Chuang Key Chia-Chi, Belfield Lanazha, Krall Jennifer Thi Wing, Gibbs Kevin W, Liu Chun, Purcell Lina, Stapleton Renee D, Poynter Matthew E, Toth Michael J, Quinn Matthew, Das Swapan K, Files D Clark
Department of Internal Medicine, Section of Pulmonary, Critical Care, Allergy and Immunologic Diseases, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States.
Department of Internal Medicine, Section of Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States.
Am J Physiol Endocrinol Metab. 2025 Jun 1;328(6):E1041-E1051. doi: 10.1152/ajpendo.00039.2025. Epub 2025 May 13.
Muscle wasting is common in patients with acute respiratory distress syndrome (ARDS). We have previously shown that acute lung-injured (ALI) mice develop muscle atrophy driven by muscle E3 ubiquitin ligase muscle RING-finger protein 1 (MuRF1). The muscle atrophy response in ALI mice can be partially alleviated by short durations of moderate-intensity treadmill exercise through unclear mechanisms. Glucocorticoid receptor (GR) signaling has been implicated in muscle wasting and repair, and the MuRF1 promoter contains a glucocorticoid response element. We examined the contribution of muscle GR signaling in ALI-associated muscle wasting and the response to exercise. Intratracheal lipopolysaccharides were instilled into wild-type (WT) mice. Mice exercised for prescribed intensity and duration on a treadmill. GR knockdown was achieved through pharmacological inhibition and the use of muscle-specific GR knockout mice. Muscle structure and function was evaluated using physiological and histochemical techniques, and GR activation was assessed under multiple conditions. Muscle wasting in ALI mice was associated with a GR transcriptional response, which was suppressed by exercise. However, neither pharmacological inhibition of muscle GR signaling, nor genetic deletion of muscle GR prevented skeletal muscle wasting or recapitulated the benefits of exercise in WT ALI mice. Moreover, RNAseq of tibialis anterior and diaphragm skeletal muscle in WT mice revealed that exercise influenced genes related to skeletal muscle tissue remodeling, but pathway analysis suggested that this was unrelated to the glucocorticoid axis. GR signaling is dispensable for both ALI muscle wasting and its partial mitigation by exercise in mice. The endogenous glucocorticoid axis is known to influence skeletal muscle structure and function and is activated during stress. Its role in driving muscle wasting and the response to exercise in the context of lung injury is unknown. Here we find that despite a strong muscle transcriptional glucocorticoid response, this axis appears dispensable for muscle wasting or the favorable response to exercise.
肌肉萎缩在急性呼吸窘迫综合征（ARDS）患者中很常见。我们之前已经表明，急性肺损伤（ALI）小鼠会出现由肌肉E3泛素连接酶肌肉环指蛋白1（MuRF1）驱动的肌肉萎缩。通过不清楚的机制，短时间的中等强度跑步机运动可部分缓解ALI小鼠的肌肉萎缩反应。糖皮质激素受体（GR）信号传导与肌肉萎缩和修复有关，并且MuRF1启动子包含一个糖皮质激素反应元件。我们研究了肌肉GR信号传导在ALI相关肌肉萎缩中的作用以及对运动的反应。将气管内脂多糖注入野生型（WT）小鼠体内。小鼠在跑步机上按照规定的强度和持续时间进行运动。通过药理学抑制和使用肌肉特异性GR基因敲除小鼠来实现GR基因敲低。使用生理和组织化学技术评估肌肉结构和功能，并在多种条件下评估GR激活情况。ALI小鼠的肌肉萎缩与GR转录反应有关，运动可抑制该反应。然而，无论是对肌肉GR信号传导的药理学抑制，还是肌肉GR的基因缺失，都不能预防WT ALI小鼠的骨骼肌萎缩，也不能重现运动的益处。此外，WT小鼠胫前肌和膈肌骨骼肌的RNA测序显示，运动影响与骨骼肌组织重塑相关的基因，但通路分析表明这与糖皮质激素轴无关。GR信号传导对于ALI小鼠的肌肉萎缩及其通过运动的部分缓解都是可有可无的。已知内源性糖皮质激素轴会影响骨骼肌结构和功能，并在应激期间被激活。其在肺损伤背景下驱动肌肉萎缩和对运动反应中的作用尚不清楚。在这里，我们发现尽管肌肉存在强烈的糖皮质激素转录反应，但该轴对于肌肉萎缩或对运动的良好反应似乎是可有可无的。
