Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Herestraat 49, B-3000, Leuven, Belgium.
Laboratory of Cell Biology and Histology, University of Antwerp, Antwerp, Belgium.
Skelet Muscle. 2023 Aug 4;13(1):12. doi: 10.1186/s13395-023-00320-4.
Critical illness is hallmarked by severe stress and organ damage. Fibroblast growth factor 21 (FGF21) has been shown to rise during critical illness. FGF21 is a pleiotropic hormone that mediates adaptive responses to tissue injury and repair in various chronic pathological conditions. Animal studies have suggested that the critical illness-induced rise in FGF21 may to a certain extent protect against acute lung, liver, kidney and brain injury. However, FGF21 has also been shown to mediate fasting-induced loss of muscle mass and force. Such loss of muscle mass and force is a frequent problem of critically ill patients, associated with adverse outcome. In the present study, we therefore investigated whether the critical illness-induced acute rise in FGF21 is muscle-protective or rather contributes to the pathophysiology of critical illness-induced muscle weakness.
In a catheterised mouse model of critical illness induced by surgery and sepsis, we first assessed the effects of genetic FGF21 inactivation, and hence the inability to acutely increase FGF21, on survival, body weight, muscle wasting and weakness, and markers of muscle cellular stress and dysfunction in acute (30 h) and prolonged (5 days) critical illness. Secondly, we assessed whether any effects were mirrored by supplementing an FGF21 analogue (LY2405319) in prolonged critical illness.
FGF21 was not required for survival of sepsis. Genetic FGF21 inactivation aggravated the critical illness-induced body weight loss (p = 0.0003), loss of muscle force (p = 0.03) and shift to smaller myofibers. This was accompanied by a more pronounced rise in markers of endoplasmic reticulum stress in muscle, without effects on impairments in mitochondrial respiratory chain enzyme activities or autophagy activation. Supplementing critically ill mice with LY2405319 did not affect survival, muscle force or weight, or markers of muscle cellular stress/dysfunction.
Endogenous FGF21 is not required for sepsis survival, but may partially protect muscle force and may reduce cellular stress in muscle. Exogenous FGF21 supplementation failed to improve muscle force or cellular stress, not supporting the clinical applicability of FGF21 supplementation to protect against muscle weakness during critical illness.
危重病的特点是严重的应激和器官损伤。成纤维细胞生长因子 21（FGF21）在危重病期间升高。FGF21 是一种多效激素，可介导各种慢性病理条件下组织损伤和修复的适应性反应。动物研究表明，危重病引起的 FGF21 升高在某种程度上可能有助于防止急性肺、肝、肾和脑损伤。然而，FGF21 也被证明介导了禁食引起的肌肉质量和力量损失。这种肌肉质量和力量的损失是危重病患者的常见问题，与不良预后相关。在本研究中，我们因此研究了危重病引起的 FGF21 急性升高是否具有肌肉保护作用，或者是否有助于危重病引起的肌肉无力的病理生理学。
在手术和脓毒症引起的危重病的导管化小鼠模型中，我们首先评估了遗传 FGF21 失活的影响，即无法急性增加 FGF21，对存活、体重、肌肉消耗和虚弱以及急性（30 小时）和延长（5 天）危重病中肌肉细胞应激和功能障碍的标志物的影响。其次，我们评估了在延长的危重病中补充 FGF21 类似物（LY2405319）是否会产生任何影响。
FGF21 不是脓毒症存活所必需的。遗传 FGF21 失活加重了危重病引起的体重减轻（p=0.0003）、肌肉力量丧失（p=0.03）和向较小肌纤维的转变。这伴随着肌肉内质网应激标志物的更明显升高，而对线粒体呼吸链酶活性或自噬激活的损害没有影响。在危重病小鼠中补充 LY2405319 不会影响存活、肌肉力量或体重，也不会影响肌肉细胞应激/功能障碍的标志物。
内源性 FGF21 不是脓毒症存活所必需的，但可能部分保护肌肉力量，并可能减少肌肉中的细胞应激。外源性 FGF21 补充未能改善肌肉力量或细胞应激，不支持 FGF21 补充以防止危重病期间肌肉无力的临床适用性。
