Saw Eng Leng, Werner Louis Dominic, Cooper Hannah L, Pimental David R, Zamani Payman, Chirinos Julio A, Valero-Muñoz María, Sam Flora
Department of Medicine, Whitaker Cardiovascular Institute, Boston University Chobanian & Avedisian School of Medicine, MA (E.L.S., L.D.W., H.L.C., D.R.P., M.V.-M., F.S.).
Division of Cardiovascular Medicine, Penn Cardiovascular Institute, Hospital of the University of Pennsylvania, Philadelphia (P.Z., J.A.C.).
Circ Heart Fail. 2025 Jun;18(6):e012350. doi: 10.1161/CIRCHEARTFAILURE.124.012350. Epub 2025 May 13.
Exercise intolerance is a hallmark of heart failure with preserved ejection fraction (HFpEF) and is characterized by skeletal muscle (SkM) dysfunction with impaired oxidative capacity. To maintain oxidative capacity, the SkM secretes myokines such as musclin, which has been shown to potentiate NP (natriuretic peptide) signaling and induce PGC-1α (peroxisome proliferator-activated receptor-γ coactivator-1 alpha) signaling. We sought to investigate the role of musclin in SkM dysfunction in HFpEF. For this study, we selected the oxidative-predominant SkM soleus in HFpEF mice and vastus lateralis from patients with HFpEF.
Using the SAUNA model, mice underwent HFpEF induction by uninephrectomy, d-aldosterone infusion, and 1% sodium chloride drinking water for 4 weeks. Exogenous musclin was given to HFpEF mice every 2 days during the last 2 weeks of HFpEF induction. Molecular analyses were conducted on blood samples and SkM from HFpEF mice and patients with HFpEF.
In HFpEF mice and patients with HFpEF, increased musclin expression was accompanied by decreased cyclic guanosine monophosphate levels and PGC-1α expression in SkM, suggesting impaired NP signaling. Exogenous administration of musclin in mice with HFpEF demonstrated augmented circulating musclin levels and potentiated NP signaling in SkM as shown by increased PKG1 (protein kinase G1) activity and PGC-1α expression. This was associated with a transition from type-2A to type-1 fiber (type-1 has more endurance) and increased succinate dehydrogenase activity, hindlimb blood flow, and capillary density in the soleus muscle. Exogenous musclin also mitigated cardiac hypertrophy without affecting blood pressure or diastolic function. Most importantly, HFpEF mice treated with musclin demonstrated improved functional and exercise capacity.
Musclin mediates beneficial effects in SkM and heart with improved exercise capacity likely by improving oxidative capacity in SkM. Future studies are warranted to address the therapeutic efficacy of exogenous musclin in humans with HFpEF.
运动不耐受是射血分数保留的心力衰竭（HFpEF）的一个标志，其特征是骨骼肌（SkM）功能障碍且氧化能力受损。为维持氧化能力，SkM会分泌如肌肉素等肌动蛋白，研究表明其可增强利钠肽（NP）信号传导并诱导过氧化物酶体增殖物激活受体γ共激活因子1α（PGC-1α）信号传导。我们试图研究肌肉素在HFpEF患者SkM功能障碍中的作用。在本研究中，我们选取了HFpEF小鼠中以氧化为主的SkM比目鱼肌以及HFpEF患者的股外侧肌。
采用SAUNA模型，通过单侧肾切除、输注d-醛固酮以及给予1%氯化钠饮用水4周来诱导小鼠发生HFpEF。在HFpEF诱导的最后2周期间，每2天给HFpEF小鼠注射一次外源性肌肉素。对HFpEF小鼠和HFpEF患者的血液样本及SkM进行分子分析。
在HFpEF小鼠和HFpEF患者中，肌肉素表达增加伴随着SkM中环磷酸鸟苷水平降低以及PGC-1α表达减少，提示NP信号传导受损。在HFpEF小鼠中给予外源性肌肉素，结果显示循环肌肉素水平升高，SkM中的NP信号传导增强，表现为蛋白激酶G1（PKG1）活性增加和PGC-1α表达增加。这与从2A型纤维向1型纤维转变（1型纤维耐力更强）以及比目鱼肌中琥珀酸脱氢酶活性增加、后肢血流量增加和毛细血管密度增加有关。外源性肌肉素还可减轻心脏肥大，而不影响血压或舒张功能。最重要的是，接受肌肉素治疗的HFpEF小鼠的功能和运动能力得到改善。
肌肉素可能通过改善SkM的氧化能力，对SkM和心脏产生有益影响，从而提高运动能力。未来有必要开展研究以探讨外源性肌肉素对HFpEF患者的治疗效果。
