miR-181a regulates p62/SQSTM1, parkin, and protein DJ-1 promoting mitochondrial dynamics in skeletal muscle aging.,Aging Cell

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miR-181a regulates p62/SQSTM1, parkin, and protein DJ-1 promoting mitochondrial dynamics in skeletal muscle aging.
Aging Cell ( IF 8.0 ) Pub Date : 2020-04-15 , DOI: 10.1111/acel.13140
Katarzyna Goljanek-Whysall _{1,

2} , Ana Soriano-Arroquia ₂ , Rachel McCormick ₂ , Caroline Chinda ₂ , Brian McDonagh ₁

Affiliation

One of the key mechanisms underlying skeletal muscle functional deterioration during aging is disrupted mitochondrial dynamics. Regulation of mitochondrial dynamics is essential to maintain a healthy mitochondrial population and prevent the accumulation of damaged mitochondria; however, the regulatory mechanisms are poorly understood. We demonstrated loss of mitochondrial content and disrupted mitochondrial dynamics in muscle during aging concomitant with dysregulation of miR‐181a target interactions. Using functional approaches and mito‐QC assay, we have established that miR‐181a is an endogenous regulator of mitochondrial dynamics through concerted regulation of Park2, p62/SQSTM1, and DJ‐1 in vitro. Downregulation of miR‐181a with age was associated with an accumulation of autophagy‐related proteins and abnormal mitochondria. Restoring miR‐181a levels in old mice prevented accumulation of p62, DJ‐1, and PARK2, and improved mitochondrial quality and muscle function. These results provide physiological evidence for the potential of microRNA‐based interventions for age‐related muscle atrophy and of wider significance for diseases with disrupted mitochondrial dynamics.

中文翻译：

miR-181a调节p62 / SQSTM1，parkin和DJ-1蛋白，促进骨骼肌衰老中的线粒体动力学。

衰老过程中骨骼肌功能退化的关键机制之一是线粒体动力学的破坏。调节线粒体动力学对于维持健康的线粒体种群并防止受损的线粒体积累至关重要。但是，对监管机制了解甚少。我们证明了衰老过程中肌肉中线粒体含量的损失和线粒体动力学的破坏，同时伴随着miR-181a目标相互作用的失调。通过功能性方法和mito-QC分析，我们已经确定miR-181a是通过体外对Park2，p62 / SQSTM1和DJ-1的协同调节来控制线粒体动力学的内源性调节剂。随着年龄的增长，miR-181a的下调与自噬相关蛋白的积累和线粒体异常有关。恢复老龄小鼠的miR-181a水平可防止p62，DJ-1和PARK2积累，并改善线粒体质量和肌肉功能。这些结果提供了生理学证据，证明了基于microRNA的干预技术对与年龄相关的肌肉萎缩的潜力，对于线粒体动力学破坏的疾病具有更广泛的意义。

更新日期：2020-04-15

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