Muscle-specific loss of Bmal1 leads to disrupted tissue glucose metabolism and systemic glucose homeostasis
Open accessAbstract
BACKGROUND: Diabetes is the seventh leading cause of death in the USA, and disruption of circadian rhythms is gaining recognition as a contributing factor to disease prevalence. This disease is characterized by hyperglycemia and glucose intolerance and symptoms caused by failure to produce and/or respond to insulin. The skeletal muscle is a key insulin-sensitive metabolic tissue, taking up ~80 % of postprandial glucose. To address the role of the skeletal muscle molecular clock to insulin sensitivity and glucose tolerance, we generated an inducible skeletal muscle-specific Bmal1 (-/-) mouse (iMSBmal1 (-/-)). RESULTS: Progressive changes in body composition (decreases in percent fat) were seen in the iMSBmal1 (-/-) mice from 3 to 12 weeks post-treatment as well as glucose intolerance and non-fasting hyperglycemia. Ex vivo analysis of glucose uptake revealed that the extensor digitorum longus (EDL) muscles did not respond to either insulin or 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) stimulation. RT-PCR and Western blot analyses demonstrated a significant decrease in mRNA expression and protein content of the muscle glucose transporter (Glut4). We also found that both mRNA expression and activity of two key rate-limiting enzymes of glycolysis, hexokinase 2 (Hk2) and phosphofructokinase 1 (Pfk1), were significantly reduced in the iMSBmal1 (-/-) muscle. Lastly, results from metabolomics analyses provided evidence of decreased glycolytic flux and uncovered decreases in some tricarboxylic acid (TCA) intermediates with increases in amino acid levels in the iMSBmal1 (-/-) muscle. These findings suggest that the muscle is relying predominantly on fat as a fuel with increased protein breakdown to support the TCA cycle. CONCLUSIONS: These data support a fundamental role for Bmal1, the endogenous circadian clock, in glucose metabolism in the skeletal muscle. Our findings have implicated altered molecular clock dictating significant changes in altered substrate metabolism in the absence of feeding or activity changes. The changes in body composition in our model also highlight the important role that changes in skeletal muscle carbohydrate, and fat metabolism can play in systemic metabolism.
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Negative metabolic consequences, such as reduction in insulin sensitivity and mitochondrial function, are attributed to both circadian misalignment and sleep loss.
“Considering the negative metabolic consequences, such as reduction in insulin sensitivity and mitochondrial function, attributed to both circadian misalignment and sleep loss [21,67] and the potential benefits of exercise in this context [17,68], further research is warranted.”
From Exercise mitigates sleep-loss-induced changes in glucose tolerance, mitochondrial function, sarcoplasmic protein synthesis, and diurnal rhythms (2021) · cites this paper as [67]
Disruption of the muscle clock has significant impact on glucose intolerance and insulin resistance with very small changes in fiber types.
“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 Harfmann et al., 2016
In muscle-specific Bmal1 knockout mice, there is no increase in glucose uptake in response to insulin ex vivo.
“When investigating glucose transport ex vivo, it was clear that there was no increase in glucose uptake in response to insulin.”
From Myosteatosis in the Context of Skeletal Muscle Function Deficit: An Interdisciplinary Workshop at the National Institute on Aging (2020) · cites this paper as Harfmann et al., 2016
Muscles from Bmal1 knockout mice exhibit reduced glycolytic enzyme activity and reduced GLUT-4 expression, suggesting the molecular clock regulates muscle mechanisms impacting glucose uptake.
“Muscles from Bmal1 knockout mice exhibit reduced glycolytic enzyme activity (e.g., 50% reduction in both hexokinase and phosphofructokinase activity) and a significant reduction in expression of the glucose transporter type 4 (GLUT-4) suggests that the molecular clock regulates muscle mechanisms that impact glucose uptake in muscle (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 Harfmann et al., 2016
In muscle-specific Bmal1 knockout mice, non-fasted blood glucose is always elevated compared to controls.
“Using an inducible muscle specific Bmal1 knockout mouse, Harfmann et al. (2016), showed that non-fasted blood glucose (measured every 4 h for about 32 h) in the mice was always elevated compared to controls.”
From Myosteatosis in the Context of Skeletal Muscle Function Deficit: An Interdisciplinary Workshop at the National Institute on Aging (2020) · cites this paper as Harfmann et al., 2016
In muscle-specific Bmal1 knockout mice, AICAR activation of AMPK does not increase glucose uptake, indicating loss of Bmal1 affects both exercise- and insulin-induced glucose uptake.
