Metabolism and exercise: the skeletal muscle clock takes centre stage

ABSTRACT Circadian rhythms that influence mammalian homeostasis and overall health have received increasing interest over the past two decades. The molecular clock, which is present in

almost every cell, drives circadian rhythms while being a cornerstone of physiological outcomes. The skeletal muscle clock has emerged as a primary contributor to metabolic health, as the

coordinated expression of the core clock factors BMAL1 and CLOCK with the muscle-specific transcription factor MYOD1 facilitates the circadian and metabolic programme that supports skeletal

muscle physiology. The phase of the skeletal muscle clock is sensitive to the time of exercise, which provides a rationale for exploring the interactions between the skeletal muscle clock,

exercise and metabolic health. Here, we review the underlying mechanisms of the skeletal muscle clock that drive muscle physiology, with a particular focus on metabolic health. Additionally,

we highlight the interaction between exercise and the skeletal muscle clock as a means of reinforcing metabolic health and discuss the possible implications of the time of exercise as a

chronotherapeutic approach. KEY POINTS * The BMAL1–CLOCK heterodimeric transcription factor is a key regulator of clock output; partnership with MYOD1 confers muscle specificity. * Skeletal

muscle substrate preference, storage and transport are highly regulated by the skeletal muscle molecular clock, aligning metabolism with physical activity and feeding patterns. * Mice with

knockouts and mutations that affect the circadian clock, and behavioural misalignment in humans, as occurs in metabolic disorders such as type 2 diabetes mellitus, have severe metabolic

consequences that affect insulin sensitivity and glucose handling. * Exercise is a potent Zeitgeber that acts to shift skeletal muscle clocks; exercising at different times of the day

results in divergent transcriptional and metabolic outputs. * Differential time-of-day exercise might prove to be a useful chronotherapeutic strategy for the treatment and management of

metabolic diseases by improving clock alignment and therefore metabolic regulation. Access through your institution Buy or subscribe This is a preview of subscription content, access via

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subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS EXERCISE METABOLISM AND ADAPTATION IN SKELETAL MUSCLE Article 24 May 2023 EXERCISE

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REFERENCES * Zhang, R., Lahens, N. F., Ballance, H. I., Hughes, M. E. & Hogenesch, J. B. A circadian gene expression atlas in mammals: implications for biology and medicine. _Proc. Natl

Acad. Sci. USA_ 111, 16219–16224 (2014). Article  CAS  PubMed  PubMed Central  Google Scholar  * Vitaterna, M. H., Takahashi, J. S. & Turek, F. W. Overview of circadian rhythms. _Alcohol

Res. Health_ 25, 85–93 (2001). CAS  PubMed  PubMed Central  Google Scholar  * Ko, C. H. & Takahashi, J. S. Molecular components of the mammalian circadian clock. _Hum. Mol. Genet._ 15,

R271–R277 (2006). Article  CAS  PubMed  Google Scholar  * Cox, K. H. & Takahashi, J. S. Circadian clock genes and the transcriptional architecture of the clock mechanism. _J. Mol.

Endocrinol._ 63, R93–R102 (2019). Article  CAS  PubMed  PubMed Central  Google Scholar  * Bunger, M. K. et al. Mop3 is an essential component of the master circadian pacemaker in mammals.

_Cell_ 103, 1009–1017 (2000). Article  CAS  PubMed  PubMed Central  Google Scholar  * Gekakis, N. et al. Role of the CLOCK protein in the mammalian circadian mechanism. _Science_ 280,

1564–1569 (1998). Article  CAS  PubMed  Google Scholar  * King, D. P. et al. Positional cloning of the mouse circadian clock gene. _Cell_ 89, 641–653 (1997). Article  CAS  PubMed  PubMed

Central  Google Scholar  * Akashi, M., Tsuchiya, Y., Yoshino, T. & Nishida, E. Control of intracellular dynamics of mammalian period proteins by casein kinase I ε (CKIε) and CKIδ in

cultured cells. _Mol. Cell. Biol._ 22, 1693–1703 (2002). Article  CAS  PubMed  PubMed Central  Google Scholar  * Camacho, F. et al. Human casein kinase Iδ phosphorylation of human circadian

clock proteins period 1 and 2. _FEBS Lett._ 489, 159–165 (2001). Article  CAS  PubMed  Google Scholar  * Eide, E. J., Vielhaber, E. L., Hinz, W. A. & Virshup, D. M. The circadian

regulatory proteins BMAL1 and cryptochromes are substrates of casein kinase Iε. _J. Biol. Chem._ 277, 17248–17254 (2002). Article  CAS  PubMed  Google Scholar  * Etchegaray, J.-P. et al.

