ß-Nicotinamide mononucleotide restores mitochondrial function and muscle strength in septic male mice

Sepsis remains a leading cause of mortality and long-term disability, with survivors frequently developing intensive care unit–acquired weakness (ICU-AW) as part of post–intensive care syndrome. Here, to identify a nutritional therapy for ICU-AW, we investigated the mechanisms underlying sepsis-induced skeletal muscle dysfunction using a cecal slurry-induced sepsis mouse model. Although body weight and skeletal muscle mass recovered at 14 days after sepsis induction, muscle strength remained impaired, accompanied by persistent mitochondrial abnormalities. Transcriptomic analysis revealed that the pathways termed “Sirtuin signaling pathway” and “Mitochondrial dysfunction” significantly enriched with downregulation of Sirt3 which is a major mitochondrial NAD?-dependent deacetylase. Biochemical analyses confirmed increased acetylated lysine of mitochondrial proteins in septic muscle tissue. Among them, mass spectrometry identified complex I subunits as candidate substrates of Sirt3. Knockdown of Sirt3 in C2C12 myotubes impaired mitochondrial respiration, whereas treatment with ß-nicotinamide mononucleotide (ß-NMN) partially rescued energy production. In vivo, acute-phase administration of ß-NMN preserved mitochondrial morphology and restored muscle strength without altering muscle mass. These findings demonstrate that sepsis induces mitochondrial dysfunction and persistent muscle weakness through Sirt3 downregulation, and highlight ß-NMN supplementation as a promising NAD?-targeted therapeutic strategy for mitigating ICU-AW. Overall design: To investigate the effects of sepsis on skeletal muscle, gastrocnemius muscles were isolated from control mice or from mice subjected to cecal slurry–induced sepsis for 4 days, and gene expression profiling analysis was performed using RNA-seq.

脓毒症仍是导致死亡与长期残疾的主要病因之一，存活患者常继发重症监护获得性肌无力（ICU-AW），这也是重症后综合征的常见表现。为筛选针对ICU-AW的营养治疗方案，本研究采用盲肠浆液诱导脓毒症小鼠模型，探究脓毒症诱发骨骼肌功能障碍的潜在机制。尽管脓毒症造模后14天，小鼠体重与骨骼肌质量可恢复至基线水平，但肌肉力量仍持续受损，并伴随持续性线粒体异常。转录组分析显示，"Sirtuin信号通路"与"线粒体功能障碍"通路显著富集，同时作为核心线粒体NAD+依赖性脱乙酰酶的Sirt3表达显著下调。生化分析证实，脓毒症小鼠骨骼肌组织内线粒体蛋白的赖氨酸乙酰化水平显著升高。进一步通过质谱分析，鉴定出线粒体复合物I亚基为Sirt3的潜在作用底物。在C2C12肌管中敲低Sirt3会损伤线粒体呼吸功能，而给予β-烟酰胺单核苷酸（β-nicotinamide mononucleotide，β-NMN）可部分挽救能量产生。在体实验中，急性期给予β-NMN可维持线粒体形态，并在不改变骨骼肌质量的前提下恢复肌肉力量。本研究结果证实，脓毒症可通过下调Sirt3表达诱发线粒体功能障碍与持续性肌无力，并表明补充β-NMN是一种极具前景的靶向NAD+治疗策略，可用于缓解ICU-AW。【实验整体设计】为探究脓毒症对骨骼肌的影响，本研究从对照组小鼠以及盲肠浆液诱导脓毒症造模4天的小鼠中分离腓肠肌，并通过RNA测序开展基因表达谱分析。