Sarcopenia is a pathophysiological malfunction induced by skeletal muscle atrophy. Several studies reported an association between sarcopenia-induced cardiac cachexia and poor prognosis in heart disease. However, due to lack of an established animal models, the underlying mechanism of disturbed cardiac repair accompanied with sarcopenia remains poorly understood. Here, we developed a novel sarcopenia-induced cardiac repair disturbance mouse model induced by tail suspension (TS) after cardiac ischemia and reperfusion (I/R). Importantly, we identified a specific exosomal-microRNA marker, miR-16-5p, in the circulating exosomes of I/R-TS mice. Of note, sarcopenia after I/R disturbed cardiac repair and raised the level of circulating-exosomal-miR-16-5p secreting from both the atrophic limbs and heart of TS mice. Likewise, miR-16-5p mimic plasmid disturbed cardiac repair in I/R mice directly. Additionally, in neonatal rat ventricular myocytes (NRVMs) cultured in vitro under hypoxic conditions in the presence of a miR-16-5p mimic, we observed increased apoptosis through p53 and Caspase3 upregulation, and also clarified that autophagosomes were decreased in NRVMs via SESN1 transcript interference-mediated mTOR activation. In conclusion, we show the pro-apoptotic effect of sarcopenia-derived miR-16-5p, which may be behind the exacerbation of myocardial infarction. Therefore, miR-16-5p can be a novel therapeutic target in the context of cardiac repair disturbances in sarcopenia–cachexia.

肌肉减少症是由骨骼肌萎缩引起的病理生理功能障碍。几项研究报告了肌肉减少症引起的心脏恶病质与心脏病预后不良之间的关联。然而，由于缺乏已建立的动物模型，心脏修复紊乱伴随肌肉减少症的潜在机制仍然知之甚少。在这里，我们开发了一种新型肌肉减少症诱导的心脏修复障碍小鼠模型，由心脏缺血再灌注（I/R）后悬尾（TS）诱导。重要的是，我们在 I/R-TS 小鼠的循环外泌体中发现了一种特定的外泌体 microRNA 标记物 miR-16-5p。值得注意的是，缺血再灌注后的肌肉减少症扰乱了心脏修复，并提高了 TS 小鼠萎缩四肢和心脏分泌的循环外泌体 miR-16-5p 的水平。同样，miR-16-5p 模拟质粒直接干扰 I/R 小鼠的心脏修复。此外，在存在 miR-16-5p 模拟物的情况下，在缺氧条件下体外培养的新生大鼠心室肌细胞 (NRVM) 中，我们观察到 p53 和 Caspase3 上调导致细胞凋亡增加，并且还阐明了通过 SESN1 转录本在 NRVM 中自噬体减少干扰介导的 mTOR 激活。总之，我们证明了肌肉减少症衍生的 miR-16-5p 的促凋亡作用，这可能是心肌梗塞恶化的原因。因此，miR-16-5p 可以成为肌肉减少症-恶病质心脏修复障碍的新治疗靶点。