shaped by the interaction between clock transcrip…”
BackgroundTicking for Metabolic Health: The Skeletal‐Muscle Clocks
Gutierrez‐Monreal, M. A., Harmsen, J., Schrauwen, P., & Esser, K. A. (2020) · Obesity · doi:10.1002/oby.22826 · Cited by 63
Skeletal muscle functions around the clock
Mayeuf-Louchart, A., Staels, B., & Duez, H. (2015) · Diabetes Obesity and Metabolism · doi:10.1111/dom.12517 · Cited by 60
“This appears to be due to reduced expression of Tbc1d1, a Rab-GTPase member implicated in the GLUT4-translocation process [26].”
BackgroundMethodInfluentialChrononutrition and Polyphenols: Roles and Diseases
Arola‐Arnal, A., Cruz‐Carrión, Á., Torres‐Fuentes, C., Ávila‐Román, J., Aragonès, G., Mulero, M., Bravo, F. I., Muguerza, B., Arola, L., & Suárez, M. (2019) · Nutrients · doi:10.3390/nu11112602 · Cited by 61
Contraction influences Per2 gene expression in skeletal muscle through a calcium‐dependent pathway
Small, L., Altıntaş, A., Laker, R. C., Ehrlich, A. M., Pattamaprapanont, P., Villarroel, J., Pillon, N. J., Zierath, J. R., & Barrès, R. (2020) · The Journal of Physiology · doi:10.1113/jp280428 · Cited by 57
“As a result, impaired physiological responses such as altered glucose handling occur (Dyar et al. 2014; Harfmann et al. 2016).”
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“In mice e.g. it has been shown that rhythmic insulin action 41 depends on the clock gene BMAL1 25,41 .”
InfluentialCircadian and Sleep Metabolomics Across Species
Malik, D. M., Paschos, G. K., Sehgal, A., & Weljie, A. M. (2020) · Journal of Molecular Biology · doi:10.1016/j.jmb.2020.04.027 · Cited by 54
Muscle-secreted neurturin couples myofiber oxidative metabolism and slow motor neuron identity
Correia, J. C., Kelahmetoglu, Y., Jannig, P. R., Schweingruber, C., Shvaikovskaya, D., Zhengye, L., Červenka, I., Khan, N. P., Stec, M. J., Oliveira, M. M. S., et al. (2021) · Cell Metabolism · doi:10.1016/j.cmet.2021.09.003 · Cited by 50
Jakubowicz, D. J., Wainstein, J., Tsameret, S., & Landau, Z. (2021) · Nutrients · doi:10.3390/nu13051558 · Cited by 57
Emerging concepts on the role of epigenetics in the relationships between nutrition and health
Stover, P. J., James, W. P. T., Krook, A., & Garza, C. (2018) · Journal of Internal Medicine · doi:10.1111/joim.12768 · Cited by 58
Re-Setting the Circadian Clock Using Exercise against Sarcopenia
Choi, Y., Cho, J., No, M., Heo, J., Cho, E., Chang, E., Park, D., Kang, J., & Kwak, H. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21093106 · Cited by 56
Basse, A. L., Dalbram, E., Larsson, L., Gerhart-Hines, Z., Zierath, J. R., & Treebak, J. T. (2018) · Frontiers in Physiology · doi:10.3389/fphys.2018.01198 · Cited by 52
Vitale, J. A., Bonato, M., Torre, A. L., & Banfi, G. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20174318 · Cited by 53
“In addition, GLUT4 glucose transporter levels, responsible for glucose uptake, were significantly lower, whereas the insulin signalling pathway was not affected [61].”
BackgroundMaier, G., Delezie, J., Westermark, P. O., Santos, G., Ritz, D., & Handschin, C. (2021) · The Journal of Physiology · doi:10.1113/jp281535 · Cited by 52
“Future experiments with inducible, skeletal muscle-specific knockout models for clock components might thus help to clarify the contribution of this system to muscle metabolism and functionality if not confounded by other consequences of such dysregulations (Dyar et al .”
Principles for circadian orchestration of metabolic pathways
Thurley, K., Herbst, C., Wesener, F., Koller, B., Wallach, T. E., Maier, B., Kramer, A., & Westermark, P. O. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1613103114 · Cited by 54
“(18) (separate data for soleus and tibialis)] of circadian gene expression in muscle metabolism.”
