Biochemical and Biophysical Research Communications
Constant light exposure aggravates POMC-mediated muscle wasting associated with hypothalamic alteration of circadian clock and SIRT1 in endotoxemia rats
Introduction
Due to nursing procedures and the lack of attention, constant light exposure is very widespread in the ICU [1]. Reported nocturnal illumination in the ICU varies widely with mean maximum levels of 5–1400 lux, which could increase the risk of brain dysfunctions in critical patients, such as delirium [2,3]. It is important to note that hypercatabolism, including breakdown of carbohydrates, lipid and protein, is common in critical patients [4,5]. The hypercatabolism, especially skeletal muscle wasting could cause serious complications and poor prognosis, which has been shown to correlate with activation of hypothalamic POMC [6]. However, there is few studies focusing on the effect of constant light exposure on hypercatabolism in critical patients.
In our previous study, we found skeletal muscle wasting was accompanied with the activation of anorexigenic POMC neuropeptides in the arcuate nucleus (ARC) of hypothalamus [6] and siRNA mediated knock down of POMC in the hypothalamus could significantly alleviate LPS-induced muscle wasting [7], which suggested the alteration of hypothalamic POMC exerts a critical role in regulating skeletal muscle wasting of endotoxemia rats. There is accumulating evidence that SIRT1, as a sirtuin protein, is expressed virtually in all POMC neurons of the hypothalamic ARC and closely involved in the regulation of energy expenditure in mammals [8]. It's proved that fasting increased the expression of SIRT1 and reduced POMC in the hypothalamus and hypothalamic SIRT1 inhibition could dampen fasting-induced decrease of POMC, which indicated SIRT1 could regulate the expression of hypothalamic POMC in the fasting state [9].
On the other hand, SIRT1 also participates in the circadian clock as a deacetylase besides being a metabolic-sensor protein [10,11]. It is well known that human physiological and behavioral processes exhibit repeating 24-h cycle called as circadian rhythm [12]. And at the cellular level, there is a transcription-translation feedback loop mediating daily oscillations, which is consisted of core circadian clock genes. Circadian Locomotor Output Cycles Kaput(CLOCK), found as a histone acetyltransferase, and its heterodimer partner BMAL1 encode activators in this loop and Cryptochrome (CRY) and Period (PER) encode repressors [13]. Previous studies have demonstrated that SIRT1 binds to CLOCK-BMAL1 heterodimer and is influenced by the oscillation of clock genes [10]. At the organism level, the suprachiasmatic nucleus (SCN) of the hypothalamus acts as a master pacemaker to synchronize circadian rhythms throughout the body and light is the most potent signal for the circadian clock [14], demonstrating constant light exposure could disrupt circadian rhythms in mammals [15].
Taking the above into consideration, we hypothesized that constant light exposure aggravates POMC-mediated skeletal muscle wasting in endotoxemia rats and it was associated with the alteration of circadian rhythm and SIRT1 expression in the hypothalamus.
Section snippets
Animals and housing condition
Fifty-four male Sprague-Dawley rats (250 ± 20 g) were obtained from the animal center of Jinling Hospital. Upon arrival, the animals were housed separately and kept in a well-ventilated animal facility under a temperature-controlled and natural photoperiod environment. They were provided with free access to standard rat pellet chow and water. The experimental protocols were approved by the Institutional Animal Care and Use Committee of Nanjing University and Jinling Hospital.
Experimental design and sampling
After a week of
Rate of protein breakdown and muscle atrophic gene expression
Compared with the control, LPS administration resulted in significant decreased food intake, loss of body weight (BW) and lower EDL:BW ratio in 7 days (all P < 0.01, Fig. 1). What's more, the significantly reduction of food intake, BW and EDL: BW ratio were found in rats with constant light exposure compared with endotoxemia rats under the 12:12 h light-dark cycle. (P < 0.05, Fig. 1).
The rate of muscle protein breakdown was measured by 3-MH and tyrosine release. Compared with the control, the
Discussion
Constant light exposure is pretty common in ICU, which could increase the risk of brain dysfunction like delirium [12,21]. And there is compelling evidence that constant light exposure could alter energy metabolism and neuroendocrine [2]. Furthermore, the hypercatabolism and subsequent skeletal muscle wasting could always result in serious complications and poor prognosis in critical patients [22]. The present data showed that constant light exposure induced significant increased expression of
Conflicts of interest
The authors declared that no conflict of interests.
Funding
This work was supported by the National Natural Science Foundation of China (No.81270884). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
References (33)
- et al.
Metabolism, metabolomics, and nutritional support of patients with sepsis
Clin. Chest Med.
(2016) - et al.
SIRT1 deacetylase in POMC neurons is required for homeostatic defenses against diet-induced obesity
Cell Metabol.
(2010) - et al.
SIRT1 and other sirtuins in metabolism
Trends Endocrinol. Metabol.
(2014) - et al.
Immunosenescence-like state is accelerated by constant light exposure and counteracted by melatonin or turmeric administration through DJ-1/Nrf2 and P53/Bax pathways
J. Photochem. Photobiol., B
(2018) - et al.
Circadian rhythm and light responsiveness of BMAL1 expression, a partner of mammalian clock gene Clock, in the suprachiasmatic nucleus of rats
Neurosci. Lett.
(1998) - et al.
Circadian regulator CLOCK is a histone acetyltransferase
Cell
(2006) - et al.
The NAD+-dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control
Cell
(2008) - et al.
SIRT1 is a circadian deacetylase for core clock components
Cell
(2008) - et al.
Antagonistic crosstalk between NF-kappaB and SIRT1 in the regulation of inflammation and metabolic disorders
Cell. Signal.
(2013) - et al.
Characterisation of sleep in intensive care using 24-hour polysomnography: an observational study
Crit. Care
(2013)
Circadian and metabolic effects of light: implications in weight homeostasis and health
Front. Neurol.
Effects of earplugs and eye masks on nocturnal sleep, melatonin and cortisol in a simulated intensive care unit environment
Crit. Care
Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care
Crit. Care Med.
Insulin ameliorating endotoxaemia-induced muscle wasting is associated with the alteration of hypothalamic neuropeptides and inflammation in rats
Clin. Endocrinol.
Hypothalamic activation is essential for endotoxemia-induced acute muscle wasting
Sci. Rep.
Hypothalamic Sirt1 regulates food intake in a rodent model system
PLoS One
Cited by (3)
Adipose improves muscular atrophy caused by Sirtuin1 deficiency by promoting mitochondria synthesis
2022, International Journal of Biochemistry and Cell BiologyCitation Excerpt :The pathogenesis of muscle atrophy or sarcopenia is far from clear. Increasing evidences suggest that Sirt1 plays a vital role in muscle remodeling (Chen et al., 2019; Myers et al., 2019a; Ross et al., 2018). Considering this, we used Sirt1+/- mice as an animal model to explore the regulatory mechanism of muscle growth and development in this study.
Circadian Disruption and Consequences on Innate Immunity and Inflammatory Response
2022, International Journal of Molecular Sciences
- 1
These authors contributed equally to this work.