“Further, use of 5-aminoimidazole-4-carboxamide-1-D-ribofuranoside (AICAR) to activate adenosine monophosphate (AMP)-activated protein kinase (AMPK) also did not increase glucose uptake indicating that loss of Bmal1 affects both exercise as well as insulin-induced glucose uptake.”
From Myosteatosis in the Context of Skeletal Muscle Function Deficit: An Interdisciplinary Workshop at the National Institute on Aging (2020) · cites this paper as Harfmann et al., 2016
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Cites
Adverse metabolic and cardiovascular consequences of circadian misalignment
Scheer, F. A. J. L., Hilton, M. F., Mantzoros, C. S., & Shea, S. A. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0808180106 · Cited by 2,351 · see citing works
Coordinated Transcription of Key Pathways in the Mouse by the Circadian Clock
Panda, S., Antoch, M. P., Miller, B. H., Su, A. I., Schook, A. C., Straume, M., Schultz, P. G., Kay, S. A., Takahashi, J. S., & Hogenesch, J. B. (2002) · Cell · doi:10.1016/s0092-8674(02)00722-5 · Cited by 2,272 · see citing works
mCRY1 and mCRY2 are essential components of the negative limb of the circadian clock feedback loop
Kume, K., Zylka, M. J., Sriram, S., Shearman, L. P., Weaver, D. R., Jin, X., Maywood, E. S., Hastings, M. H., & Reppert, S. M. (1999) · Cell · doi:10.1016/s0092-8674(00)81014-4 · Cited by 1,617 · see citing works
Extensive and divergent circadian gene expression in liver and heart
Storch, K.-F., Lipan, O., Leykin, I., Viswanathan, N., Davis, F. C., Wong, W. H., & Weitz, C. J. (2002) · Nature · doi:10.1038/nature744 · Cited by 1,509 · see citing works
Exercise, GLUT4, and skeletal muscle glucose uptake
Richter, E. A., & Hargreaves, M. (2013) · Physiological Reviews · doi:10.1152/physrev.00038.2012 · Cited by 1,407 · see citing works
Interacting molecular loops in the mammalian circadian clock
Shearman, L. P., Sriram, S., Weaver, D. R., Maywood, E. S., Chaves, I., Zheng, B., Kume, K., Lee, C. C., van der, G. T. J., Horst, et al. (2000) · Science · doi:10.1126/science.288.5468.1013 · Cited by 1,367 · see citing works
The key role of anaplerosis and cataplerosis for citric acid cycle function
Owen, O. E., Kalhan, S. C., & Hanson, R. W. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.r200006200 · Cited by 1,172 · cited 1× · see citing works
“In healthy muscle, pyruvate generated from glycolysis may enter the TCA cycle as acetyl CoA at oxaloacetate and then the TCA cycle proceeds [23].”
BackgroundRudic, R. D., McNamara, P., Curtis, A.-M., Boston, R. C., Panda, S., Hogenesch, J. B., & FitzGerald, G. A. (2004) · PLoS Biology · doi:10.1371/journal.pbio.0020377 · Cited by 1,059 · see citing works
Physiological significance of a peripheral tissue circadian clock
Lamia, K. A., Storch, K.-F., & Weitz, C. J. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0806717105 · Cited by 1,048 · see citing works
Goodpaster, B. H., Kelley, D. E., Thaete, F. L., He, J., & Ross, R. (2000) · Journal of Applied Physiology · doi:10.1152/jappl.2000.89.1.104 · Cited by 956 · see citing works
Karlsson, B., Knutsson, A., & Lindahl, B. (2001) · Occupational and Environmental Medicine · doi:10.1136/oem.58.11.747 · Cited by 924 · see citing works
Post-translational modifications regulate the ticking of the circadian clock
Gallego, M., & Virshup, D. M. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2106 · Cited by 863 · see citing works
Zisman, A., Peroni, O. D., Abel, E. D., Michael, M. D., Mauvais-Jarvis, F., Lowell, B. B., Wojtaszewski, J. F. P., Hirshman, M. F., Virkamaki, A., Goodyear, L. J., et al. (2000) · Nature Medicine · doi:10.1038/78693 · Cited by 743 · see citing works
Muscle insulin sensitivity and glucose metabolism are controlled by the intrinsic muscle clock
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., et al. (2014) · Molecular Metabolism · doi:10.1016/j.molmet.2013.10.005 · Cited by 454 · see citing works
Crabtree, B., & Newsholme, E. A. (1972) · Biochemical Journal · doi:10.1042/bj1260049 · Cited by 382 · see citing works
Yoo, S. H., Mohawk, J. A., Siepka, S. M., Shan, Y., Huh, S. K., Hong, H., Kornblum, I., Kumar, V., Koike, N., Xu, M., et al. (2013) · Cell · doi:10.1016/j.cell.2013.01.055 · Cited by 341 · see citing works
A Daily Rhythm in Glucose Tolerance
la Fleur, S. E., Kalsbeek, A., Wortel, J., Fekkes, M. L., & Buijs, R. M. (2001) · Diabetes · doi:10.2337/diabetes.50.6.1237 · Cited by 337 · see citing works
Sadacca, L. A., Lamia, K. A., deLemos, A. S., Blum, B., & Weitz, C. J. (2011) · Diabetologia · doi:10.1007/s00125-010-1920-8 · Cited by 314 · see citing works
The disposal of an oral glucose load in patients with non-insulin-dependent diabetes
Ferrannini, E., Simonson, D. C., Katz, L. D., Reichard, G., Bevilacqua, S., Barrett, E. J., Olsson, M., & DeFronzo, R. A. (1988) · Metabolism · doi:10.1016/0026-0495(88)90033-9 · Cited by 305 · see citing works
Invited Review: Intracellular signaling in contracting skeletal muscle
Sakamoto, K., & Goodyear, L. J. (2002) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00167.2002 · Cited by 260 · see citing works
Work characteristics and incidence of type 2 diabetes in women.