BackgroundMethodInfluentialSarcopenia and cachexia: molecular mechanisms and therapeutic interventions
Wang, T., Zhou, D., & Hong, Z. (2025) · MedComm · doi:10.1002/mco2.70030 · Cited by 46
Circadian Metabolomics in Time and Space
Dyar, K. A. (2017) · Frontiers in Neuroscience · doi:10.3389/fnins.2017.00369 · Cited by 50
“For example, while muscle-specific Bmal1 knockout mice (mKO) display reduced muscle insulin sensitivity and impaired muscle glucose oxidation compared to wildtype littermates, robust circadian cycles of most glycolytic intermediates are apparently normal (Dyar et al., 2014).”
BackgroundThe role of exercise-induced peripheral factors in sleep regulation
Tan, X. W., van Egmond, L. T., Cedernaes, J., & Benedict, C. (2020) · Molecular Metabolism · doi:10.1016/j.molmet.2020.101096 · Cited by 52
“For instance, using both constitutive and inducible muscle-specific Bmal1 knockout models, insulin-stimulated glucose uptake was found to be impaired in the skeletal muscles from muscle-specific Bmal1 knockout mice, likely due to reduced transcript and protein levels of glucose transporter 4 (Glut4), the insulin-depen…”
BackgroundMorris, H., Gonçalves, C. F., Dudek, M., Hoyland, J. A., & Meng, Q. (2021) · Annals of the Rheumatic Diseases · doi:10.1136/annrheumdis-2020-219515 · Cited by 49
Differential Phasing between Circadian Clocks in the Brain and Peripheral Organs in Humans
Hughey, J., & Butte, A. J. (2016) · Journal of Biological Rhythms · doi:10.1177/0748730416668049 · Cited by 45
“For all other datasets (Bray et al., 2008; Dyar et al., 2014; Haspel et al., 2014; Hughes et al., 2009; Zhang et al., 2014; Boorman et al., 2005; Almon et al., 2008a; Almon et al., 2008b), we analyzed the publicly available microarray data identically to how we analyzed the data from human blood…”
MethodThe importance of being rhythmic: Living in harmony with your body clocks
Dibner, C. (2019) · Acta Physiologica · doi:10.1111/apha.13281 · Cited by 52
Do not neglect the role of circadian rhythm in muscle atrophy
Zhang, H., Liang, J., & Chen, N. (2020) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101155 · Cited by 47
Hasan, N., Nagata, N., Morishige, J., Islam, M. T., Jing, Z., Harada, K., Mieda, M., Ono, M., Fujiwara, H., Daikoku, T., et al. (2021) · Molecular Metabolism · doi:10.1016/j.molmet.2021.101202 · Cited by 43
“[21] demonstrated that the muscle clock controls glucose uptake and metabolism, and our group [22] revealed that the hepatic clock regulates the daily rhythms of gluconeogenesis and fasting glucose levels using muscle- and liverspecific Bmal1 KO mice, respectively.”
BackgroundDaytime-restricted feeding enhances running endurance without prior exercise in mice
Xin, H., Huang, R., Zhou, M., Chen, J., Zhang, J., Zhou, T., Ji, S., Liu, X., Tian, H., Lam, S. M., et al. (2023) · Nature Metabolism · doi:10.1038/s42255-023-00826-7 · Cited by 46
BMAL1 drives muscle repair through control of hypoxic NAD+ regeneration in satellite cellsPreprint
Zhu, P., Hamlish, N. X., Thakkar, A. V., Steffeck, A. W. T., Rendleman, E. J., Khan, N. H., Waldeck, N. J., DeVilbiss, A., Martin-Sandoval, M. S., Mathews, T. P., et al. (2022) · Genes & Development · doi:10.1101/gad.349066.121 · Cited by 46
“For example, the molecular clock in mature skeletal muscle controls the rhythmic expression of metabolic proteins to adapt to the daily changes in muscle metabolic demand imposed from feeding and movement (McCarthy et al. 2007; Dyar et al. 2014; Harfmann et al. 2016).”
