Cao Chun, Gao Tao, Cheng Minhua, Xi Fengchan, Zhao Chenyan, Yu Wenkui
Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, PR China.
Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, PR China.
Biochem Biophys Res Commun. 2017 Aug 26;490(3):882-888. doi: 10.1016/j.bbrc.2017.06.135. Epub 2017 Jun 21.
Sepsis, always developing muscle wasting, contributes to serious complications and mortality. Mild hypothermia has been reported to have protective effects on the prognosis of septic patients. However, the underlying mechanisms remain unclear. We therefore hypothesized that mild hypothermia could ameliorate muscle wasting during sepsis and whether it was associated with hypothalamus AMPK-induced autophagy and neuropeptides. Adult male Sprague-Dawley rats were intraperitoneally injected with lipopolysaccharide (LPS) (5 mg/kg) or saline. Mild hypothermia was instantly induced at 33 °C for 3h after LPS injected. Meanwhile, the control and sepsis groups were simultaneously placed on the thermal mattress to maintain the a normal temperature in control group whatever the changes induced by anesthesia. Twenty-four hours after injection, skeletal muscle and hypothalamus tissues were obtained. Muscle wasting was measured by the mRNA expression of two muscle atrophic genes, muscle ring finger 1 (MuRF-1) and muscle atrophy F-box (MAFbx), as well as 3-methylhistidine (3-MH) and tyrosine release. Hypothalamic AMPK-induced autophagy markers and neuropeptides expression were also detected. Results showed that LPS administration significantly decreased hypothalamic AMPK-induced autophagy together with muscle wasting. Also, increased hypothalamic neuropeptides, proopiomelanocortin (POMC), cocaine and amphetamine-related transcript (CART) and neuro-peptides Y (NPY) and decreased agouti-related protein (AgRP) were observed. Mild hypothermia significantly increased hypothalamic AMPK-induced autophagy and ameliorated LPS-induced muscle wasting, and attenuated the alteration of neuropeptides, POMC, CART and NPY. In conclusion, mild hypothermia could alleviate muscle wasting by LPS injection, which was associated with reversing the level of hypothalamic AMPK-induced autophagy and the alteration of neuropeptides. These results suggested that mild hypothermia could be a potential treatment concept and a novel mechanism in management of muscle wasting in critically ill patients.
脓毒症常伴有肌肉萎缩，会导致严重并发症和死亡。据报道，轻度低温对脓毒症患者的预后具有保护作用。然而，其潜在机制仍不清楚。因此，我们推测轻度低温可改善脓毒症期间的肌肉萎缩，以及它是否与下丘脑AMPK诱导的自噬和神经肽有关。成年雄性Sprague-Dawley大鼠腹腔注射脂多糖（LPS）（5mg/kg）或生理盐水。注射LPS后立即在33°C诱导轻度低温3小时。同时，对照组和脓毒症组同时置于热床垫上，以保持对照组的正常体温，无论麻醉引起何种变化。注射后24小时，获取骨骼肌和下丘脑组织。通过两个肌肉萎缩基因即肌肉环形指蛋白1（MuRF-1）和肌肉萎缩F盒（MAFbx）的mRNA表达以及3-甲基组氨酸（3-MH）和酪氨酸释放来测量肌肉萎缩。还检测下丘脑AMPK诱导的自噬标志物和神经肽表达。结果显示，给予LPS显著降低下丘脑AMPK诱导的自噬以及肌肉萎缩。此外，观察到下丘脑神经肽促肾上腺皮质激素原（POMC）、可卡因和苯丙胺调节转录肽（CART）以及神经肽Y（NPY）增加，而刺鼠相关蛋白（AgRP）减少。轻度低温显著增加下丘脑AMPK诱导的自噬，改善LPS诱导的肌肉萎缩，并减弱神经肽POMC、CART和NPY的改变。总之，轻度低温可减轻LPS注射引起的肌肉萎缩，这与逆转下丘脑AMPK诱导的自噬水平和神经肽改变有关。这些结果表明，轻度低温可能是治疗重症患者肌肉萎缩的一种潜在治疗理念和新机制。