Casein kinase 1 delta regulates the pace of the mammalian circadian clock. _Mol. Cell Biol._ 29, 3853–3866 (2009). Article  CAS  PubMed  PubMed Central  Google Scholar  * Akashi, M. &

Takumi, T. The orphan nuclear receptor RORα regulates circadian transcription of the mammalian core-clock Bmal1. _Nat. Struct. Mol. Biol._ 12, 441–448 (2005). Article  CAS  PubMed  Google

Scholar  * Guillaumond, F., Dardente, H., Giguère, V. & Cermakian, N. Differential control of Bmal1 circadian transcription by REV-ERB and ROR nuclear receptors. _J. Biol. Rhythms_ 20,

391–403 (2005). Article  CAS  PubMed  Google Scholar  * Lee, C., Weaver, D. R. & Reppert, S. M. Direct association between mouse PERIOD and CKIε is critical for a functioning circadian

clock. _Mol. Cell Biol._ 24, 584–594 (2004). Article  CAS  PubMed  PubMed Central  Google Scholar  * Xu, Y. et al. Modeling of a human circadian mutation yields insights into clock

regulation by PER2. _Cell_ 128, 59–70 (2007). Article  CAS  PubMed  PubMed Central  Google Scholar  * Reischl, S. et al. β-TrCP1-mediated degradation of PERIOD2 is essential for circadian

dynamics. _J. Biol. Rhythms_ 22, 375–386 (2007). Article  CAS  PubMed  Google Scholar  * Wu, G. et al. Structure of a β-TrCP1-Skp1-β-catenin complex: destruction motif binding and lysine

specificity of the SCFβ-TrCP1 ubiquitin ligase. _Mol. Cell_ 11, 1445–1456 (2003). Article  CAS  PubMed  Google Scholar  * Ohsaki, K. et al. The role of β-TrCP1 and β-TrCP2 in circadian

rhythm generation by mediating degradation of clock protein PER2. _J. Biochem._ 144, 609–618 (2008). Article  CAS  PubMed  Google Scholar  * Meng, Q.-J. et al. Setting clock speed in

mammals: the CK1ɛ tau mutation in mice accelerates circadian pacemakers by selectively destabilizing PERIOD proteins. _Neuron_ 58, 78–88 (2008). Article  CAS  PubMed  PubMed Central  Google

Scholar  * Busino, L. et al. SCF Fbxl3 controls the oscillation of the circadian clock by directing the degradation of cryptochrome proteins. _Science_ 316, 900–904 (2007). Article  CAS 

PubMed  Google Scholar  * Lamia, K. A. et al. AMPK regulates the circadian clock by cryptochrome phosphorylation and degradation. _Science_ 326, 437–440 (2009). Article  CAS  PubMed  PubMed

Central  Google Scholar  * Hirano, A. et al. FBXL21 regulates oscillation of the circadian clock through ubiquitination and stabilization of cryptochromes. _Cell_ 152, 1106–1118 (2013).

Article  CAS  PubMed  Google Scholar  * Hirano, A., Fu, Y.-H. & Ptáček, L. J. The intricate dance of post-translational modifications in the rhythm of life. _Nat. Struct. Mol. Biol._ 23,

1053–1060 (2016). Article  CAS  PubMed  Google Scholar  * Wheaton, K. L. et al. The phosphorylation of CREB at serine 133 is a key event for circadian clock timing and entrainment in the

suprachiasmatic nucleus. _J. Biol. Rhythms_ 33, 497–514 (2018). Article  CAS  PubMed  PubMed Central  Google Scholar  * Gau, D. et al. Phosphorylation of CREB Ser142 regulates light-induced

phase shifts of the circadian clock. _Neuron_ 34, 245–253 (2002). Article  CAS  PubMed  Google Scholar  * Travnickova-Bendova, Z., Cermakian, N., Reppert, S. M. & Sassone-Corsi, P.