Time for Exercise? Exercise and Its Influence on the Skeletal Muscle Clock
Martin, R. A., & Esser, K. A. (2022) · Journal of Biological Rhythms · doi:10.1177/07487304221122662 · Cited by 45
“Consistent with the GTT results, muscles in the muscle-specific Bmal1–/– mice have lower mRNA and protein levels of Glut4 (Slc2a4) as well as reduced glucose uptake stimulated through insulin-dependent or independent mechanisms (Dyar et al., 2014; Harfmann et al., 2016).”
BackgroundResultTargeting of the circadian clock via CK1δ/ε to improve glucose homeostasis in obesity
Cunningham, P. S., Ahern, S. A., Smith, L. C., Santos, C. S. D. S., Wager, T. T., & Bechtold, D. A. (2016) · Scientific Reports · doi:10.1038/srep29983 · Cited by 42
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Knudsen, J. G., Gudiksen, A., Bertholdt, L., Overby, P., Villesen, I., Schwartz, C. L., & Pilegaard, H. (2017) · PLOS ONE · doi:10.1371/journal.pone.0189301 · Cited by 42
“This possibility is in accordance with the previous observations that PDHa activity indeed oscillates in a circadian manner [36, 37].”
ResultMetabolic Implications of Circadian–HIF Crosstalk
Peek, C. B. (2020) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2020.02.008 · Cited by 44
Masi, D., Spoltore, M. E., Rossetti, R., Watanabe, M., Tozzi, R., Caputi, A., Risi, R., Balena, A., Gandini, O., Mariani, S., et al. (2022) · Nutrients · doi:10.3390/nu14071410 · Cited by 45
“Specifically, the pancreatic clock regulates insulin secretion in relation to meals [9], the hepatic clock regulates glycemic control under fasting conditions [10], the adipose tissue clock regulates lipid metabolism [11], while the skeletal muscle clock regulates glucose metabolism [12].”
BackgroundEpigenetic regulation of skeletal muscle metabolism
Howlett, K. F., & McGee, S. L. (2016) · Clinical Science · doi:10.1042/cs20160115 · Cited by 40
Clocking In, Working Out: Circadian Regulation of Exercise Physiology
Duglan, D., & Lamia, K. A. (2019) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2019.04.003 · Cited by 43
“These changes are accompanied by decreased muscle force generation, despite only modest changes in fiber type distribution [53, 60, 61].”
Backgroundde Goede, P., Foppen, E., Ritsema, W. I. G. R., Korpel, N. L., Yi, C., & Kalsbeek, A. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00554 · Cited by 41
“Moreover, TBC1D1, a protein that regulates translocation of GLUT4 to the cell membrane has consistently been shown to be expressed rhythmically on both the mRNA and protein level, as well as displaying rhythmic phosphorylation statuses (19, 20).”
BackgroundAlmeida, S., Madalena Chaves, A., & Delaunay, F. (2019) · Journal of Theoretical Biology · doi:10.1016/j.jtbi.2019.110015 · Cited by 37
Daily running enhances molecular and physiological circadian rhythms in skeletal muscle
Casanova-Vallve, N., Duglan, D., Vaughan, M. E., Pariollaud, M., Handzlik, M. K., Fan, W., Yu, R. T., Liddle, C., Downes, M., Delezie, J., et al. (2022) · Molecular Metabolism · doi:10.1016/j.molmet.2022.101504 · Cited by 42
The central clock suffices to drive the majority of circulatory metabolic rhythms
Petrus, P., Smith, J. G., Koronowski, K. B., Chen, S., Sato, T., Greco, C. M., Mortimer, T., Welz, P.-S., Zinna, V. M., Shimaji, K., et al. (2022) · Science Advances · doi:10.1126/sciadv.abo2896 · Cited by 36
“Although the hepatic and muscle clocks alone cannot drive systemic oscillations of carbohydrate metabolites, they are necessary to buffer these rhythms (19, 20).”
