Unique Transcriptome Signature Distinguishes Patients With Heart Failure With Myopathy.
Unique Transcriptome Signature Distinguishes Patients With Heart Failure With Myopathy.
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DOI：
10.1161/jaha.120.017091
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发表时间：
2020-09-15
影响因子：
5.4
通讯作者：
Bowen TS
中科院分区：
文献类型：
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作者：
Caspi T;Straw S;Cheng C;Garnham JO;Scragg JL;Smith J;Koshy AO;Levelt E;Sukumar P;Gierula J;Beech DJ;Kearney MT;Cubbon RM;Wheatcroft SB;Witte KK;Roberts LD;Bowen TS
慢性心力衰竭（CHF）患者会出现严重的骨骼肌功能障碍，其特征是线粒体异常，这会加剧运动不耐受的主要症状。然而，CHF引起的线粒体异常的分子触发因素和特征仍然知之甚少。我们招募了28例射血分数降低引起的CHF患者和9例对照。我们同时从上肢胸大肌和下肢股外侧肌活检骨骼肌。我们对这两个位点的透化肌纤维中的线粒体功能进行了表型分析，随后进行了完整的RNA测序，以确定CHF骨骼肌中的新分子异常。CHF患者表现为上肢和下肢骨骼肌线粒体功能损伤，具有类似的缺陷，提示肌病。线粒体异常与症状密切相关。进一步的RNA测序揭示了CHF骨骼肌中独特的转录组特征，其特征在于与能量代谢缺陷相关的新型三联体差异表达基因，包括腺苷酸脱氨酶3、吡啶核苷酸二硫化物氧化还原酶结构域2和乳酸脱氢酶C。我们的数据表明，上下肢代谢性肌病的特点是一个独特的转录组签名在骨骼肌的人与CHF。
People with chronic heart failure (CHF) experience severe skeletal muscle dysfunction, characterized by mitochondrial abnormalities, which exacerbates the primary symptom of exercise intolerance. However, the molecular triggers and characteristics underlying mitochondrial abnormalities caused by CHF remain poorly understood. We recruited 28 patients with CHF caused by reduced ejection fraction and 9 controls. We simultaneously biopsied skeletal muscle from the pectoralis major in the upper limb and from the vastus lateralis in the lower limb. We phenotyped mitochondrial function in permeabilized myofibers from both sites and followed this by complete RNA sequencing to identify novel molecular abnormalities in CHF skeletal muscle. Patients with CHF presented with upper and lower limb skeletal muscle impairments to mitochondrial function that were of a similar deficit and indicative of a myopathy. Mitochondrial abnormalities were strongly correlated to symptoms. Further RNA sequencing revealed a unique transcriptome signature in CHF skeletal muscle characterized by a novel triad of differentially expressed genes related to deficits in energy metabolism including adenosine monophosphate deaminase 3, pyridine nucleotide‐disulphide oxidoreductase domain 2, and lactate dehydrogenase C. Our data suggest an upper and lower limb metabolic myopathy that is characterized by a unique transcriptome signature in skeletal muscle of humans with CHF.