Bimodal regulation of mPeriod promoters by CREB-dependent signaling and CLOCK/BMAL1 activity. _Proc. Natl Acad. Sci. USA_ 99, 7728–7733 (2002). Article  CAS  PubMed  PubMed Central  Google

Scholar  * Impey, S. et al. Defining the CREB regulon: a genome-wide analysis of transcription factor regulatory regions. _Cell_ 119, 1041–1054 (2004). CAS  PubMed  Google Scholar  *

Tischkau, S. A., Mitchell, J. W., Tyan, S.-H., Buchanan, G. F. & Gillette, M. U. Ca2+/cAMP response element-binding protein (CREB)-dependent activation of Per1 is required for

light-induced signaling in the suprachiasmatic nucleus circadian clock. _J. Biol. Chem._ 278, 718–723 (2003). Article  CAS  PubMed  Google Scholar  * Small, L. et al. Contraction influences

Per2 gene expression in skeletal muscle through a calcium‐dependent pathway. _J. Physiol._ 598, 5739–5752 (2020). Article  CAS  PubMed  Google Scholar  * Wolff, C. A. & Esser, K. A.

Exercise sets the muscle clock with a calcium assist. _J. Physiol._ 598, 5591–5592 (2020). Article  CAS  PubMed  Google Scholar  * Gabriel, B. M. et al. Disrupted circadian oscillations in

type 2 diabetes are linked to altered rhythmic mitochondrial metabolism in skeletal muscle. _Sci. Adv._ 7, eabi9654 (2021). Article  CAS  PubMed  PubMed Central  Google Scholar  * Koike, N.

et al. Transcriptional architecture and chromatin landscape of the core circadian clock in mammals. _Science_ 338, 349–354 (2012). Article  CAS  PubMed  PubMed Central  Google Scholar  *

Menet, J. S., Rodriguez, J., Abruzzi, K. C. & Rosbash, M. Nascent-Seq reveals novel features of mouse circadian transcriptional regulation. _eLife_ 1, e00011 (2012). Article  PubMed 

PubMed Central  Google Scholar  * Davis, R., Weintraub, H. & Lassar, A. Expression of a single transfected cDNA converts fibroblasts to myoblasts. _Cell_ 51, 987–1000 (1988). Article 

Google Scholar  * Miller, B. H. et al. Circadian and CLOCK-controlled regulation of the mouse transcriptome and cell proliferation. _Proc. Natl Acad. Sci. USA_ 104, 3342–3347 (2007). Article

  CAS  PubMed  PubMed Central  Google Scholar  * Andrews, J. L. et al. CLOCK and BMAL1 regulate MyoD and are necessary for maintenance of skeletal muscle phenotype and function. _Proc. Natl

Acad. Sci. USA_ 107, 19090–19095 (2010). Article  CAS  PubMed  PubMed Central  Google Scholar  * Hodge, B. A. et al. MYOD1 functions as a clock amplifier as well as a critical co-factor for

downstream circadian gene expression in muscle. _eLife_ 8, e43017 (2019). Article  PubMed  PubMed Central  Google Scholar  * Dyar, K. A. et al. The calcineurin-NFAT pathway controls

activity-dependent circadian gene expression in slow skeletal muscle. _Mol. Metab._ 4, 823–833 (2015). Article  CAS  PubMed  PubMed Central  Google Scholar  * Pizarro, A., Hayer, K., Lahens,

N. F. & Hogenesch, J. B. CircaDB: a database of mammalian circadian gene expression profiles. _Nucleic Acids Res._ 41, D1009–D1013 (2012). Article  PubMed  PubMed Central  Google

Scholar  * Gutierrez‐Monreal, M. A., Harmsen, J., Schrauwen, P. & Esser, K. A. Ticking for metabolic health: the skeletal‐muscle clocks. _Obesity_ 28(Suppl. 1), 46–54 (2020). Google

Scholar  * Perrin, L. et al. Transcriptomic analyses reveal rhythmic and CLOCK-driven pathways in human skeletal muscle. _eLife_ 7, e34114 (2018). Article  PubMed  PubMed Central  Google

Scholar  * Rey, G. et al. Genome-wide and phase-specific DNA-binding rhythms of BMAL1 control circadian output functions in mouse liver. _PLoS Biol._ 9, e1000595 (2011). Article  CAS  PubMed

  PubMed Central  Google Scholar  * Dai, Z., Ramesh, V. & Locasale, J. W. The evolving metabolic landscape of chromatin biology and epigenetics. _Nat. Rev. Genet._ 21, 737–753 (2020).