Kroenke, C. H., Spiegelman, D., Manson, J., Schernhammer, E. S., Colditz, G. A., & Kawachi, I. (2006) · American Journal of Epidemiology · doi:10.1093/aje/kwj355 · Cited by 220 · see citing works
Inducible Cre transgenic mouse strain for skeletal muscle-specific gene targeting
McCarthy, J. J., Srikuea, R., Kirby, T. J., Peterson, C. A., & Esser, K. A. (2012) · Skeletal Muscle · doi:10.1186/2044-5040-2-8 · Cited by 194 · see citing works
Self-citationHodge, B. A., Wen, Y., Riley, L. A., Zhang, X., England, J. H., Harfmann, B. D., Schroder, E. A., & Esser, K. A. (2015) · Skeletal Muscle · doi:10.1186/s13395-015-0039-5 · Cited by 175 · see citing works
Self-citationCLOCK/BMAL1 regulates circadian change of mouse hepatic insulin sensitivity by SIRT1
Zhou, B. Z., Zhang, Y., Zhang, F., Xia, Y., Liu, J., Huang, R., Wang, Y., Hu, Y., Wu, J., Dai, C., et al. (2014) · Hepatology · doi:10.1002/hep.26992 · Cited by 149 · see citing works
Exercise-induced AMPK activity in skeletal muscle: Role in glucose uptake and insulin sensitivity
Friedrichsen, M., Mortensen, B., Pehmøller, C., Birk, J. B., & Wojtaszewski, J. F. P. (2013) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2012.06.013 · Cited by 143 · see citing works
Phosphofructokinase Deficiency Past, Present and Future
Nakajima, H., Raben, N., Hamaguchi, T., & Yamasaki, T. (2002) · Current Molecular Medicine · doi:10.2174/1566524024605734 · Cited by 102 · see citing works
Contraction-activated glucose uptake is normal in insulin-resistant muscle of the obese Zucker rat
Brozinick, J. T., Etgen, G. J., Yaspelkis, B. B., & Ivy, J. L. (1992) · Journal of Applied Physiology · doi:10.1152/jappl.1992.73.1.382 · Cited by 89 · see citing works
Ferroni, P., Riondino, S., Buonomo, O., Palmirotta, R., Guadagni, F., & Roselli, M. (2015) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2015/183928 · Cited by 87 · see citing works
Fueger, P. T., Heikkinen, S., Bracy, D. P., Malabanan, C. M., Pencek, R., Laakso, M., & Wasserman, D. H. (2003) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00190.2003 · Cited by 72 · see citing works
Hesselbarth, N., Pettinelli, C., Gericke, M. T., Berger, C., Kunath, A., Stümvoll, M., Blüher, M., & Klöting, N. (2015) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2015.07.015 · Cited by 63 · see citing works
Circadian regulation of adipose function
Shostak, A., Husse, J., & Oster, H. (2013) · Adipocyte · doi:10.4161/adip.26007 · Cited by 60 · see citing works
The role of clock genes and rhythmicity in the liver
Schmutz, I., Albrecht, U., & Ripperger, J. A. (2011) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2011.05.007 · Cited by 55 · see citing works
Kowalski, G. M., Souza, D. P. D., Burch, M. L., Hamley, S., Kloehn, J., Selathurai, A., Tull, D., O’Callaghan, S., McConville, M. J., & Bruce, C. R. (2015) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2015.04.096 · Cited by 41 · see citing works
An improved assay for hexokinase activity in human tissue homogenates
Scheer, W. D., Lehmann, H. P., & Beeler, M. F. (1978) · Analytical Biochemistry · doi:10.1016/0003-2697(78)90531-6 · Cited by 40 · see citing works
A metabolomic study of adipose tissue in mice with a disruption of the circadian system
Castro, C., Briggs, W., Paschos, G. K., FitzGerald, G. A., & Griffin, J. L. (2015) · Molecular BioSystems · doi:10.1039/c5mb00032g · Cited by 33 · see citing works
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., et al. (2014) · Molecular Metabolism · doi:10.1016/j.molmet.2014.09.002 · Cited by 29 · see citing works
Pettingill, O. S. (1985) · Elsevier eBooks · doi:10.1016/b978-0-12-552455-1.50008-3 · Cited by 21 · see citing works
Pergola, G. D., Nardecchia, A., Cirillo, M., Boninfante, B., Sciaraffia, M., Giagulli, V. A., Triggiani, V., & Silvestris, F. (2015) · Endocrine Metabolic & Immune Disorders - Drug Targets · doi:10.2174/1871530315666150506125651 · Cited by 4 · see citing works
