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

Abstract

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.

Epigenetic mechanisms in Tendon Ageing

“… 39 , 40 SIRT1 is also a validated target of the miR-181 family, which has extensive regulatory functions in apoptosis and mitochondrial function, through targeting B-cell lymphoma 2 apoptosis regulator (Bcl-2) family proteins, 41 , 42 ubiquitin-binding protein p62 and Parkin. 43 miR-181 also regulates inflammation through interaction with the nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB), tumor necrosis factor (TNF) and toll-like receptor 4 (TLR-4) pathways. 44 , 45 Down regulation of miR-29 has been associated with fibrosis in multiple organs, regulating collagen production both directly 46 and indirectly, via the TGF-β signaling pathway 56 .…”

Inflamma-miR-21 Negatively Regulates Myogenesis during Ageing

“…Changes in muscle and satellite cells at the mRNA and protein levels during ageing have been demonstrated in both humans and rodents [15,25,27]. Moreover, changes in the levels of miRs, post-transcriptional gene expression regulators, have also been demonstrated in muscle during ageing and disease [15,16,[24][25][26][27]. microRNAs are predicted to regulate 2/3 of the human genome and are likely important regulators of ageing-related decline in muscle regeneration [15].…”

“…Protein lysis and Western blots were done as described [24]. Primer sequences are listed in Table 1.…”

“…miR binding to its target(s) results in degradation of the mRNA and/or translational block resulting in a decrease in protein levels. Muscle-specific miRs, also referred to as "myomiRs", are important regulators of skeletal muscle function [18][19][20][21][22][23][24]. Changes in microRNA expression in muscle have been demonstrated during ageing and disease [12,[24][25][26][27][28][29].…”

“…Muscle-specific miRs, also referred to as "myomiRs", are important regulators of skeletal muscle function [18][19][20][21][22][23][24]. Changes in microRNA expression in muscle have been demonstrated during ageing and disease [12,[24][25][26][27][28][29]. Satellite cell-specific knock-out of Dicer, an enzyme responsible for generation of the majority of mature miRs, in a mouse model resulted in mild myofiber atrophy [30].miR-21 has been proposed a circulating marker of inflammation during ageing: inflamma-miR [31-34] and is also classified as an oncomiR due to its role in cancer progression [35].…”