Article  CAS  PubMed  PubMed Central  Google Scholar  * Grimaldi, B. et al. Chromatin remodeling and circadian control: master regulator CLOCK is an enzyme. _Cold Spring Harb. Symp. Quant.

Biol._ 72, 105–112 (2007). Article  CAS  PubMed  Google Scholar  * Katada, S. & Sassone-Corsi, P. The histone methyltransferase MLL1 permits the oscillation of circadian gene expression.

_Nat. Struct. Mol. Biol._ 17, 1414–1421 (2010). Article  CAS  PubMed  PubMed Central  Google Scholar  * Zhu, H., Wang, G. & Qian, J. Transcription factors as readers and effectors of

DNA methylation. _Nat. Rev. Genet._ 17, 551–565 (2016). Article  CAS  PubMed  PubMed Central  Google Scholar  * Menet, J. S., Pescatore, S. & Rosbash, M. CLOCK:BMAL1 is a pioneer-like

transcription factor. _Genes Dev._ 28, 8–13 (2014). Article  CAS  PubMed  PubMed Central  Google Scholar  * Petrany, M. J. et al. Single-nucleus RNA-seq identifies transcriptional

heterogeneity in multinucleated skeletal myofibers. _Nat. Commun._ 11, 6374 (2020). Article  CAS  PubMed  PubMed Central  Google Scholar  * Dos Santos, M. et al. Single-nucleus RNA-seq and

FISH identify coordinated transcriptional activity in mammalian myofibers. _Nat. Commun._ 11, 5102 (2020). Article  PubMed  PubMed Central  Google Scholar  * Kim, M. et al. Single-nucleus

transcriptomics reveals functional compartmentalization in syncytial skeletal muscle cells. _Nat. Commun._ 11, 6375 (2020). Article  CAS  PubMed  PubMed Central  Google Scholar  * Zeng, W.

et al. Single-nucleus RNA-seq of differentiating human myoblasts reveals the extent of fate heterogeneity. _Nucleic Acids Res._ 44, e158 (2016). PubMed  PubMed Central  Google Scholar  *

Zitting, K.-M. et al. Human resting energy expenditure varies with circadian phase. _Curr. Biol._ 28, 3685–3690.e3 (2018). Article  CAS  PubMed  PubMed Central  Google Scholar  * Harmsen, J.

et al. Circadian misalignment disturbs the skeletal muscle lipidome in healthy young men. _FASEB J._ 35, e21611 (2021). Article  CAS  PubMed  Google Scholar  * Wefers, J. et al. Circadian

misalignment induces fatty acid metabolism gene profiles and compromises insulin sensitivity in human skeletal muscle. _Proc. Natl Acad. Sci. USA_ 115, 7789–7794 (2018). Article  CAS  PubMed

  PubMed Central  Google Scholar  * Morris, C. J. et al. Endogenous circadian system and circadian misalignment impact glucose tolerance via separate mechanisms in humans. _Proc. Natl Acad.

Sci. USA_ 112, E2225–E2234 (2015). Article  CAS  PubMed  PubMed Central  Google Scholar  * Morris, J. K. et al. Mild cognitive impairment and donepezil impact mitochondrial respiratory

capacity in skeletal muscle. _Function_ 2, zqab045 (2021). Article  PubMed  PubMed Central  Google Scholar  * Hodge, B. A. et al. The endogenous molecular clock orchestrates the temporal

separation of substrate metabolism in skeletal muscle. _Skelet. Muscle_ 5, 17 (2015). Article  PubMed  PubMed Central  Google Scholar  * Ezagouri, S. et al. Physiological and molecular

dissection of daily variance in exercise capacity. _Cell Metab._ 30, 78–91.e4 (2019). Article  CAS  PubMed  Google Scholar  * Harfmann, B. D. et al. Muscle-specific loss of Bmal1 leads to

disrupted tissue glucose metabolism and systemic glucose homeostasis. _Skelet. Muscle_ 6, 12 (2016). Article  PubMed  PubMed Central  Google Scholar  * Yin, H. et al. Metabolic‐sensing of

the skeletal muscle clock coordinates fuel oxidation. _FASEB J._ 34, 6613–6627 (2020). Article  CAS  PubMed  Google Scholar  * Dyar, K. A. et al. Muscle insulin sensitivity and glucose

metabolism are controlled by the intrinsic muscle clock. _Mol. Metab._ 3, 29–41 (2014). Article  CAS  PubMed  Google Scholar  * McCarthy, J. J. et al. Identification of the circadian