BackgroundMorán‐Ramos, S., Báez‐Ruíz, A., Buijs, R. M., & Escobar, C. (2016) · Nutrition Research Reviews · doi:10.1017/s095442241600010x · Cited by 37
Interplay of central and peripheral circadian clocks in energy metabolism regulation
Kolbe, I., Brehm, N., & Oster, H. (2018) · Journal of Neuroendocrinology · doi:10.1111/jne.12659 · Cited by 38
Circadian regulation of muscle growth independent of locomotor activity
Kelu, J. J., Pipalia, T. G., & Hughes, S. M. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2012450117 · Cited by 35
Brain–body communication in metabolic control
Furlan, A., & Petrus, P. (2023) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2023.08.014 · Cited by 34
Lee, K. M., Chand, K. K., Hammond, L. A., Lavidis, N. A., & Noakes, P. G. (2017) · Aging · doi:10.18632/aging.101198 · Cited by 36
“The remaining unstained fibres were grouped as Type IIX, as noted by other researchers [54, 55].”
BackgroundMethodDalbram, E., Basse, A. L., Zierath, J. R., & Treebak, J. T. (2019) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00737.2018 · Cited by 37
“Furthermore, mice with a liver-specific deletion of Bmal1 exhibit decreased insulin tolerance (36), whereas skeletal muscle-specific ablation of Bmal1 impairs insulin-stimulated skeletal muscle glucose uptake and whole body glucose tolerance (11).”
BackgroundCavieres-Lepe, J., & Ewer, J. (2021) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2021.666673 · Cited by 40
The molecular clock as a metabolic rheostat
Perelis, M., Ramsey, K. M., & Bass, J. T. (2015) · Diabetes Obesity and Metabolism · doi:10.1111/dom.12521 · Cited by 36
“Although skeletal muscle ablation of the clock has been achieved in our group and others, the biochemical pathways through which clock abrogation impairs oxidative capacity remain largely unknown [48].”
BackgroundRev‐erbα and the circadian transcriptional regulation of metabolism
Gerhart‐Hines, Z., & Lazar, M. A. (2015) · Diabetes Obesity and Metabolism · doi:10.1111/dom.12510 · Cited by 37
“The activator, BMAL1, modulates the switch to carbohydrate utilization prior to arousal from sleep [33], whereas Rev-erbα functions in the control of lipid oxidation [30].”
BackgroundCircadian control of metabolism and pathological consequences of clock perturbations
Mayeuf-Louchart, A., Zecchin, M., Staels, B., & Duez, H. (2017) · Biochimie · doi:10.1016/j.biochi.2017.07.017 · Cited by 37
de Goede, P., Wüst, R. C. I., Schomakers, B. V., Denis, S. W., Vaz, F. M., Pras‐Raves, M. L., van Weeghel, M., Yi, C., Kalsbeek, A., & Houtkooper, R. H. (2022) · The FASEB Journal · doi:10.1096/fj.202100707r · Cited by 36
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“Satellite cell-specific knock out of the enzyme Dicer leads to defective muscle regeneration and premature muscle wasting suggesting that miRNAs may play a pivotal role in maintaining satellite cell potential in adulthood (Cheung et al. 2012).”
BackgroundInfluentialLack of miR-378 attenuates muscular dystrophy in mdx mice
Podkalicka, P., Mucha, O., Bronisz-Budzyńska, I., Kozakowska, M., Pietraszek‐Gremplewicz, K., Cetnarowska, A., Głowniak-Kwitek, U., Bukowska-Straková, K., Cieśla, M., Kulecka, M., et al. (2020) · JCI Insight · doi:10.1172/jci.insight.135576 · Cited by 34
“Immunofluorescent staining of different muscle fiber types was performed as described by Dyar et al. (72).”
Cryptochromes Suppress HIF1α in Muscles
Vaughan, M. E., Wallace, M., Handzlik, M. K., Chan, A. B., Metallo, C. M., & Lamia, K. A. (2020) · iScience · doi:10.1016/j.isci.2020.101338 · Cited by 33
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Circadian NAD(P)(H) cycles in cell metabolism
Levine, D. C., Ramsey, K. M., & Bass, J. T. (2021) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2021.07.008 · Cited by 33
Role of Circadian Transcription Factor Rev-Erb in Metabolism and Tissue Fibrosis
Raza, G. S., Sodum, N., Kaya, Y., & Herzig, K. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232112954 · Cited by 35
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“The central circadian factor BMAL1 regulates the expression rhythms of glucose transporter carriers through transcriptional, translational and feedback regulation [67].”
