Constant light exposure aggravates POMC-mediated muscle wasting associated with hypothalamic alteration of circadian clock and SIRT1 in endotoxemia rats

https://doi.org/10.1016/j.bbrc.2018.12.020Get rights and content

Highlights

  • Endotoxemia increases POMC expression and results in skeletal muscle wasting.

  • Constant light exposure aggravates muscle wasting and POMC activation in endotoxemia.

  • Constant light exposure disrupts circadian rhythm and decreases the expression of SIRT1 in the hypothalamus.

Abstract

Constant light exposure is widespread in the intensive care unit (ICU) and could increase the rate of brain dysfunction as delirium and sleep disorders in critical patients. And the activation of hypothalamic neuropeptides is proved to play a crucial role in regulating hypercatabolism, especially skeletal muscle wasting in critical patients, which could lead to serious complications and poor prognosis. Here we investigated the hypothesis that constant light exposure could aggravate skeletal muscle wasting in endotoxemia rats and whether it was associated with alterations of circadian clock and hypothalamic proopiomelanocortin(POMC) expression. Fifty-four adult male Sprague-Dawley rats were intraperitoneally injected with lipopolysaccharide(LPS) or saline, subjected to constant light or a 12:12 h light-dark cycle for 7 days. On day 8, rats were sacrificed across six time points in 24 h and hypothalamus tissues and skeletal muscle were obtained. Rates of muscle wasting were measured by 3-methylhistidine(3-MH) and tyrosine release as well as expression of two muscle atrophic genes, muscle ring finger 1(MuRF-1) and muscle atrophy F-box(MAFbx). The expression of circadian clock genes, silent information regulator 1(SIRT1), POMC and hypothalamic inflammatory cytokines were also detected. Results showed that LPS administration significantly increased hypothalamic POMC expression, inflammatory cytokine levels and muscle wasting rates. Meanwhile constant light exposure disrupted the circadian rhythm, declined the expression of SIRT1 as well as aggravated hypothalamic POMC overexpression and skeletal muscle wasting in rats with endotoxemia. Taken together, the results demonstrated that constant light exposure could aggravate POMC-mediated skeletal muscle wasting in endotoxemia rats, which is associated with alteration of circadian clocks and SIRT1 in the hypothalamus.

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.

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