transcriptome in adult mouse skeletal muscle. _Physiol. Genomics_ 31, 86–95 (2007). Article  CAS  PubMed  Google Scholar  * van Moorsel, D. et al. Demonstration of a day-night rhythm in

human skeletal muscle oxidative capacity. _Mol. Metab._ 5, 635–645 (2016). Article  PubMed  PubMed Central  Google Scholar  * de Goede, P. et al. Time-restricted feeding improves glucose

tolerance in rats, but only when in line with the circadian timing system. _Front. Endocrinol._ 10, 554 (2019). Article  Google Scholar  * de Goede, P. et al. Differential effects of diet

composition and timing of feeding behavior on rat brown adipose tissue and skeletal muscle peripheral clocks. _Neurobiol. Sleep Circadian Rhythms_ 4, 24–33 (2018). Article  PubMed  Google

Scholar  * Lamia, K. A., Storch, K.-F. & Weitz, C. J. Physiological significance of a peripheral tissue circadian clock. _Proc. Natl Acad. Sci. USA_ 105, 15172–15177 (2008). Article  CAS

  PubMed  PubMed Central  Google Scholar  * Kondratov, R. V., Kondratova, A. A., Gorbacheva, V. Y., Vykhovanets, O. V. & Antoch, M. P. Early aging and age-related pathologies in mice

deficient in BMAL1, the core component of the circadian clock. _Genes Dev._ 20, 1868–1873 (2006). Article  CAS  PubMed  PubMed Central  Google Scholar  * Dyar, K. A. et al. Transcriptional

programming of lipid and amino acid metabolism by the skeletal muscle circadian clock. _PLoS Biol._ 16, e2005886 (2018). Article  PubMed  PubMed Central  Google Scholar  * Schroder, E. A. et

al. Intrinsic muscle clock is necessary for musculoskeletal health. _J. Physiol._ 593, 5387–5404 (2015). Article  CAS  PubMed  PubMed Central  Google Scholar  * Lee, S. & Dong, H. H.

FoxO integration of insulin signaling with glucose and lipid metabolism. _J. Endocrinol._ 233, R67–R79 (2017). Article  CAS  PubMed  PubMed Central  Google Scholar  * Karanth, S. et al.

FOXN3 controls liver glucose metabolism by regulating gluconeogenic substrate selection. _Physiol. Rep._ 7, e14238 (2019). Article  CAS  PubMed  PubMed Central  Google Scholar  * Bruno, N.

E. et al. Creb coactivators direct anabolic responses and enhance performance of skeletal muscle. _EMBO J._ 33, 1027–1043 (2014). Article  CAS  PubMed  PubMed Central  Google Scholar  *

Bruno, N. E. et al. Activation of Crtc2/Creb1 in skeletal muscle enhances weight loss during intermittent fasting. _FASEB J._ 35, e21999 (2021). Article  CAS  PubMed  Google Scholar  *

Pillon, N. J. et al. Transcriptomic profiling of skeletal muscle adaptations to exercise and inactivity. _Nat. Commun._ 11, 470 (2020). Article  CAS  PubMed  PubMed Central  Google Scholar 

* Pastore, S. & Hood, D. A. Endurance training ameliorates the metabolic and performance characteristics of circadian Clock mutant mice. _J. Appl. Physiol._ 114, 1076–1084 (2013).

Article  CAS  PubMed  Google Scholar  * Bae, K. et al. Differential effects of two period genes on the physiology and proteomic profiles of mouse anterior tibialis muscles. _Mol. Cell_ 22,

275–284 (2006). CAS  Google Scholar  * Woldt, E. et al. Rev-erb-α modulates skeletal muscle oxidative capacity by regulating mitochondrial biogenesis and autophagy. _Nat. Med._ 19, 1039–1046

(2013). Article  CAS  PubMed  PubMed Central  Google Scholar  * Jordan, S. D. et al. CRY1/2 selectively repress PPARδ and limit exercise capacity. _Cell Metab._ 26, 243–255.e6 (2017).