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Sorted by citations
Circadian clocks and insulin resistance
Stenvers, D. J., Scheer, F. A. J. L., Schrauwen, P., la Fleur, S. E., & Kalsbeek, A. (2019) · Nature Reviews Endocrinology · doi:10.1038/s41574-018-0122-1 · Cited by 733 · see citing works
Circadian clock genes and the transcriptional architecture of the clock mechanism
Cox, K. H., & Takahashi, J. S. (2019) · Journal of Molecular Endocrinology · doi:10.1530/jme-19-0153 · Cited by 481 · see citing works
Correa-de-Araujo, R., Addison, O., Miljkovic, I., Goodpaster, B. H., Bergman, B. C., Clark, R. V., Elena, J. W., Esser, K. A., Ferrucci, L., Harris-Love, M. O., et al. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.00963 · Cited by 468 · see citing works
Self-citationCircadian rhythms and exercise — re-setting the clock in metabolic disease
Gabriel, B. M., & Zierath, J. R. (2019) · Nature Reviews Endocrinology · doi:10.1038/s41574-018-0150-x · Cited by 382 · see citing works
Exercise Metabolism and Adaptation in Skeletal Muscle
Smith, J. A. B., Murach, K. A., Dyar, K. A., & Zierath, J. R. (2023) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-023-00606-x · Cited by 342 · see citing works
Endocrine Crosstalk Between Skeletal Muscle and the Brain
Delezie, J., & Handschin, C. (2018) · Frontiers in Neurology · doi:10.3389/fneur.2018.00698 · Cited by 270 · see citing works
Circadian Etiology of Type 2 Diabetes Mellitus
Javeed, N., & Matveyenko, A. V. (2018) · Physiology · doi:10.1152/physiol.00003.2018 · Cited by 205 · see citing works
Intersection of the Gut Microbiome and Circadian Rhythms in Metabolism
Frazier, K., & Chang, E. B. (2019) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2019.08.013 · Cited by 169 · see citing works
Interconnections between circadian clocks and metabolism
Guan, D., & Lazar, M. A. (2021) · Journal of Clinical Investigation · doi:10.1172/jci148278 · Cited by 166 · see citing works
Circadian rhythms and obesity: Timekeeping governs lipid metabolism
Li, Y., Ma, J., Kang, Y., Su, W., Tan, B., Wu, X., Huang, X., Li, T., Yin, Y., Tosini, G., et al. (2020) · Journal of Pineal Research · doi:10.1111/jpi.12682 · Cited by 159 · see citing works
Villanueva, J. E., Livelo, C., Trujillo, A. S., Chandran, S., Woodworth, B., Andrade, L., Le, H. D., Manor, U., Panda, S., & Melkani, G. C. (2019) · Nature Communications · doi:10.1038/s41467-019-10563-9 · Cited by 158 · see citing works
Dyar, K. A., Hubert, M. J., Mir, A. A., Ciciliot, S., Lutter, D., Greulich, F., Quagliarini, F., Kleinert, M., Fischer, K., Eichmann, T. O., et al. (2018) · PLoS Biology · doi:10.1371/journal.pbio.2005886 · Cited by 154 · see citing works
Development and Therapeutic Potential of Small-Molecule Modulators of Circadian Systems
Chen, Z., Yoo, S. H., & Takahashi, J. S. (2017) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010617-052645 · Cited by 153 · see citing works
Bmal1 function in skeletal muscle regulates sleep
Ehlen, J. C., Brager, A. J., Baggs, J. E., Pinckney, L., Gray, C. L., DeBruyne, J. P., Esser, K. A., Takahashi, J. S., & Paul, K. N. (2017) · eLife · doi:10.7554/elife.26557 · Cited by 144 · see citing works
Self-citationTranscriptomic analyses reveal rhythmic and CLOCK-driven pathways in human skeletal muscle
Perrin, L., Loizides-Mangold, U., Chanon, S., Gobet, C., Hulo, N., Isenegger, L., Weger, B. D., Migliavacca, E., Charpagne, A., Betts, J. A., et al. (2018) · eLife · doi:10.7554/elife.34114 · Cited by 139 · see citing works
Muscle-to-Brain Signaling Via Myokines and Myometabolites
Rai, M., & Demontis, F. (2022) · Brain Plasticity · doi:10.3233/bpl-210133 · Cited by 121 · see citing works
