Abstract
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.
Highlights
Sarcopenia is a pathophysiological malfunction induced by skeletal muscle atrophy
Of note, comparing the fiber crosssectional area (CSA) present per a unit area in the two groups revealed an evident reduction in tail suspension (TS) (+) mice compared to TS (−) mice [TS (−) vs. TS (+); 1421.1 ± 81.4 vs. 1193.4 ± 63 0.7 μm[2], respectively; p = 0.030; Fig. 1e, f]
We established a cardio-repair disturbance model mimicking cardiac cachexia based on limb unloading-induced sarcopenia after myocardial ischemia/reperfusion
Summary
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. HF in MI patients, often prevents their early mobilization from bed rest This leads, in turn, to sarcopenia defined as the atrophy of skeletal muscles and the rapid loss of muscle mass and s trength[3]. Reported the harmful pathophysiological effect of sarcopenia in patients with cardiac disease accompanied by skeletal muscle loss, the fundamental mechanism behind cardiac cachexia is still unclear. This is probably due to the fact that preclinical models used to study such mechanism could not adequately mimic cardiac cachexia[16,17,18,19,20]. Our model is closely mimicking the pathophysiological processes in post-MI patients, to clarify the mode-of-action of miR-16-5p in sarcopenia may facilitate the development of new postMI therapeutic strategies, something that is very much needed in an aging society
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