Article  CAS  PubMed  PubMed Central  Google Scholar  * Fan, W. et al. PPARδ promotes running endurance by preserving glucose. _Cell Metab._ 25, 1186–1193.e4 (2017). Article  CAS  PubMed 

PubMed Central  Google Scholar  * Yamamoto, H. et al. NCoR1 is a conserved physiological modulator of muscle mass and oxidative function. _Cell_ 147, 827–839 (2011). Article  CAS  PubMed 

PubMed Central  Google Scholar  * Marcheva, B. et al. Disruption of the clock components CLOCK and BMAL1 leads to hypoinsulinaemia and diabetes. _Nature_ 466, 627–631 (2010). Article  CAS 

PubMed  PubMed Central  Google Scholar  * Loizides-Mangold, U. et al. Lipidomics reveals diurnal lipid oscillations in human skeletal muscle persisting in cellular myotubes cultured in

vitro. _Proc. Natl Acad. Sci. USA_ 114, E8565–E8574 (2017). Article  CAS  PubMed  PubMed Central  Google Scholar  * Dibner, C. The importance of being rhythmic: living in harmony with your

body clocks. _Acta Physiol._ 228, e13281 (2020). Article  CAS  Google Scholar  * Vetter, C. Circadian disruption: what do we actually mean? _Eur. J. Neurosci._ 51, 531–550 (2020). Article 

PubMed  Google Scholar  * Harmsen, J.-F. et al. The influence of bright and dim light on substrate metabolism, energy expenditure and thermoregulation in insulin-resistant individuals

depends on time of day. _Diabetologia_ 65, 721–732 (2022). Article  CAS  PubMed  PubMed Central  Google Scholar  * Morris, C. J., Purvis, T. E., Mistretta, J. & Scheer, F. A. J. L.

Effects of the internal circadian system and circadian misalignment on glucose tolerance in chronic shift workers. _J. Clin. Endocrinol. Metab._ 101, 1066–1074 (2016). Article  CAS  PubMed 

PubMed Central  Google Scholar  * Qian, J. & Scheer, F. A. Circadian system and glucose metabolism: implications for physiology and disease. _Trends Endocrinol. Metab._ 27, 282–293

(2016). Article  CAS  PubMed  PubMed Central  Google Scholar  * Scheer, F. A. J. L., Hilton, M. F., Mantzoros, C. S. & Shea, S. A. Adverse metabolic and cardiovascular consequences of

circadian misalignment. _Proc. Natl Acad. Sci. USA_ 106, 4453–4458 (2009). Article  CAS  PubMed  PubMed Central  Google Scholar  * Eckel, R. H. et al. Morning circadian misalignment during

short sleep duration impacts insulin sensitivity. _Curr. Biol._ 25, 3004–3010 (2015). Article  CAS  PubMed  Google Scholar  * Karthikeyan, R. et al. Should we listen to our clock to prevent

type 2 diabetes mellitus? _Diabetes Res. Clin. Pract._ 106, 182–190 (2014). Article  PubMed  Google Scholar  * Hansen, J. et al. Synchronized human skeletal myotubes of lean, obese and type

2 diabetic patients maintain circadian oscillation of clock genes. _Sci. Rep._ 6, 35047 (2016). Article  CAS  PubMed  PubMed Central  Google Scholar  * Cardinali, D. P., Brown, G. M. &

Pandi-Perumal, S. R. in _The Human Hypothalamus: Anterior Region_ Handbook of Clinical Neurology series vol. 179 (eds Swaab, D. F., Kreier, F., Lucassen, P. J., Salehe, A. & Buijs, R.

M.) 357–370 (Elsevier, 2021). * Lee, Y., Field, J. M. & Sehgal, A. Circadian rhythms, disease and chronotherapy. _J. Biol. Rhythms_ 36, 503–531 (2021). Article  CAS  PubMed  PubMed

Central  Google Scholar  * Ruan, W., Yuan, X. & Eltzschig, H. K. Circadian rhythm as a therapeutic target. _Nat. Rev. Drug. Discov._ 20, 287–307 (2021). Article  CAS  PubMed  PubMed

Central  Google Scholar  * Yoo, S.-H. et al. PERIOD2: LUCIFERASE real-time reporting of circadian dynamics reveals persistent circadian oscillations in mouse peripheral tissues. _Proc. Natl

Acad. Sci. USA_ 101, 5339–5346 (2004). Article  CAS  PubMed  PubMed Central  Google Scholar  * Wolff, G. & Esser, K. A. Scheduled exercise phase shifts the circadian clock in skeletal

muscle. _Med. Sci. Sports Exerc._ 44, 1663–1670 (2012). Article  PubMed  PubMed Central  Google Scholar  * Kemler, D., Wolff, C. A. & Esser, K. A. Time‐of‐day dependent effects of

contractile activity on the phase of the skeletal muscle clock. _J. Physiol._ 598, 3631–3644 (2020). Article  CAS  PubMed  Google Scholar  * Adamovich, Y. et al. Clock proteins and training

modify exercise capacity in a daytime-dependent manner. _Proc. Natl Acad. Sci. USA_ 118, e2101115118 (2021). Article  CAS  PubMed  PubMed Central  Google Scholar  * Hoffman, N. J. et al.

