Department of Applied Physiology and Kinesiology, College of Health and Human Performance, University of Florida, Gainesville, FL.
Department of Microbiology and Cell Science, Institute of Food and Agricultural Sciences, University of Florida, Gainesville, FL.
Crit Care Explor. 2024 Aug 20;6(8):e1144. doi: 10.1097/CCE.0000000000001144. eCollection 2024 Aug 1.
Sepsis leads to multiple organ dysfunction and negatively impacts patient outcomes. Skeletal muscle disuse is a significant comorbidity in septic patients during their ICU stay due to prolonged immobilization.
Combination of sepsis and muscle disuse will promote a unique proteomic signature in skeletal muscle in comparison to disuse and sepsis separately.
Following cecal ligation and puncture (CLP) or Sham surgeries, mice were subjected to hindlimb suspension (HLS) or maintained normal ambulation (NA). Tibialis anterior muscles from 24 C57BL6/J male mice were harvested for proteomic analysis. Proteomic profiles were assessed using nano-liquid chromatography with tandem mass spectrometry, followed by data analysis including Partial Least Squares Discriminant Analysis (PLS-DA), to compare the differential protein expression across groups.
A total of 2876 differentially expressed proteins were identified, with marked differences between groups. In mice subjected to CLP and HLS combined, there was a distinctive proteomic signature characterized by a significant decrease in the expression of proteins involved in mitochondrial function and muscle metabolism, alongside a marked increase in proteins related to muscle degradation pathways. The PLS-DA demonstrated a clear separation among experimental groups, highlighting the unique profile of the CLP/HLS group. This suggests an important interaction between sepsis-induced inflammation and disuse atrophy mechanisms in sepsis-induced myopathy.
Our findings reveal a complex proteomic landscape in skeletal muscle exposed to sepsis and disuse, consistent with an exacerbation of muscle protein degradation under these combined stressors. The identified proteins and their roles in cellular stress responses and muscle pathology provide potential targets for intervention to mitigate muscle dysfunction in septic conditions, highlighting the importance of addressing both sepsis and disuse concurrently in clinical and experimental settings.
败血症会导致多器官功能障碍，并对患者的预后产生负面影响。由于长时间固定不动，败血症患者在 ICU 住院期间会出现骨骼肌废用，这是一种严重的合并症。
与单独的废用或败血症相比，败血症和肌肉废用的结合将在骨骼肌中产生独特的蛋白质组特征。
在进行盲肠结扎和穿刺（CLP）或假手术后，小鼠接受后肢悬吊（HLS）或保持正常活动（NA）。从 24 只 C57BL6/J 雄性小鼠的比目鱼肌中采集肌肉进行蛋白质组学分析。使用纳升液相色谱与串联质谱联用进行蛋白质组谱分析，然后进行数据分析，包括偏最小二乘判别分析（PLS-DA），以比较各组之间的差异蛋白表达。
共鉴定出 2876 个差异表达蛋白，组间差异显著。在同时接受 CLP 和 HLS 的小鼠中，存在一个独特的蛋白质组特征，其特征是与线粒体功能和肌肉代谢相关的蛋白表达显著下降，同时与肌肉降解途径相关的蛋白表达明显增加。PLS-DA 清楚地显示了实验各组之间的分离，突出了 CLP/HLS 组的独特特征。这表明败血症引起的炎症和废用萎缩机制在败血症性肌病中存在重要的相互作用。
我们的研究结果揭示了暴露于败血症和废用的骨骼肌中的复杂蛋白质组学景观，这与在这些联合应激下肌肉蛋白降解的加剧一致。所鉴定的蛋白质及其在细胞应激反应和肌肉病理学中的作用为干预措施提供了潜在的靶点，以减轻败血症条件下的肌肉功能障碍，强调了在临床和实验环境中同时解决败血症和废用的重要性。
