Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.
Department for Cardiovascular Physiology, European Center of Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Nat Commun. 2022 Jan 10;13(1):149. doi: 10.1038/s41467-021-27634-5.
Cachexia is associated with poor prognosis in chronic heart failure patients, but the underlying mechanisms of cachexia triggered disease progression remain poorly understood. Here, we investigate whether the dysregulation of myokine expression from wasting skeletal muscle exaggerates heart failure. RNA sequencing from wasting skeletal muscles of mice with heart failure reveals a reduced expression of Ostn, which encodes the secreted myokine Musclin, previously implicated in the enhancement of natriuretic peptide signaling. By generating skeletal muscle specific Ostn knock-out and overexpressing mice, we demonstrate that reduced skeletal muscle Musclin levels exaggerate, while its overexpression in muscle attenuates cardiac dysfunction and myocardial fibrosis during pressure overload. Mechanistically, Musclin enhances the abundance of C-type natriuretic peptide (CNP), thereby promoting cardiomyocyte contractility through protein kinase A and inhibiting fibroblast activation through protein kinase G signaling. Because we also find reduced OSTN expression in skeletal muscle of heart failure patients, augmentation of Musclin might serve as therapeutic strategy.
恶病质与慢性心力衰竭患者的预后不良相关，但导致恶病质的潜在机制仍知之甚少。在这里，我们研究了消耗性骨骼肌中肌肽表达的失调是否会加剧心力衰竭。心力衰竭小鼠消耗性骨骼肌的 RNA 测序显示，编码分泌性肌肽 Musclin 的 Ostn 表达减少，Musclin 先前被认为能增强利钠肽信号。通过生成骨骼肌特异性 Ostn 敲除和过表达小鼠，我们证明了骨骼肌 Musclin 水平降低会加剧，而肌肉中 Musclin 的过表达则会在压力超负荷期间减轻心脏功能障碍和心肌纤维化。在机制上，Musclin 增加 C 型利钠肽 (CNP) 的丰度，从而通过蛋白激酶 A 促进心肌细胞收缩，并通过蛋白激酶 G 信号抑制成纤维细胞激活。因为我们还发现心力衰竭患者骨骼肌中的 OSTN 表达减少，因此增加 Musclin 可能是一种治疗策略。