Global phosphoproteomic analysis of human skeletal muscle reveals a network of exercise-regulated kinases and AMPK substrates. _Cell Metab._ 22, 922–935 (2015). Article  CAS  PubMed  PubMed

Central  Google Scholar  * Vieira, E. et al. Relationship between AMPK and the transcriptional balance of clock-related genes in skeletal muscle. _Am. J. Physiol. Endocrinol. Metab._ 295,

E1032–E1037 (2008). Article  CAS  PubMed  Google Scholar  * Casanova-Vallve, N. et al. Daily running enhances molecular and physiological circadian rhythms in skeletal muscle. _Mol. Metab._

61, 101504 (2022). Article  CAS  PubMed  PubMed Central  Google Scholar  * Sato, S. et al. Time of exercise specifies the impact on muscle metabolic pathways and systemic energy homeostasis.

_Cell Metab._ 30, 92–110.e4 (2019). Article  CAS  PubMed  Google Scholar  * Hawley, J. A., Sassone-Corsi, P. & Zierath, J. R. Chrono-nutrition for the prevention and treatment of

obesity and type 2 diabetes: from mice to men. _Diabetologia_ 63, 2253–2259 (2020). Article  PubMed  Google Scholar  * Savikj, M. et al. Afternoon exercise is more efficacious than morning

exercise at improving blood glucose levels in individuals with type 2 diabetes: a randomised crossover trial. _Diabetologia_ 62, 233–237 (2019). Article  CAS  PubMed  Google Scholar  *

Savikj, M. et al. Exercise timing influences multi-tissue metabolome and skeletal muscle proteome profiles in type 2 diabetic patients — a randomized crossover trial. _Metabolism_ 135,

155268 (2022). Article  CAS  PubMed  Google Scholar  * Moholdt, T. et al. The effect of morning vs evening exercise training on glycaemic control and serum metabolites in overweight/obese

men: a randomised trial. _Diabetologia_ 64, 2061–2076 (2021). Article  CAS  PubMed  PubMed Central  Google Scholar  * Mancilla, R. et al. Exercise training elicits superior metabolic effects

when performed in the afternoon compared to morning in metabolically compromised humans. _Physiol. Rep._ 8, e14669 (2021). Article  CAS  PubMed  Google Scholar  Download references

ACKNOWLEDGEMENTS The authors acknowledge the support of NIH grants U01AG055137 and R01AR079220 to K.A.E. The authors also thank L. Denes, Institute for Systems Genetics, New York, for kindly

providing the image of the myofibre in Fig. 4b. AUTHOR INFORMATION Author notes * These authors contributed equally: Ryan Martin, Mark Viggars. AUTHORS AND AFFILIATIONS * Department of

Physiology and Aging, University of Florida, Gainesville, FL, USA Ryan A. Martin, Mark R. Viggars & Karyn A. Esser * Myology Institute, University of Florida, Gainesville, FL, USA Ryan

A. Martin, Mark R. Viggars & Karyn A. Esser Authors * Ryan A. Martin View author publications You can also search for this author inPubMed Google Scholar * Mark R. Viggars View author

publications You can also search for this author inPubMed Google Scholar * Karyn A. Esser View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS

R.A.M. and M.R.V. researched data for the article. R.A.M, M.R.V and K.A.E. contributed substantially to discussion of the content, wrote the article and reviewed and/or edited the manuscript

before submission. CORRESPONDING AUTHOR Correspondence to Karyn A. Esser. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing interests. PEER REVIEW PEER REVIEW

INFORMATION _Nature Reviews Endocrinology_ thanks Charna Dibner, Ke Ma and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. ADDITIONAL INFORMATION

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permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Martin, R.A., Viggars, M.R. & Esser, K.A. Metabolism and exercise: the skeletal muscle clock takes centre stage. _Nat Rev Endocrinol_ 19,

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