Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.