Gabriel, B. M., Altıntaş, A., Smith, J. A. B., Puig, L. S., Zhang, X., Basse, A. L., Laker, R. C., Gao, H., Liu, Z., Dollet, L., et al. (2021) · Science Advances · doi:10.1126/sciadv.abi9654 · Cited by 118 · see citing works
Self-citationOpperhuizen, A., Stenvers, D. J., Jansen, R., Foppen, E., Fliers, E., & Kalsbeek, A. (2017) · Diabetologia · doi:10.1007/s00125-017-4262-y · Cited by 114 · see citing works
Circadian Rhythms and Mitochondria: Connecting the Dots
Sardon Puig, L., Valera-Alberni, M., Cantó, C., & Pillon, N. J. (2018) · Frontiers in Genetics · doi:10.3389/fgene.2018.00452 · Cited by 113 · see citing works
Aoyama, S., & Shibata, S. (2017) · Frontiers in Neuroscience · doi:10.3389/fnins.2017.00063 · Cited by 106 · see citing works
The Circadian Clock, Shift Work, and Tissue-Specific Insulin Resistance
Oosterman, J. E., Wopereis, S., & Kalsbeek, A. (2020) · Endocrinology · doi:10.1210/endocr/bqaa180 · Cited by 105 · see citing works
Loizides‐Mangold, U., Perrin, L., Vandereycken, B., Betts, J. A., Walhin, J., Templeman, I., Chanon, S., Weger, B. D., Durand, C., Robert, M., et al. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1705821114 · Cited by 104 · see citing works
Metabolism and exercise: the skeletal muscle clock takes centre stage
Martin, R. A., Viggars, M. R., & Esser, K. A. (2023) · Nature Reviews Endocrinology · doi:10.1038/s41574-023-00805-8 · Cited by 101 · see citing works
Self-citationCoupled network of the circadian clocks: a driving force of rhythmic physiology
Finger, A., Dibner, C., & Kramer, A. (2020) · FEBS Letters · doi:10.1002/1873-3468.13898 · Cited by 99 · see citing works
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Speksnijder, E. M., Bisschop, P. H. L. T., Siegelaar, S. E., Stenvers, D. J., & Kalsbeek, A. (2024) · Journal of Pineal Research · doi:10.1111/jpi.12956 · Cited by 98 · see citing works
Bisphenol S exposure impairs glucose homeostasis in male zebrafish (Danio rerio)
Zhao, F., Jiang, G., Wei, P., Wang, H., & Ru, S. (2017) · Ecotoxicology and Environmental Safety · doi:10.1016/j.ecoenv.2017.09.048 · Cited by 96 · see citing works
Time-of-Day-Dependent Physiological Responses to Meal and Exercise
Aoyama, S., & Shibata, S. (2020) · Frontiers in Nutrition · doi:10.3389/fnut.2020.00018 · Cited by 95 · see citing works
Time-of-day dependent effects of contractile activity on the phase of the skeletal muscle clock
Kemler, D., Wolff, C. A., & Esser, K. A. (2020) · The Journal of Physiology · doi:10.1113/jp279779 · Cited by 87 · see citing works
Self-citationMcGinnis, G. R., Tang, Y., Brewer, R. A., Brahma, M. K., Stanley, H. L., Shanmugam, G., Rajasekaran, N. S., Rowe, G. C., Frank, S. J., Wende, A. R., et al. (2017) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2017.07.005 · Cited by 77 · see citing works
The circadian protein CLOCK regulates cell metabolism via the mitochondrial carrier SLC25A10
Cai, T., Hua, B., Luo, D., Xu, L., Cheng, Q., Yuan, G., Yan, Z., Sun, N., Hua, L., & Lü, C. (2019) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2019.03.016 · Cited by 74 · see citing works
Timmons, G. A., Carroll, R. G., O’Siorain, J. R., Cervantes‐Silva, M. P., Fagan, L. E., Cox, S. L., Pålsson‐McDermott, E. M., Finlay, D. K., Vincent, E. E., Jones, N., et al. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.700431 · Cited by 72 · see citing works
Timing of meals: when is as critical as what and how much
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Fatima, N., & Rana, S. (2020) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-020-02381-6 · Cited by 71 · see citing works
Saner, N. J., Lee, M. J.-C., Kuang, J., Pitchford, N. W., Roach, G. D., Garnham, A., Genders, A. J., Stokes, T., Schroder, E. A., Huo, Z., et al. (2021) · Molecular Metabolism · doi:10.1016/j.molmet.2020.101110 · Cited by 68 · see citing works