Viggars, M. R., Berko, H. E., Hesketh, S. J., Wolff, C. A., Gutierrez‐Monreal, M. A., Martin, R. A., Jennings, I. G., Huo, Z., & Esser, K. A. (2024) · Molecular Metabolism · doi:10.1016/j.molmet.2024.101980 · Cited by 33
“Circadian transcription factors and their autoregulatory transcription-translation feedback loops (TTFL) regulate skeletal muscle homeostasis through both transcriptional and epigenetic regulation [1 e 3].”
BackgroundRiley, L. A., & Esser, K. A. (2017) · Current Osteoporosis Reports · doi:10.1007/s11914-017-0363-2 · Cited by 35
Circadian mRNA expression: insights from modeling and transcriptomics
Lück, S., & Westermark, P. O. (2015) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-015-2072-2 · Cited by 33
“Also in mouse skeletal muscle, widespread circadian rhythms in metabolite levels were found [94]; this study is also noteworthy since it paired a metabolome and a transcriptome analysis.”
Wada, T., Ichihashi, Y., Suzuki, E., Kosuge, Y., Ishige, K., Uchiyama, T., Makishima, M., Nakao, R., Oishi, K., & Shimba, S. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19092813 · Cited by 34
“With regard to the skeletal muscle, metabolomics analysis revealed that deletion of the Bmal1 gene leads to reduced glucose oxidation and a diversion of glycolytic intermediates to alternative metabolic pathway [19,20].”
BackgroundInfluentialRenna, L. V., Bosè, F., Brigonzi, E., Fossati, B., Meola, G., & Cardani, R. (2019) · PLoS ONE · doi:10.1371/journal.pone.0214254 · Cited by 34
Sevilla-Lorente, R., Carneiro-Barrera, A., Molina-Garcia, P., Ruiz, J. R., & Amaro-Gahete, F. (2023) · Journal of Science and Medicine in Sport · doi:10.1016/j.jsams.2023.03.004 · Cited by 30
Exercise Training Impacts Skeletal Muscle Clock Machinery in Prediabetes
Erickson, M. L., ZHANG, H., Mey, J. T., & Kirwan, J. P. (2020) · Medicine & Science in Sports & Exercise · doi:10.1249/mss.0000000000002368 · Cited by 31
Therapeutic potential of melatonin as a chronobiotic and cytoprotective agent in diabetes mellitus
Wajid, F., Poolacherla, R., Mim, F. K., Bangash, A., & Rutkofsky, I. H. (2020) · Journal of Diabetes & Metabolic Disorders · doi:10.1007/s40200-020-00585-2 · Cited by 33
“because it impaired the regulation of insulin-mediated suppression of hepatic glucose production [43].”
BackgroundJuliana, N., Azmi, L., Effendy, N. M., Teng, N. I. M. F., Abu, I. F., Bakar, N. N. A., Azmani, S., Yazit, N. A. A., Kadiman, S., & Das, S. (2023) · Nutrients · doi:10.3390/nu15030734 · Cited by 33
“Studies using the skeletal muscle-specific Bmal1 KO have shown that the muscle clock is essential in anticipating the transition from resting to active phase at awakening and promoting glucose uptake and metabolism, as the predominant fuel for skeletal muscle [78].”
BackgroundXu, J., Li, C., & Kang, X. (2023) · Frontiers in Physiology · doi:10.3389/fphys.2023.1267456 · Cited by 32
Targeted Bmal1 restoration in muscle prolongs lifespan with systemic health effects in aging model
Gutierrez‐Monreal, M. A., Wolff, C. A., Rijos, E. E., Viggars, M. R., Douglas, C. M., Pagala, V., Peng, J., Hunt, L. C., Ding, H., Huo, Z., et al. (2024) · JCI Insight · doi:10.1172/jci.insight.174007 · Cited by 31
Rodent Models for the Analysis of Tissue Clock Function in Metabolic Rhythms Research
Tsang, A. H. K., Astiz, M., Leinweber, B., & Oster, H. (2017) · Frontiers in Endocrinology · doi:10.3389/fendo.2017.00027 · Cited by 30
“In the M-Bmal1 KO study discussed above, a muscle strength phenotype was only observed in mutants with conventional, but not inducible CRE deletion (50).”
