Research Unit of Biomedicine and Internal Medicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland.
Heart Institute, Medical School, and Szentágothai Research Centre, University of Pécs, Pécs, Hungary.
Am J Physiol Cell Physiol. 2024 May 1;326(5):C1437-C1450. doi: 10.1152/ajpcell.00427.2023. Epub 2024 Mar 25.
Plasma apelin levels are reduced in aging and muscle wasting conditions. We aimed to investigate the significance of apelin signaling in cardiac and skeletal muscle responses to physiological stress. Apelin knockout (KO) and wild-type (WT) mice were subjected to high-intensity interval training (HIIT) by treadmill running. The effects of apelin on energy metabolism were studied in primary mouse skeletal muscle myotubes and cardiomyocytes. Apelin increased mitochondrial ATP production and mitochondrial coupling efficiency in myotubes and promoted the expression of mitochondrial genes both in primary myotubes and cardiomyocytes. HIIT induced mild concentric cardiac hypertrophy in WT mice, whereas eccentric growth was observed in the left ventricles of apelin KO mice. HIIT did not affect myofiber size in skeletal muscles of WT mice but decreased the myofiber size in apelin KO mice. The decrease in myofiber size resulted from a fiber type switch toward smaller slow-twitch type I fibers. The increased proportion of slow-twitch type I fibers in apelin KO mice was associated with upregulation of myosin heavy chain slow isoform expression, accompanied with upregulated expression of genes related to fatty acid transport and downregulated expression of genes related to glucose metabolism. Mechanistically, skeletal muscles of apelin KO mice showed defective induction of insulin-like growth factor-1 signaling in response to HIIT. In conclusion, apelin is required for proper skeletal and cardiac muscle adaptation to high-intensity exercise. Promoting apelinergic signaling may have benefits in aging- or disease-related muscle wasting conditions. Apelin levels decline with age. This study demonstrates that in trained mice, apelin deficiency results in a switch from fast type II myofibers to slow oxidative type I myofibers. This is associated with a concomitant change in gene expression profile toward fatty acid utilization, indicating an aged-muscle phenotype in exercised apelin-deficient mice. These data are of importance in the design of exercise programs for aging individuals and could offer therapeutic target to maintain muscle mass.
血浆apelin 水平在衰老和肌肉减少症中降低。我们旨在研究 apelin 信号在心脏和骨骼肌对生理应激的反应中的意义。apelin 敲除（KO）和野生型（WT）小鼠通过跑步机跑步进行高强度间歇训练（HIIT）。在原代小鼠骨骼肌肌管和心肌细胞中研究了 apelin 对能量代谢的影响。apelin 增加了肌管中的线粒体 ATP 产生和线粒体偶联效率，并促进了原代肌管和心肌细胞中线粒体基因的表达。HIIT 诱导 WT 小鼠轻度向心性心脏肥大，而 apelin KO 小鼠的左心室则观察到离心性生长。HIIT 不影响 WT 小鼠骨骼肌中的肌纤维大小，但减少了 apelin KO 小鼠的肌纤维大小。肌纤维大小的减少是由于向较小的慢收缩型 I 型纤维的纤维类型转换所致。apelin KO 小鼠中慢收缩型 I 型纤维比例的增加与肌球蛋白重链慢同工型表达的上调有关，伴随着与脂肪酸转运相关的基因表达上调和与葡萄糖代谢相关的基因表达下调。从机制上讲，apelin KO 小鼠的骨骼肌在对 HIIT 的反应中显示出胰岛素样生长因子-1 信号转导的缺陷诱导。总之，apelin 是适当的骨骼肌和心肌适应高强度运动所必需的。促进 apelin 信号可能有益于与衰老或疾病相关的肌肉减少症。apelin 水平随年龄增长而下降。这项研究表明，在训练有素的小鼠中，apelin 缺乏导致从快型 II 型肌纤维向慢氧化型 I 型肌纤维的转换。这与向脂肪酸利用的基因表达谱的伴随变化相关，表明在运动的 apelin 缺乏小鼠中出现了衰老的肌肉表型。这些数据对于为老年人设计运动计划非常重要，并为维持肌肉质量提供了治疗靶标。