Self-citationHodge, B. A., Zhang, X., Gutierrez‐Monreal, M. A., Cao, Y., Hammers, D. W., Yao, Z., Wolff, C. A., Du, P., Kemler, D., Judge, A. R., et al. (2019) · eLife · doi:10.7554/elife.43017 · Cited by 68 · see citing works
Self-citationGlucose Homeostasis: Regulation by Peripheral Circadian Clocks in Rodents and Humans
Gachon, F., Loizides‐Mangold, U., Petrenko, V., & Dibner, C. (2017) · Endocrinology · doi:10.1210/en.2017-00218 · Cited by 63 · see citing works
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Manickam, R., Oh, H. Y. P., Tan, C. K., Paramalingam, E., & Wahli, W. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19082418 · Cited by 63 · see citing works
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Epigenetic/circadian clocks and PCOS
Vatier, C., & Christin‐Maître, S. (2024) · Human Reproduction · doi:10.1093/humrep/deae066 · Cited by 58 · see citing works
Gut microbes and the liver circadian clock partition glucose and lipid metabolism
Frazier, K., Manzoor, S. S., Carroll, K., DeLeon, O., Miyoshi, S., Miyoshi, J., George, M. S., Tan, A., Chrisler, E. A., Izumo, M., et al. (2023) · Journal of Clinical Investigation · doi:10.1172/jci162515 · Cited by 57 · see citing works
Liver and muscle circadian clocks cooperate to support glucose tolerance in mice
Smith, J. G., Koronowski, K. B., Mortimer, T., Sato, T., Greco, C. M., Petrus, P., Verlande, A., Chen, S., Samad, M., Deyneka, E., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.112588 · Cited by 56 · see citing works
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 56 · see citing works
Female ClockΔ19/Δ19 mice are protected from the development of age-dependent cardiomyopathy
Alibhai, F. J., Reitz, C. J., Peppler, W. T., Basu, P., Sheppard, P. A. S., Choleris, E., Bakovic, M., & Martino, T. A. (2017) · Cardiovascular Research · doi:10.1093/cvr/cvx185 · Cited by 55 · see citing works
Linking Cancer Cachexia‐Induced Anabolic Resistance to Skeletal Muscle Oxidative Metabolism
Hardee, J. P., Montalvo, R. N., & Carson, J. A. (2017) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2017/8018197 · Cited by 53 · see citing works
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 · see citing works
Sarcopenia and cachexia: molecular mechanisms and therapeutic interventions
Wang, T., Zhou, D., & Hong, Z. (2025) · MedComm · doi:10.1002/mco2.70030 · Cited by 46 · see citing works
Xu, L., Yang, T., Zhou, Y., Wu, M., Shen, J., Cheng, J., Liu, Q.-X., Cao, S., Wang, J., & Zhang, L. (2021) · Acta Pharmacologica Sinica · doi:10.1038/s41401-021-00658-9 · Cited by 46 · see citing works
Circadian Clocks, Redox Homeostasis, and Exercise: Time to Connect the Dots?
McClean, C. M., & Davison, G. W. (2022) · Antioxidants · doi:10.3390/antiox11020256 · Cited by 46 · see citing works
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 · see citing works
Self-citationThe importance of being rhythmic: Living in harmony with your body clocks
Dibner, C. (2019) · Acta Physiologica · doi:10.1111/apha.13281 · Cited by 45 · see citing works
Brito, L. C., Marin, T. C., Azevêdo, L. M., Rosa‐Silva, J. M., Shea, S. A., & Thosar, S. S. (2022) · Comprehensive physiology · doi:10.1002/cphy.c210036 · Cited by 45 · see citing works
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 43 · see citing works
Metabolic Implications of Circadian–HIF Crosstalk
Peek, C. B. (2020) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2020.02.008 · Cited by 42 · see citing works
Hunt, L. C., Jiao, J., Wang, Y., Finkelstein, D., Rao, D., Curley, M., Robles‐Murguia, M., Shirinifard, A., Pagala, V., Peng, J., et al. (2019) · Genome Research · doi:10.1101/gr.246884.118 · Cited by 42 · see citing works
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 41 · see citing works
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 38 · see citing works
Peripheral Circadian Oscillators.