BackgroundMetabolic‐sensing of the skeletal muscle clock coordinates fuel oxidation
Yin, H., Li, W., Chatterjee, S., Xiong, X., Saha, P., Yechoor, V. K., & Ma, K. (2020) · The FASEB Journal · doi:10.1096/fj.201903226rr · Cited by 31
Diurnal Regulation of Peripheral Glucose Metabolism: Potential Effects of Exercise Timing
Mancilla, R., Krook, A., Schrauwen, P., & Hesselink, M. K. C. (2020) · Obesity · doi:10.1002/oby.22811 · Cited by 29
“However, it is important to note that mice with inducible muscle-specific ablation of BMAL-1 showed compromised insulin-stimulated glucose uptake in muscle, partly originating from downregulation of key insulin-signaling genes and lower levels of the main glucose transporter GLUT4 (8).”
BackgroundInfluentialQuattrocelli, M., Wintzinger, M., Miz, K., Levine, D. C., Peek, C. B., Bass, J. T., & McNally, E. M. (2022) · Science Advances · doi:10.1126/sciadv.abm1189 · Cited by 30
Transcriptomics for Clinical and Experimental Biology Research: Hang on a Seq
Stokes, T., Cen, H. H., Kapranov, P., Gallagher, I. J., Pitsillides, A. A., Volmar, C., Kraus, W. E., Johnson, J. D., Phillips, S. M., Wahlestedt, C., et al. (2023) · Advanced Genetics · doi:10.1002/ggn2.202200024 · Cited by 28
Patel, V. R., Ceglia, N., Zeller, M., Eckel‐Mahan, K. L., Sassone‐Corsi, P., & Baldi, P. (2015) · Bioinformatics · doi:10.1093/bioinformatics/btv353 · Cited by 33
Zhong, L.-X., Li, X.-N., Yang, G., Zhang, X., Li, W., Zhang, Q.-Q., Pan, H.-X., Zhang, H.-H., Zhou, M., Wang, Y., et al. (2019) · PLoS ONE · doi:10.1371/journal.pone.0225813 · Cited by 32
Teng, Z., Yang, G., Wang, L., Fu, T., Lian, H., Sun, Y., Han, L., Zhang, L., & Gao, T. (2021) · Journal of Dairy Science · doi:10.3168/jds.2020-19679 · Cited by 30
Circadian Misalignment and Metabolic Consequences
Banks, S., Dorrian, J., Grant, C., & Coates, A. M. (2015) · Elsevier eBooks · doi:10.1016/b978-0-12-420168-2.00017-x · Cited by 30
da Silva, F. M., Esser, K. A., Murach, K. A., & Greene, N. P. (2023) · The Journal of Physiology · doi:10.1113/jp284808 · Cited by 31
Exercise-induced regulation of key factors in substrate choice and gluconeogenesis in mouse liver
Knudsen, J. G., Biensø, R. S., Hassing, H. A., Jakobsen, A. H., & Pilegaard, H. (2015) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-015-2351-0 · Cited by 28
“Finally, it may be noted that the changes in PDK4 protein and PDH phosphorylations observed late in recovery may be a result of circadian rhythm rather than exercise-induced effects as PDK4 protein content and PDH phosphorylation have been shown to have a circadian rhythm in skeletal muscle [29].”
A Moderate Daily Dose of Resveratrol Mitigates Muscle Deconditioning in a Martian Gravity Analog
Mortreux, M., Riveros, D., Bouxsein, M. L., & Rutkove, S. B. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.00899 · Cited by 27
The Role of Prenatal Melatonin in the Regulation of Childhood Obesity
Иванов, Д. О., Evsyukova, I. I., Mazzoccoli, G., Anderson, G., Polyakova, V. O., Kvetnoy, I. M., Carbone, A., & Nasyrov, R. A. (2020) · Biology · doi:10.3390/biology9040072 · Cited by 27
“This could suggest that the α7nAChR, like BMAL1, mediates pineal melatonin's induction of mitochondrial melatonin via PDC disinhibition [109].”
