Physiological and Molecular Dissection of Daily Variance in Exercise Capacity

Ezagouri, Saar; Zwighaft, Ziv; Sobel, Jonathan; Baillieul, Sébastien; Doutreleau, Stéphane; Ladeuix, Benjamin; Golik, Marina; Vergès, Samuel; Asher, Gad

doi:10.1016/j.cmet.2019.03.012

Cited by 123 publications

(157 citation statements)

References 59 publications

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“…However, it is more well known as a drug that is given to activate AMP kinase, but was recently shown to be endogenously produced by intense endurance exercise (Ezagouri et al . 2019).…”

Section: Discussionmentioning

confidence: 99%

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Delayed metabolic dysfunction in myocardium following exertional heat stroke in mice

Laitano

Garcia

Mattingly

et al. 2020

The Journal of Physiology

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Key points Exposure to exertional heat stroke (EHS) is associated with increased risk of long‐term cardiovascular disorders in humans. We demonstrate that in female mice, severe EHS results in metabolic changes in the myocardium, emerging only after 9–14 days. This was not observed in males that were symptom‐limited at much lower exercise levels and heat loads compared to females. At 14 days of recovery in females, there were marked elevations in myocardial free fatty acids, ceramides and diacylglycerols, consistent with development of underlying cardiac abnormalities. Glycolysis shifted towards the pentose phosphate and glycerol‐3‐phosphate dehydrogenase pathways. There was evidence for oxidative stress, tissue injury and microscopic interstitial inflammation. The tricarboxylic acid cycle and nucleic acid metabolism pathways were also negatively affected. We conclude that exposure to EHS in female mice has the capacity to cause delayed metabolic disorders in the heart that could influence long‐term health. Abstract Exposure to exertional heat stroke (EHS) is associated with a higher risk of long‐term cardiovascular disease in humans. Whether this is a cause‐and‐effect relationship remains unknown. We studied the potential of EHS to contribute to the development of a ‘silent’ form of cardiovascular disease using a preclinical mouse model of EHS. Plasma and ventricular myocardial samples were collected over 14 days of recovery. Male and female C57bl/6J mice underwent forced wheel running for 1.5–3 h in a 37.5°C/40% relative humidity until symptom limitation, characterized by CNS dysfunction. They reached peak core temperatures of 42.2 ± 0.3°C. Females ran ∼40% longer, reaching ∼51% greater heat load. Myocardial and plasma samples (n = 8 per group) were obtained between 30 min and 14 days of recovery, analysed using metabolomics/lipidomics platforms and compared to exercise controls. The immediate recovery period revealed an acute energy substrate crisis from which both sexes recovered within 24 h. However, at 9–14 days, the myocardium of female mice developed marked elevations in free fatty acids, ceramides and diacylglycerols. Glycolytic and tricarboxylic acid cycle metabolites revealed bottlenecks in substrate flow, with build‐up of intermediate metabolites consistent with oxidative stress and damage. Males exhibited only late stage reductions in acylcarnitines and elevations in acetylcarnitine. Histopathology at 14 days showed interstitial inflammation in the female hearts only. The results demonstrate that the myocardium of female mice is vulnerable to a slowly emerging metabolic disorder following EHS that may harbinger long‐term cardiovascular complications. Lack of similar findings in males may reflect their lower heat exposure.

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“…However, it is more well known as a drug that is given to activate AMP kinase, but was recently shown to be endogenously produced by intense endurance exercise (Ezagouri et al . 2019).…”

Section: Discussionmentioning

confidence: 99%

“…AICAR is an intermediate in the synthesis of inosine monophosphate (IMP), reviewed in Daignan-Fornier & Pinson (2012). However, it is more well known as a drug that is given to activate AMP kinase, but was recently shown to be endogenously produced by intense endurance exercise (Ezagouri et al 2019).…”

Section: Differences Between Males and Femalesmentioning

confidence: 99%

Delayed metabolic dysfunction in myocardium following exertional heat stroke in mice

Laitano

Garcia

Mattingly

et al. 2020

The Journal of Physiology

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“…Exercise is a well-known stimulus that can alter skeletal muscle and organismal physiology. While emerging data have shown potent time-of-day specific outcomes of exercise on skeletal muscle gene expression and metabolism (Ezagouri et al 2019;Gabriel & Zierath, 2019;Sato et al 2019), studies of the potential role of exercise as an environmental time cue for circadian clocks have been limited. Specifically, studies have performed time-of-day exercise interventions and measured both behavioural as well as clock outcomes but all these studies performed repeated exercise training (Edgar & Dement, 1991;Marchant & Mistlberger, 1996;Yamanaka et al 2008;Wolff & Esser, 2012).…”

Section: Discussionmentioning

confidence: 99%

Time‐of‐day dependent effects of contractile activity on the phase of the skeletal muscle clock

Kemler

Wolff

Esser

2020

The Journal of Physiology

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Key points Disruptions in circadian rhythms across an organism are associated with negative health outcomes, such as cardiometabolic and neurodegenerative diseases. Exercise has been proposed as a time cue for the circadian clock in rodents and humans. In this study, we assessed the effect of a single bout of endurance exercise on the skeletal muscle clock in vivo and a bout of muscle contractions in vitro. Timing of exercise or contractions influences the directional response of the muscle clock phase in vivo and in vitro. Our findings demonstrate that muscle contractions, as a component of exercise, can directly modulate the expression of muscle clock components in a time‐of‐day dependent manner. Abstract Exercise has been proposed to be a zeitgeber for the muscle circadian clock mechanism. However, this is not well defined and it is unknown if exercise timing induces directional shifts of the muscle clock. Our purpose herein was to assess the effect of one bout of treadmill exercise on skeletal muscle clock phase changes. We subjected PERIOD2::LUCIFERASE mice (n = 30F) to one 60 min treadmill exercise bout at three times of day. Exercise at ZT5, 5 h after lights on, induced a phase advance (100.2 ± 25.8 min; P = 0.0002), whereas exercise at ZT11, 1 h before lights off, induced a phase delay (62.1 ± 21.1 min; P = 0.0003). Exercise at ZT17, middle of the dark phase, did not alter the muscle clock phase. Exercise induces diverse systemic changes so we developed an in vitro model system to examine the effects of contractile activity on muscle clock phase. Contractions applied at peak or trough Bmal1 expression induced significant phase delays (applied at peak: 27.2 ± 10.2 min; P = 0.0017; applied at trough: 64.6 ± 6.5 min, P < 0.0001). Contractions applied during the transition from peak to trough Bmal1 expression induced a phase advance (49.8 ± 23.1 min; P = 0.0051). Lastly, contractions at different times of day resulted in differential changes of core clock gene expression, demonstrating an exercise and clock interaction, providing insight into potential mechanisms of exercise‐induced phase shifts. These data demonstrate that muscle contractions, as part of exercise, are sufficient to shift the muscle circadian clock phase, likely through changes in core clock gene expression. Additionally, our findings that exercise induces directional muscle clock phase changes confirms that exercise is a bona fide environmental time cue for skeletal muscle.

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“…In many individuals, especially in people with a late chronotype, an advance of the internal circadian rhythm would better align internal rhythms with the environment and with standard social schedules. Recent studies in mice showed that exercise performance, gene transcription, and energy utilization depend on the time of day of exercise (31,32). Clinical studies have conflicting results, but some have shown that morning or early afternoon exercise phase advances, while evening exercise phase delays the internal circadian rhythm (21,(33)(34)(35)(36).…”

Section: L I N I C a L M E D I C I N Ementioning

confidence: 99%