Department of Laboratory Medicine, Section of Clinical Physiology, Karolinska Institutet, Huddinge, Sweden.
Department of Physiology and Pharmacology, Biomedicum C5, Karolinska Institutet, Solna, Sweden.
J Cachexia Sarcopenia Muscle. 2022 Oct;13(5):2551-2561. doi: 10.1002/jcsm.13029. Epub 2022 Jul 18.
Activation of sphingomyelinase (SMase) as a result of a general inflammatory response has been implicated as a mechanism underlying disease-related loss of skeletal muscle mass and function in several clinical conditions including heart failure. Here, for the first time, we characterize the effects of SMase activity on human muscle fibre contractile function and assess skeletal muscle SMase activity in heart failure patients.
The effects of SMase on force production and intracellular Ca handling were investigated in single intact human muscle fibres. Additional mechanistic studies were performed in single mouse toe muscle fibres. RNA sequencing was performed in human muscle bundles exposed to SMase. Intramuscular SMase activity was measured from heart failure patients (n = 61, age 69 ± 0.8 years, NYHA III-IV, ejection fraction 25 ± 1.0%, peak VO 14.4 ± 0.6 mL × kg × min) and healthy age-matched control subjects (n = 10, age 71 ± 2.2 years, ejection fraction 60 ± 1.2%, peak VO 25.8 ± 1.1 mL × kg × min). SMase activity was related to circulatory factors known to be associated with progression and disease severity in heart failure.
Sphingomyelinase reduced muscle fibre force production (-30%, P < 0.05) by impairing sarcoplasmic reticulum (SR) Ca release (P < 0.05) and reducing myofibrillar Ca sensitivity. In human muscle bundles exposed to SMase, RNA sequencing analysis revealed 180 and 291 genes as up-regulated and down-regulated, respectively, at a FDR of 1%. Gene-set enrichment analysis identified 'proteasome degradation' as an up-regulated pathway (average fold-change 1.1, P = 0.008), while the pathway 'cytoplasmic ribosomal proteins' (average fold-change 0.8, P < 0.0001) and factors involving proliferation of muscle cells (average fold-change 0.8, P = 0.0002) where identified as down-regulated. Intramuscular SMase activity was ~20% higher (P < 0.05) in human heart failure patients than in age-matched healthy controls and was positively correlated with markers of disease severity and progression, and with several circulating inflammatory proteins, including TNF-receptor 1 and 2. In a longitudinal cohort of heart failure patients (n = 6, mean follow-up time 2.5 ± 0.2 years), SMase activity was demonstrated to increase by 30% (P < 0.05) with duration of disease.
The present findings implicate activation of skeletal muscle SMase as a mechanism underlying human heart failure-related loss of muscle mass and function. Moreover, our findings strengthen the idea that SMase activation may underpin disease-related loss of muscle mass and function in other clinical conditions, acting as a common patophysiological mechanism for the myopathy often reported in diseases associated with a systemic inflammatory response.
由于全身炎症反应导致的神经鞘磷脂酶（SMase）的激活，被认为是几种临床情况下与疾病相关的骨骼肌质量和功能丧失的机制，包括心力衰竭。在这里，我们首次描述了 SMase 活性对人肌纤维收缩功能的影响，并评估了心力衰竭患者的骨骼肌 SMase 活性。
在单个完整的人肌纤维中研究了 SMase 对力产生和细胞内 Ca 处理的影响。在单个小鼠趾肌纤维中进行了额外的机制研究。在暴露于 SMase 的人肌束中进行了 RNA 测序。从心力衰竭患者（n=61，年龄 69±0.8 岁，NYHA III-IV，射血分数 25±1.0%，峰值 VO 14.4±0.6 mL×kg×min）和年龄匹配的健康对照组（n=10，年龄 71±2.2 岁，射血分数 60±1.2%，峰值 VO 25.8±1.1 mL×kg×min）中测量了肌肉内 SMase 活性。SMase 活性与已知与心力衰竭进展和疾病严重程度相关的循环因子有关。
SMase 通过损害肌浆网（SR）Ca 释放（P<0.05）和降低肌球蛋白 Ca 敏感性，降低肌肉纤维的力产生（-30%，P<0.05）。在暴露于 SMase 的人肌束中，RNA 测序分析显示，在 FDR 为 1%时，分别有 180 和 291 个基因上调和下调。基因集富集分析发现“蛋白酶体降解”为上调途径（平均倍数变化 1.1，P=0.008），而“细胞质核糖体蛋白”途径（平均倍数变化 0.8，P<0.0001）和涉及肌肉细胞增殖的因子（平均倍数变化 0.8，P=0.0002）被鉴定为下调途径。肌肉内 SMase 活性在人类心力衰竭患者中约高 20%（P<0.05），与年龄匹配的健康对照组相比，并与疾病严重程度和进展的标志物以及几种循环炎症蛋白（包括 TNF 受体 1 和 2）呈正相关。在心力衰竭患者的纵向队列中（n=6，平均随访时间 2.5±0.2 年），发现 SMase 活性随疾病持续时间增加 30%（P<0.05）。
本研究结果提示，骨骼肌 SMase 的激活可能是心力衰竭相关肌肉质量和功能丧失的机制。此外，我们的发现进一步证实，SMase 激活可能是与疾病相关的肌肉质量和功能丧失的机制，是与全身性炎症反应相关的疾病中常报道的肌病的共同病理生理机制。
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