BackgroundCircadian rhythms in the tissue-specificity from metabolism to immunity: insights from omics studies
Kinouchi, K., Mikami, Y., Kanai∥, T., & Itoh, H. (2021) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2021.100984 · Cited by 28
Circadian Clock-Controlled Checkpoints in the Pathogenesis of Complex Disease
Li, M., Xin, H., Yuan, Y., Yang, X., Li, H., Tian, D., Zhang, H., Zhang, Z., Han, T.-L., Chen, Q., et al. (2021) · Frontiers in Genetics · doi:10.3389/fgene.2021.721231 · Cited by 29
Li, Y., Zhang, Y., Hu, Q., Egranov, S. D., Xing, Z., Zhang, Z., Liang, K., Ye, Y., Pan, Y., Chatterjee, S. S., et al. (2021) · Genome Medicine · doi:10.1186/s13073-021-00937-4 · Cited by 27
Time to Train: The Involvement of the Molecular Clock in Exercise Adaptation of Skeletal Muscle
Mansingh, S., & Handschin, C. (2022) · Frontiers in Physiology · doi:10.3389/fphys.2022.902031 · Cited by 29
“…an important role in anticipating metabolic fluctuations, e.g., due to feeding time or activity patterns, and therefore prepares the transition from fasting/rest phases to feeding/active phases by regulating a pleiotropic response (Dyar et al., 2014; Hodge et al., 2015; Harfmann et al., 2016).”
BackgroundSkeletal muscle gene expression dysregulation in long-term spaceflights and aging is clock-dependent
Malhan, D., Yalçın, M., Schoenrock, B., Blottner, D., & Relógio, A. (2023) · npj Microgravity · doi:10.1038/s41526-023-00273-4 · Cited by 28
Zeitgebers of skeletal muscle and implications for metabolic health
Gabriel, B. M., & Zierath, J. R. (2021) · The Journal of Physiology · doi:10.1113/jp280884 · Cited by 29
“Additionally, metabolic gene-sets are influenced by these knock-out models, and core-clock genes directly bind to the promoter regions of genes controlling pathways involved in lipid, amino acid and mitochondrial metabolism (Dyar et al. 2014, 2018a).”
BackgroundInfluentialThe circadian rhythm: an influential soundtrack in the diabetes story
Hariri, A., Mirian, M., Zarrabi, A., Kohandel, M., Amini-Pozveh, M., Aref, A. R., Tabatabaee, A., Prabhakar, P. K., & Sivakumar, P. M. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1156757 · Cited by 30
McAinch, A. J., Cornall, L. M., Watts, R. P., Hryciw, D. H., O’Brien, P. E., & Cameron‐Smith, D. (2014) · European Journal of Nutrition · doi:10.1007/s00394-014-0780-2 · Cited by 28
“With reference to PDK4 expression, a number of studies have demonstrated coordinated regulation of PDK4 mRNA and protein expression [15, 19, 22, 30, 31, 44, 45].”
BackgroundLassiter, D. G., Sjögren, R. J. O., Gabriel, B. M., Krook, A., & Zierath, J. R. (2018) · Molecular Metabolism · doi:10.1016/j.molmet.2018.07.004 · Cited by 25
Chronodisruption, Metabolic Homeostasis, and the Regulation of Inflammation in Adipose Tissues.
Kolbe, I., & Oster, H. (2019) · PubMed Central · Cited by 27
The metabolic significance of peripheral tissue clocks
Hunter, L., & Bechtold, D. A. (2025) · Communications Biology · doi:10.1038/s42003-025-07932-0 · Cited by 33
E-box binding transcription factors in cancer
Pan, Y., van der Watt, P. J., & Kay, S. A. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1223208 · Cited by 24
Harmsen, J., Kotte, M., Habets, I., Bosschee, F., Frenken, K. G., Jörgensen, J. A., de Kam, S. S., Moonen‐Kornips, E., Cissen, J., Doligkeit, D., et al. (2023) · The Journal of Physiology · doi:10.1113/jp285523 · Cited by 25
Scotton, C., Bovolenta, M., Schwartz, E., Falzarano, M. S., Martoni, E., Passarelli, C., Armaroli, A., Osman, H., Rodolico, C., Messina, S., et al. (2016) · Journal of Cell Science · doi:10.1242/jcs.175927 · Cited by 25
“In particular, expression profiling has identified genes expressed in a circadian manner in the gastrocnemius, soleus and tibialis anterior muscles of mice (McCarthy et al., 2007; Dyar et al., 2013; Hodge et al., 2015).”