Brown, A. J., Pendergast, J. S., & Yamazaki, S. (2019) · PubMed Central · Cited by 36 · see citing works
Circadian 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 35 · see citing works
Mariné-Casadó, R., Domenech-Coca, C., Bas-Prior, J. M. D., Bladé, C., Arola, L., & Caimari, A. (2018) · Frontiers in Physiology · doi:10.3389/fphys.2018.00416 · Cited by 34 · see citing works
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 · see citing works
Self-citationCryptochromes 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 · see citing works
Hunt, L. C., & Demontis, F. (2021) · The Journals of Gerontology Series A · doi:10.1093/gerona/glab260 · Cited by 33 · see citing works
Qiu, Z., Ming, H., Zhang, Y., Yu, Y., Lei, S., & Xia, Z. (2021) · Cardiovascular Drugs and Therapy · doi:10.1007/s10557-021-07159-1 · Cited by 33 · see citing works
Circadian Rhythm Effects on the Molecular Regulation of Physiological Systems
Crislip, G. R., Johnston, J. G., Douma, L. G., Costello, H. M., Juffre, A., Boyd, K., Li, W. W., Maugans, C. C., Gutierrez‐Monreal, M. A., Esser, K. A., et al. (2021) · Comprehensive physiology · doi:10.1002/cphy.c210011 · Cited by 33 · see citing works
Self-citationRole of Circadian Rhythm and Impact of Circadian Rhythm Disturbance on the Metabolism and Disease
Han, H., Dou, J., Hou, Q., & Wang, H. (2021) · Journal of Cardiovascular Pharmacology · doi:10.1097/fjc.0000000000001178 · Cited by 32 · see citing works
Riley, L. A., & Esser, K. A. (2017) · Current Osteoporosis Reports · doi:10.1007/s11914-017-0363-2 · Cited by 32 · see citing works
Self-citationWada, 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 32 · see citing works
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 31 · see citing works
Self-citationExercise 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 · see citing works
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 30 · see citing works
Self-citationThe metabolic significance of peripheral tissue clocks
Hunter, L., & Bechtold, D. A. (2025) · Communications Biology · doi:10.1038/s42003-025-07932-0 · Cited by 30 · see citing works
Metabolic‐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 30 · see citing works
Wang, H., Wang, X., Qi, D., Sun, M., Hou, Q., Li, Y., & Jiang, H. (2020) · Journal of Translational Medicine · doi:10.1186/s12967-020-02222-1 · Cited by 29 · see citing works
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 · see citing works
Quattrocelli, 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 29 · see citing works
da Silva, F. M., Esser, K. A., Murach, K. A., & Greene, N. P. (2023) · The Journal of Physiology · doi:10.1113/jp284808 · Cited by 28 · see citing works
Self-citationTime 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 28 · see citing works
The 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 28 · see citing works
Moraes, M. N., Mezzalira, N., de Assis, L. V. M., Menaker, M., Güler, A. D., & Castrucci, A. M. D. L. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2016.11.010 · Cited by 28 · see citing works
Bmal1 deletion in mice facilitates adaptation to disrupted light/dark conditions
Yang, G., Chen, L., Zhang, J., Ren, B., & FitzGerald, G. A. (2019) · JCI Insight · doi:10.1172/jci.insight.125133 · Cited by 28 · see citing works
Control 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 27 · see citing works
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 27 · see citing works
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 · see citing works
Kalev‐Zylinska, M. L., Hearn, J. I., Rong, J., Zhu, M. F., Munro, J. T., Cornish, J., Dalbeth, N., & Poulsen, R. C. (2018) · Osteoarthritis and Cartilage · doi:10.1016/j.joca.2018.06.015 · Cited by 25 · see citing works
Food deprivation during active phase induces skeletal muscle atrophy via IGF-1 reduction in mice
Abe, T., Kazama, R., Okauchi, H., & Oishi, K. (2019) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2019.108160 · Cited by 25 · see citing works
Bu, L., Cao, X., Zhang, Z., Wu, H., Guo, R., & Ma, M. (2020) · Life Sciences · doi:10.1016/j.lfs.2020.117304 · Cited by 24 · see citing works
