Mechanistic basis of exercise responses in liver disease

肌肉减少症，或骨骼肌质量损失，收缩功能受损，导致身体虚弱， 运动能力降低在肝硬化中是常见的，并导致不良的临床结果。行使 训练改善了肌肉质量和运动能力的一些措施，但这些措施的机械基础 肝硬化的反应尚不清楚。在健康受试者中，耐力运动（EE）可提高最大氧含量 消耗（VO 2 max），而阻力运动（RE）增加肌肉质量和力量。患者 肝硬化，肌肉质量的增加提高了生存率。相比之下，较高的VO 2 max与较好的 但是最大摄氧量的增加是否转化为肝硬化临床结果的改善尚不清楚。 对规定的运动训练的低依从性是肝硬化患者和家庭患者的另一个挑战， 无人监督的程序并不总是有效的。肠道微生物组和微生物代谢物的变化 （xenometabulin）发生在健康受试者的运动中，但运动是否会引起肠道的变化， 肝硬化中的微生物组/代谢物，以及这些变化是否与骨骼肌合成代谢反应有关 也是未知的。在初步研究中，我们注意到，氨，一种捕虏物，在 在临床前模型中，肝硬化患者的血浆和骨骼肌中，引起肌肉减少症。拟议 研究，我们将整合假设和数据驱动的方法，以确定分子和代谢 肝硬化患者对运动训练计划的反应，以逆转肌肉减少症。我们将测试 总体假设，一个有监督的，结构化的耐力或阻力运动将导致 肝硬化中骨骼肌分子、代谢和功能紊乱改善在AIM中 1、在特征明确的、病情稳定的患者中，运动训练的分子和代谢反应 将确定肝硬化。患者将被随机分配至家庭远程医疗监督EE或RE 计划或标准护理（SOC）管理12周。肌肉质量，身体虚弱的衡量标准， 肌肉蛋白质合成、线粒体功能和细胞信号应答将被定量。患者 将在完成运动计划后随访6个月，以了解死亡率、失代偿和 住院这些一流的研究将评估监督，个性化培训的有效性 肝硬化患者的治疗方案在AIM 2中，将比较EE、RE之间的全球多组学缓解 骨骼肌转录组、蛋白质组、磷酸化蛋白质组、代谢组;血浆 蛋白质组/代谢组;和粪便微生物组/代谢组将被定量。综合多组学 将使用机器学习算法进行包括功能富集分析在内的方法， 将肌肉和血浆反应与肝硬化中微生物组的改变联系起来。这些研究将 同时帮助解决对EE或RE的反应的机械基础，同时提高遵守率， 为肝硬化患者制定有针对性的个性化培训方案。

Sarcopenia, or loss of skeletal muscle mass, with impaired contractile function that causes physical frailty and decreased exercise capacity are frequent in cirrhosis and contribute to adverse clinical outcomes. Exercise training improves some measures of muscle mass and exercise capacity but the mechanistic basis of these responses in cirrhosis is not known. In healthy subjects, endurance exercise (EE) improves maximum oxygen consumption (VO2max) while resistance exercise (RE) increases muscle mass and strength. In patients with cirrhosis, an increase in muscle mass improves survival. In contrast, higher VO2max is associated with better survival but whether an increase in VO2max translates to improved clinical outcomes in cirrhosis is not known. Low adherence to prescribed exercise training is another challenge in patients with cirrhosis and home-based, unsupervised programs are not consistently effective. Changes in gut microbiome and microbial metabolites (xenometabolites) occur with exercise in healthy subjects, but whether exercise causes changes in the gut microbiome/metabolites in cirrhosis and if the changes can be related to skeletal muscle anabolic responses are also not known. In preliminary studies, we noted that ammonia, a xenometabolite that is increased in the plasma and skeletal muscle in patients with cirrhosis, causes sarcopenia in preclinical models. In the proposed studies, we will integrate hypothesis- and data-driven approaches to identify the molecular and metabolic responses to an exercise training program in patients with cirrhosis to reverse sarcopenia. We will test the overall hypothesis that a supervised, structured endurance or resistance exercise will result in improvement in skeletal muscle molecular, metabolic and functional perturbations in cirrhosis. In AIM 1, the molecular and metabolic responses to exercise training in well-characterized, stable patients with cirrhosis will be determined. Patients will be randomized to a home-based, telemedicine supervised EE or RE program or standard of care (SOC) management for 12 weeks. Muscle mass, measures of physical frailty, muscle protein synthesis, mitochondrial function and cellular signaling responses will be quantified. Patients will be followed for 6-months after completion of the exercise program for mortality, decompensation, and hospitalization. These first-in-class studies will evaluate the efficacy of a supervised, personalized training program in patients with cirrhosis. In AIM 2, global multiomics responses will be compared between EE, RE and SOC. Skeletal muscle transcriptome, proteome, phosphoproteome, metabolome; plasma proteome/metabolome; and stool microbiome/metabolome will be quantified. An integrated multiomics approach including functional enrichment analyses will be performed using machine learning algorithms to relate the muscle and plasma responses to alterations in microbiome in cirrhosis. These studies will simultaneously help address the mechanistic basis of responses to EE or RE while enhancing compliance in patients with cirrhosis to develop targeted and personalized training programs.