BackgroundControl of circadian muscle glucose metabolism through the BMAL1–HIF axis in obesity
Chaikin, C., Thakkar, A. V., Steffeck, A. W. T., Pfrender, E. M., Hung, K., Zhu, P., Waldeck, N. J., Nozawa, R., Song, W., Futtner, C. R., et al. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2424046122 · Cited by 29
“Similar to regular chow studies, we revealed that chronic HFD feeding in Bmal1 mKO mice leads to impaired whole - body glucose tolerance and skeletal muscle–specific glucose utilization ( 26 , 27 ).”
InfluentialYamaguchi, S., Moseley, A. C., Almeda‐Valdés, P., Stromsdorfer, K. L., Franczyk, M. P., Okunade, A. L., Patterson, B. W., Klein, S., & Yoshino, J. (2017) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2017-02230 · Cited by 23
Aoyama, S., Kojima, S., Sasaki, K., Ishikawa, R., Tanaka, M., Shimoda, T., Hattori, Y., Aoki, N., Takahashi, K., Hirooka, R., et al. (2018) · EBioMedicine · doi:10.1016/j.ebiom.2018.10.057 · Cited by 23
“Bmal1 knockoutmice show extreme muscle loss with aging [18], though skeletal musclespecific Bmal1 knockout mice did not show this phenotype [11], suggesting that a non-muscle clock could control muscle mass.”
Background
Metadata
- Authors
- Dyar, K. A., Ciciliot, S., Wright, L. E., Biensø, R. S., Tagliazucchi, G. M., Patel, V. R., Forcato, M., Paz, M. I. P., Gudiksen, A., Solagna, F., Albiero, M., Moretti, I., Eckel-Mahan, K. L., Baldi, P., Sassone-Corsi, P., Rizzuto, R., Bicciato, S., Pilegaard, H., Blaauw, B., & Schiaffino, S.
- Affiliations
- Veneto Institute of Molecular Medicine (IT)
- University of Padua (IT)
- University of Copenhagen (DK)
- University of Modena and Reggio Emilia (IT)
- University of California, Irvine (US)
- Corresponding author
- Dyar, Kenneth A.
- Schiaffino, Stefano
- ORCID
- Venue
- Molecular Metabolism
- Publisher
- Elsevier BV
- Published
- 2014-02
- Volume
- 3
- Issue
- 1
- Pages
- 29-41
- ISSN
- 2212-8778 (ISSN-L)
- PMC
- PMC3929910
- OpenAlex
- W1964634897
- Cited by
- 454
- References
- 73
- Citations by year
- 2026: 34 · 2025: 37 · 2024: 40 · 2023: 46 · 2022: 42 · 2021: 33 · 2020: 53 · 2019: 34 · 2018: 36 · 2017: 28 · 2016: 42 · 2015: 19 · 2014: 9
- FWCI
- 12.78
- Type
- journal article
- Language
- en
- Update notices
- erratum (2014-12-01)
- Open access
- gold
- doi.org
- Licence
- Locations
- Molecular Metabolism (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-sa)
- IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by-nc-sa)
- Padua Research Archive (University of Padova) (submittedVersion)
- Funders
- European Commission (223576, 294777)
- Italian Space Agency (ASI, project OSMA)
- Italian Ministries of Health (Ricerca Finalizzata) and of Education, University and Research (PRIN, FIRB), NIA (2P01AG025532-06A1)
- Cariparo Foundation (Padua)
- Italian Association for Cancer Research (AIRC) and Telethon–Italy (GPP1005A, GGP11082)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Keywords
- circadian rhythm, Bmal1, insulin sensitivity, glucose uptake, GLUT4, TBC1D1, pyruvate dehydrogenase, PDK4, PDP1, glucose oxidation, glycolysis, metabolome, conditional knockout mice
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