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 · see citing works
Sussman, W., Stevenson, M., Mowdawalla, C., Mota, S., Ragolia, L., & Pan, X. (2019) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00058.2019 · Cited by 23 · see citing works
Counts, B. R., Hardee, J. P., Fix, D. K., VanderVeen, B. N., Montalvo, R. N., & Carson, J. A. (2019) · Medicine & Science in Sports & Exercise · doi:10.1249/mss.0000000000002166 · Cited by 23 · see citing works
Pourabdi, R., Shahidi, F., Tabandeh, M. R., & Salehpour, M. (2024) · Journal of Physiology and Biochemistry · doi:10.1007/s13105-024-01066-3 · Cited by 22 · see citing works
Local cryotherapy minimally impacts the metabolome and transcriptome of human skeletal muscle
Sarver, D. C., Sugg, K. B., Disser, N. P., Enselman, E. R. S., Awan, T. M., & Mendias, C. L. (2017) · Scientific Reports · doi:10.1038/s41598-017-02754-5 · Cited by 22 · see citing works
Petrenko, V., Stolovich-Rain, M., Vandereycken, B., Giovannoni, L., Storch, K.-F., Dor, Y., Chera, S., & Dibner, C. (2020) · Genes & Development · doi:10.1101/gad.343137.120 · Cited by 22 · see citing works
Kim, E., Yoo, S. H., & Chen, Z. (2022) · F1000Research · doi:10.12688/f1000research.126364.1 · Cited by 21 · see citing works
Systemic Actions of Breast Cancer Facilitate Functional Limitations
Wang, R., & Nakshatri, H. (2020) · Cancers · doi:10.3390/cancers12010194 · Cited by 20 · see citing works
Chrono-Nutrition Has Potential in Preventing Age-Related Muscle Loss and Dysfunction
Aoyama, S., Nakahata, Y., & Shinohara, K. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.659883 · Cited by 20 · see citing works
Dystrophin deficiency disrupts muscle clock expression and mitochondrial quality control in mdx mice
Hardee, J. P., Caldow, M. K., Chan, A. S. M., Plenderleith, S. K., Trieu, J., Koopman, R., & Lynch, G. S. (2021) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00188.2021 · Cited by 20 · see citing works
Overview of the Circadian Clock in the Hair Follicle Cycle
Niu, Y., Wang, Y., Chen, H., Liu, X., & Liu, J. (2023) · Biomolecules · doi:10.3390/biom13071068 · Cited by 20 · see citing works
Kelu, J. J., & Hughes, S. M. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2422446122 · Cited by 19 · see citing works
- Authors
- Harfmann, B. D., Schroder, E. A., Kachman, M. T., Hodge, B. A., Zhang, X., & Esser, K. A.
- Affiliations
- University of Kentucky (US)
- University of Michigan (US)
- Corresponding author
- Esser, Karyn A.
- ORCID
- Venue
- Skeletal Muscle
- Published
- 2016-03-30
- Volume
- 6
- Issue
- 1
- Pages
- 12-12
- ISSN
- 2044-5040 (ISSN-L)
- PMC
- PMC4969979
- OpenAlex
- W2333878333
- Cited by
- 231
- References
- 38
- Citations by year
- 2026: 24 · 2025: 30 · 2024: 24 · 2023: 20 · 2022: 29 · 2021: 19 · 2020: 33 · 2019: 17 · 2018: 15 · 2017: 18 · 2016: 2
- FWCI
- 11.03
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Skeletal Muscle (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- University of Florida Digital Collections (University of Florida) (submittedVersion, other-oa)
- UKnowledge (University of Kentucky) (submittedVersion, cc-by)
- Funders
- National Institutes of Health (R01AR066082, RC1ES018636)
- 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 › Adipose Tissue and Metabolism
- Keywords
- Bmal1, circadian clock, glucose metabolism, glucose homeostasis, impaired glucose tolerance, hyperglycemia, insulin sensitivity, GLUT4, hexokinase 2, phosphofructokinase-1, glycolysis, TCA cycle, substrate metabolism, fat metabolism, protein degradation, body composition, diabetes mellitus
- MeSH terms
- Adipose Tissue, Aminoimidazole Carboxamide, Animals, Blood Glucose, Body Weight, Circadian Rhythm, Female, Hexokinase, Homeostasis, Hypoglycemic Agents, Insulin, Male, Motor Activity, Ribonucleotides, RNA, Messenger, Mice, Knockout, Muscle, Skeletal, Phosphofructokinase-1, Muscle Type, Glucose Transporter Type 4, Mice, ARNTL Transcription Factors
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